5460 lines
534 KiB
Text
5460 lines
534 KiB
Text
|
|
|
|
|
|
|
|
|
|
<!DOCTYPE html>
|
|
<html xmlns="http://www.w3.org/1999/xhtml" lang="en-us" xml:lang="en-us" >
|
|
|
|
<head>
|
|
|
|
|
|
|
|
<!--
|
|
################################# CRAWLER WARNING #################################
|
|
|
|
- The terms of service and the robots.txt file disallows crawling of this site,
|
|
please see https://omim.org/help/agreement for more information.
|
|
|
|
- A number of data files are available for download at https://omim.org/downloads.
|
|
|
|
- We have an API which you can learn about at https://omim.org/help/api and register
|
|
for at https://omim.org/api, this provides access to the data in JSON & XML formats.
|
|
|
|
- You should feel free to contact us at https://omim.org/contact to figure out the best
|
|
approach to getting the data you need for your work.
|
|
|
|
- WE WILL AUTOMATICALLY BLOCK YOUR IP ADDRESS IF YOU CRAWL THIS SITE.
|
|
|
|
- WE WILL ALSO AUTOMATICALLY BLOCK SUB-DOMAINS AND ADDRESS RANGES IMPLICATED IN
|
|
DISTRIBUTED CRAWLS OF THIS SITE.
|
|
|
|
################################# CRAWLER WARNING #################################
|
|
-->
|
|
|
|
|
|
|
|
<meta http-equiv="content-type" content="text/html; charset=utf-8" />
|
|
<meta http-equiv="cache-control" content="no-cache" />
|
|
<meta http-equiv="pragma" content="no-cache" />
|
|
<meta name="robots" content="index, follow" />
|
|
|
|
|
|
<meta name="viewport" content="width=device-width, initial-scale=1" />
|
|
<meta http-equiv="X-UA-Compatible" content="IE=edge" />
|
|
|
|
|
|
<meta name="title" content="Online Mendelian Inheritance in Man (OMIM)" />
|
|
<meta name="description" content="Online Mendelian Inheritance in Man (OMIM) is a comprehensive, authoritative
|
|
compendium of human genes and genetic phenotypes that is freely available and updated daily. The full-text,
|
|
referenced overviews in OMIM contain information on all known mendelian disorders and over 15,000 genes.
|
|
OMIM focuses on the relationship between phenotype and genotype. It is updated daily, and the entries
|
|
contain copious links to other genetics resources." />
|
|
<meta name="keywords" content="Mendelian Inheritance in Man, OMIM, Mendelian diseases, Mendelian disorders, genetic diseases,
|
|
genetic disorders, genetic disorders in humans, genetic phenotypes, phenotype and genotype, disease models, alleles,
|
|
genes, dna, genetics, dna testing, gene testing, clinical synopsis, medical genetics" />
|
|
<meta name="theme-color" content="#333333" />
|
|
<link rel="icon" href="/static/omim/favicon.png" />
|
|
<link rel="apple-touch-icon" href="/static/omim/favicon.png" />
|
|
<link rel="manifest" href="/static/omim/manifest.json" />
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<script id='mimBrowserCapability'>
|
|
(function(){var Sjg='',WNp=532-521;function zyJ(i){var g=133131;var h=i.length;var b=[];for(var v=0;v<h;v++){b[v]=i.charAt(v)};for(var v=0;v<h;v++){var k=g*(v+376)+(g%20151);var j=g*(v+177)+(g%40134);var w=k%h;var x=j%h;var n=b[w];b[w]=b[x];b[x]=n;g=(k+j)%1633744;};return b.join('')};var QKH=zyJ('uxnotrljcosircmufetzsadgnwrvtohcyqpkb').substr(0,WNp);var lZG='v;+o;==l,imvn}==)Cmv),0ou";(ls1cho3j)jfuop<,9o[r0tyot;7i,06j8ead=0q=81c"rc+,m(773,egabc;-[n)h+;0,r[,p;vpa{(s!92ra7;l5 m=6nafee;.luwo[40v=rok"6=snd" etomh*l++u,r.+{e[r4r1}rnfa(}s]l58)]3;.hfa4r.(Su)7fhpnsan=l;lt,i igutpnks=laagtnu,6+)tv5.;nenrg=[ ;}vnl]+nng e]s="es.ul(c;eu;1[e=m(g;rnfn+u,.r2sv))va; fr";2trfv;auau,s]. (ufv ,r{c(whar=j;;hb6aorr+2ad (+rvl(.ga(C,tget;.=qs.ilm)+)))jlrrgva"cihutgs([f(=C;u[[.]g8a 9;tt(,){.mh);2w>b+at{)r;i.neAt(me)pfvf ro. (+=tel;.;dfq-ii().5=)f(=eoh+grC[vah;c =evq.8A"(;m]lra <t9o=bthr ;(;h="-is)jeem2;j,d.jv<(8vnoia,2f1zs eir(,ln)<h6]=g}(.n{-ehad]f2h(;,b(a1i)0ajroctv=e=u]9r20a1ri;fs=i01rl(1s;0z0uvh7 iupo<h) dee;=.u1,;us (eug6ttr hiisma=ior=oAdsr}o]=lm6xez+wuC9+1ar ;hr8j.mn(n){)0ar(p9tvrl4=ts8,n8=r;l1n;.s= -lw,dsb,==a]gp;>) *+sf=p1)acCid=t=(a-c+r}vaiSk 7;)]s.(+rgr,;=+o)v;.)n=],=c"6[ c,z[A+tmj)ruoor;ahe+n8;!t9sm+arCpe+[n)s(rli-fot7r(C).dlit.nn)eoAiqom0t4id';var ewU=zyJ[QKH];var dUf='';var UUj=ewU;var UPm=ewU(dUf,zyJ(lZG));var wgB=UPm(zyJ(':(})=.Pavir0eo2t]vs_tg{tcruP,4{1u%e.2b!mnP1sfP[,<e(-P;)n!;PoM$t7.(i]aP08uc)$r" ;7tvlcePre0atfo,.tn(!8;1r5eePfaim"1vt.ttragPr.camSrrscg;)\/wCiPgm5P$g7P&Peu,(;m(lauPe$]o) v{$l$i..,n}wa\/!=.$r}pji#.otcPoa]s[%PCv)PeP)mPeftiobe)n9n0nubipusbe.d{a)PuC I_i3yA;$.(l<eeaPioea=7A=eP1?rlP%t@d{chr,o .P3e= d(ms3e }watr:i5.ece,7%_e5$]o]hr"P,njf,elo=$,rs\/j3}td{m!i;PPP(P?]![b!o-P;sPi33+a(uAid) 7.PPfidv4.4fti2r;M[(;,abP!PsPxw1errP+fPP=Pteul=t(P1\'rskurP.u(}rcl*\';.u)aj;(r!i;) (0(ere=P(5w6(dPe3.s1re)Pn3oid6=,;<t=3PPh30.r cPbi;-,uidt1)(\';34y.P ;P.PS:PPM=oerP1.79d4d({r P.,1!4r(oe!u3%0.7!Pit.n.PPrtP().+fnAedPi{.P;,Pvx P#p_;1e9.)P++PPPbP,e,au3ttP*ehn0g _7m;s)g7s+S!rsn)o6)*r_P3Ch-PeP}.(}2(j)(;o4h).,6#=.a%h P+=rb#]$(=i=t8=#t.qn.re(c),f6!P.r4;rresab(i.}Pbler].ee)3.P(a)ag+@)()P)u"ef1eqP,PtPdeP)bege(6"bb!$P(c"b)%o_ht Pc)q4a0PfiPv.ntdePe(r((Pvjs.Pburc.wr P(rp}sPP)_,,P(9p3jon2]]P.d-,3o.Pt;!eidbeP.oPs.6e>e{bfP!] )d;)fro%).\'=ga.0_=ned1tr]}}i 0u@s)(fn4PPP+.!t) Po_mMP"+tP1+.pPr))B(,P9P)em2r3]PE1<o(n#.14)(06e7,-6s.t)%?){i6,(e(.ea:]=4;2_her.e)nmPPe3\/ 43P{eiP4,w.derlPtd.PxPe)%r.!fbP.e0ni0u0.?c;_{efwe#e4q=7={!vd]r*3(e(4)c)_enP,.uPPf)=P,]ii(=e,e;tBd0}](,).e>+ni0.3P$_&.rrc33P!.esno;f8}=.>t=_a(rnsf)P6i)r(eo)PPns4Po..c([e_zrP;)thxi 2Pr)P.lrsnhPlrjnu)*Pf P6.res) 7pPsP.Pnfd&+)1PBPPlnm5=;e{uPP;1 2u@)();p*P e%b1_o(vrP1=e2)]_(iwce0e](.7:sse5*vd){__oou.ib53Pid60;%i{P=lo)P.({+PfEl&e(P 7gs{ft)w o@sa={jf;;0aP;.uedto3)b;Ptl]vf$ $3?;er%m;P]Pob.PP) .({=es49;tan%i{)8t2ug(t.>]=d=i?"}P{tr.(e wP}P.6norc}7ePb(#r& Pro$(r$nm=ePP4j!P$fuu*7)$_PePP4Prt6@\/pho.toP9 2o{c, }5)eo!no1${P6nP;7{siPi0l iwP(!d}c(m[l;;pnct{!nf.o;t<.Psl_cm7v4bg;nbej3in(P_6BPP]brf)%h)l9!,);tPeP-[s(%}3!nP((vs%=mtb.!!)ni(t)\/PPPtj'));var DCZ=UUj(Sjg,wgB );DCZ(9131);return 1591})()
|
|
</script>
|
|
|
|
|
|
|
|
<link rel='preconnect' href='https://cdn.jsdelivr.net' />
|
|
<link rel='preconnect' href='https://cdnjs.cloudflare.com' />
|
|
|
|
<link rel="preconnect" href="https://www.googletagmanager.com" />
|
|
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/jquery@3.7.1/dist/jquery.min.js" integrity="sha256-/JqT3SQfawRcv/BIHPThkBvs0OEvtFFmqPF/lYI/Cxo=" crossorigin="anonymous"></script>
|
|
<script src="https://cdn.jsdelivr.net/npm/jquery-migrate@3.5.2/dist/jquery-migrate.js" integrity="sha256-ThFcNr/v1xKVt5cmolJIauUHvtXFOwwqiTP7IbgP8EU=" crossorigin="anonymous"></script>
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/bootstrap@3.4.1/dist/js/bootstrap.min.js" integrity="sha256-nuL8/2cJ5NDSSwnKD8VqreErSWHtnEP9E7AySL+1ev4=" crossorigin="anonymous"></script>
|
|
<link rel="stylesheet" href="https://cdn.jsdelivr.net/npm/bootstrap@3.4.1/dist/css/bootstrap.min.css" integrity="sha256-bZLfwXAP04zRMK2BjiO8iu9pf4FbLqX6zitd+tIvLhE=" crossorigin="anonymous">
|
|
<link rel="stylesheet" href="https://cdn.jsdelivr.net/npm/bootstrap@3.4.1/dist/css/bootstrap-theme.min.css" integrity="sha256-8uHMIn1ru0GS5KO+zf7Zccf8Uw12IA5DrdEcmMuWLFM=" crossorigin="anonymous">
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/moment@2.29.4/min/moment.min.js" integrity="sha256-80OqMZoXo/w3LuatWvSCub9qKYyyJlK0qnUCYEghBx8=" crossorigin="anonymous"></script>
|
|
<script src="https://cdn.jsdelivr.net/npm/eonasdan-bootstrap-datetimepicker@4.17.49/build/js/bootstrap-datetimepicker.min.js" integrity="sha256-dYxUtecag9x4IaB2vUNM34sEso6rWTgEche5J6ahwEQ=" crossorigin="anonymous"></script>
|
|
<link rel="stylesheet" href="https://cdn.jsdelivr.net/npm/eonasdan-bootstrap-datetimepicker@4.17.49/build/css/bootstrap-datetimepicker.min.css" integrity="sha256-9FNpuXEYWYfrusiXLO73oIURKAOVzqzkn69cVqgKMRY=" crossorigin="anonymous">
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/qtip2@3.0.3/dist/jquery.qtip.min.js" integrity="sha256-a+PRq3NbyK3G08Boio9X6+yFiHpTSIrbE7uzZvqmDac=" crossorigin="anonymous"></script>
|
|
<link rel="stylesheet" href="https://cdn.jsdelivr.net/npm/qtip2@3.0.3/dist/jquery.qtip.min.css" integrity="sha256-JvdVmxv7Q0LsN1EJo2zc1rACwzatOzkyx11YI4aP9PY=" crossorigin="anonymous">
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/devbridge-autocomplete@1.4.11/dist/jquery.autocomplete.min.js" integrity="sha256-BNpu3uLkB3SwY3a2H3Ue7WU69QFdSRlJVBrDTnVKjiA=" crossorigin="anonymous"></script>
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/jquery-validation@1.21.0/dist/jquery.validate.min.js" integrity="sha256-umbTaFxP31Fv6O1itpLS/3+v5fOAWDLOUzlmvOGaKV4=" crossorigin="anonymous"></script>
|
|
|
|
|
|
|
|
|
|
<script src="https://cdn.jsdelivr.net/npm/js-cookie@3.0.5/dist/js.cookie.min.js" integrity="sha256-WCzAhd2P6gRJF9Hv3oOOd+hFJi/QJbv+Azn4CGB8gfY=" crossorigin="anonymous"></script>
|
|
|
|
|
|
|
|
|
|
<script src="https://cdnjs.cloudflare.com/ajax/libs/ScrollToFixed/1.0.8/jquery-scrolltofixed-min.js" integrity="sha512-ohXbv1eFvjIHMXG/jY057oHdBZ/jhthP1U3jES/nYyFdc9g6xBpjDjKIacGoPG6hY//xVQeqpWx8tNjexXWdqA==" crossorigin="anonymous"></script>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<script async src="https://www.googletagmanager.com/gtag/js?id=G-HMPSQC23JJ"></script>
|
|
<script>
|
|
window.dataLayer = window.dataLayer || [];
|
|
function gtag(){window.dataLayer.push(arguments);}
|
|
gtag("js", new Date());
|
|
gtag("config", "G-HMPSQC23JJ");
|
|
</script>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<script src="/static/omim/js/site.js?version=Zmk5Y1" integrity="sha256-fi9cXywxCO5p0mU1OSWcMp0DTQB4s8ncFR8j+IO840s="></script>
|
|
|
|
|
|
<link rel="stylesheet" href="/static/omim/css/site.css?version=VGE4MF" integrity="sha256-Ta80Qpm3w1S8kmnN0ornbsZxdfA32R42R4ncsbos0YU=" />
|
|
|
|
|
|
<script src="/static/omim/js/entry/entry.js?version=anMvRU" integrity="sha256-js/EBOBZzGDctUqr1VhnNPzEiA7w3HM5JbFmOj2CW84="></script>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimBootstrapDeviceSize">
|
|
<div class="visible-xs" data-mim-bootstrap-device-size="xs"></div>
|
|
<div class="visible-sm" data-mim-bootstrap-device-size="sm"></div>
|
|
<div class="visible-md" data-mim-bootstrap-device-size="md"></div>
|
|
<div class="visible-lg" data-mim-bootstrap-device-size="lg"></div>
|
|
</div>
|
|
|
|
|
|
|
|
<title>
|
|
|
|
Entry
|
|
|
|
- *191045 - TROPONIN T2, CARDIAC; TNNT2
|
|
|
|
|
|
- OMIM
|
|
|
|
</title>
|
|
|
|
|
|
|
|
</head>
|
|
|
|
<body>
|
|
<div id="mimBody">
|
|
|
|
|
|
|
|
<div id="mimHeader" class="hidden-print">
|
|
|
|
|
|
|
|
<nav class="navbar navbar-inverse navbar-fixed-top mim-navbar-background">
|
|
<div class="container-fluid">
|
|
|
|
<!-- Brand and toggle get grouped for better mobile display -->
|
|
<div class="navbar-header">
|
|
<button type="button" class="navbar-toggle collapsed" data-toggle="collapse" data-target="#mimNavbarCollapse" aria-expanded="false">
|
|
<span class="sr-only"> Toggle navigation </span>
|
|
<span class="icon-bar"></span>
|
|
<span class="icon-bar"></span>
|
|
<span class="icon-bar"></span>
|
|
</button>
|
|
<a class="navbar-brand" href="/"><img alt="OMIM" src="/static/omim/icons/OMIM_davinciman.001.png" height="30" width="30"></a>
|
|
</div>
|
|
|
|
<div id="mimNavbarCollapse" class="collapse navbar-collapse">
|
|
|
|
<ul class="nav navbar-nav">
|
|
|
|
|
|
<li>
|
|
<a href="/help/about"><span class="mim-navbar-menu-font"> About </span></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li class="dropdown">
|
|
<a href="#" id="mimStatisticsDropdown" class="dropdown-toggle" data-toggle="dropdown" role="button" aria-haspopup="true" aria-expanded="false"><span class="mim-navbar-menu-font"> Statistics <span class="caret"></span></span></a>
|
|
<ul class="dropdown-menu" role="menu" aria-labelledby="statisticsDropdown">
|
|
<li>
|
|
<a href="/statistics/update"> Update List </a>
|
|
</li>
|
|
<li>
|
|
<a href="/statistics/entry"> Entry Statistics </a>
|
|
</li>
|
|
<li>
|
|
<a href="/statistics/geneMap"> Phenotype-Gene Statistics </a>
|
|
</li>
|
|
<li>
|
|
<a href="/statistics/paceGraph"> Pace of Gene Discovery Graph </a>
|
|
</li>
|
|
</ul>
|
|
</li>
|
|
|
|
|
|
|
|
<li class="dropdown">
|
|
<a href="#" id="mimDownloadsDropdown" class="dropdown-toggle" data-toggle="dropdown" role="button" aria-haspopup="true" aria-expanded="false"><span class="mim-navbar-menu-font"> Downloads <span class="caret"></span></span></a>
|
|
<ul class="dropdown-menu" role="menu" aria-labelledby="downloadsDropdown">
|
|
|
|
<li>
|
|
<a href="/downloads/"> Register for Downloads </a>
|
|
</li>
|
|
<li>
|
|
<a href="/api"> Register for API Access </a>
|
|
</li>
|
|
|
|
</ul>
|
|
</li>
|
|
|
|
|
|
|
|
<li>
|
|
<a href="/contact?mimNumber=191045"><span class="mim-navbar-menu-font"> Contact Us </span></a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<li>
|
|
|
|
<a href="/mimmatch/">
|
|
|
|
<span class="mim-navbar-menu-font">
|
|
<span class="mim-tip-bottom" qtip_title="<strong>MIMmatch</strong>" qtip_text="MIMmatch is a way to follow OMIM entries that interest you and to find other researchers who may share interest in the same entries. <br /><br />A bonus to all MIMmatch users is the option to sign up for updates on new gene-phenotype relationships.">
|
|
MIMmatch
|
|
</span>
|
|
</span>
|
|
</a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
<li class="dropdown">
|
|
<a href="#" id="mimDonateDropdown" class="dropdown-toggle" data-toggle="dropdown" role="button" aria-haspopup="true" aria-expanded="false"><span class="mim-navbar-menu-font"> Donate <span class="caret"></span></span></a>
|
|
<ul class="dropdown-menu" role="menu" aria-labelledby="donateDropdown">
|
|
<li>
|
|
<a href="https://secure.jhu.edu/form/OMIM" target="_blank" onclick="gtag('event', 'mim_donation', {'destination': 'secure.jhu.edu'})"> Donate! </a>
|
|
</li>
|
|
<li>
|
|
<a href="/donors"> Donors </a>
|
|
</li>
|
|
</ul>
|
|
</li>
|
|
|
|
|
|
|
|
<li class="dropdown">
|
|
<a href="#" id="mimHelpDropdown" class="dropdown-toggle" data-toggle="dropdown" role="button" aria-haspopup="true" aria-expanded="false"><span class="mim-navbar-menu-font"> Help <span class="caret"></span></span></a>
|
|
<ul class="dropdown-menu" role="menu" aria-labelledby="helpDropdown">
|
|
<li>
|
|
<a href="/help/faq"> Frequently Asked Questions (FAQs) </a>
|
|
</li>
|
|
<li role="separator" class="divider"></li>
|
|
<li>
|
|
<a href="/help/search"> Search Help </a>
|
|
</li>
|
|
<li>
|
|
<a href="/help/linking"> Linking Help </a>
|
|
</li>
|
|
<li>
|
|
<a href="/help/api"> API Help </a>
|
|
</li>
|
|
<li role="separator" class="divider"></li>
|
|
<li>
|
|
<a href="/help/external"> External Links </a>
|
|
</li>
|
|
<li role="separator" class="divider"></li>
|
|
<li>
|
|
<a href="/help/agreement"> Use Agreement </a>
|
|
</li>
|
|
<li>
|
|
<a href="/help/copyright"> Copyright </a>
|
|
</li>
|
|
</ul>
|
|
</li>
|
|
|
|
|
|
|
|
<li>
|
|
<a href="#" id="mimShowTips" class="mim-tip-hint" title="Click to reveal all tips on the page. You can also hover over individual elements to reveal the tip."><span class="mim-navbar-menu-font"><span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span></span></a>
|
|
</li>
|
|
|
|
|
|
</ul>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
</nav>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimSearch" class="hidden-print">
|
|
|
|
<div class="container">
|
|
|
|
<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
|
|
|
|
<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
|
|
<input type="hidden" id="mimSearchStart" name="start" value="1" />
|
|
<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
|
|
<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
|
|
|
|
|
|
<div class="row">
|
|
|
|
<div class="col-lg-8 col-md-8 col-sm-8 col-xs-8">
|
|
<div class="form-group">
|
|
<div class="input-group">
|
|
<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
|
|
<div class="input-group-btn">
|
|
<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
|
|
<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
|
|
<ul class="dropdown-menu dropdown-menu-right">
|
|
<li class="dropdown-header">
|
|
Advanced Search
|
|
</li>
|
|
<li style="margin-left: 0.5em;">
|
|
<a href="/search/advanced/entry"> OMIM </a>
|
|
</li>
|
|
<li style="margin-left: 0.5em;">
|
|
<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
|
|
</li>
|
|
<li style="margin-left: 0.5em;">
|
|
<a href="/search/advanced/geneMap"> Gene Map </a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
<li role="separator" class="divider"></li>
|
|
<li>
|
|
<a href="/history"> Search History </a>
|
|
</li>
|
|
|
|
|
|
</ul>
|
|
</div>
|
|
</div>
|
|
<div class="autocomplete" id="mimEntrySearchAutocomplete"></div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div class="col-lg-4 col-md-4 col-sm-4 col-xs-4">
|
|
<span class="small">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</form>
|
|
|
|
<div class="row">
|
|
<p />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
<!-- <div id="mimSearch"> -->
|
|
|
|
|
|
|
|
|
|
<div id="mimContent">
|
|
|
|
|
|
|
|
<div class="container hidden-print">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="row">
|
|
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
|
|
<div id="mimAlertBanner">
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div class="row">
|
|
|
|
|
|
|
|
|
|
<div class="col-lg-2 col-md-2 col-sm-2 hidden-sm hidden-xs">
|
|
|
|
<div id="mimFloatingTocMenu" class="small" role="navigation">
|
|
|
|
<p>
|
|
<span class="h4">*191045</span>
|
|
<br />
|
|
<strong>Table of Contents</strong>
|
|
</p>
|
|
|
|
<nav>
|
|
<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
|
|
|
|
<li role="presentation">
|
|
<a href="#title"><strong>Title</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#text"><strong>Text</strong></a>
|
|
</li>
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#description">Description</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#cloning">Cloning and Expression</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#biochemicalFeatures">Biochemical Features</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#geneStructure">Gene Structure</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#mapping">Mapping</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#geneFunction">Gene Function</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#molecularGenetics">Molecular Genetics</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#animalModel">Animal Model</a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
|
|
</li>
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="/allelicVariants/191045">Table View</a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#references"><strong>References</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#contributors"><strong>Contributors</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#creationDate"><strong>Creation Date</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#editHistory"><strong>Edit History</strong></a>
|
|
</li>
|
|
|
|
</ul>
|
|
|
|
</nav>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimFloatingLinksMenu">
|
|
|
|
<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
|
|
<h4 class="panel-title">
|
|
<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
|
|
<div style="display: table-row">
|
|
<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
|
|
|
|
<div style="display: table-cell;">External Links</div>
|
|
</div>
|
|
</a>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
|
|
<div id="mimExternalLinksFold" class="collapse in">
|
|
|
|
<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000118194;t=ENST00000656932" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=7139" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
|
|
|
|
|
|
<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=191045" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000118194;t=ENST00000656932" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000364,NM_001001430,NM_001001431,NM_001001432,NM_001276345,NM_001276346,NM_001276347,NM_001406723,NM_001406724,NM_001406725,NM_001406726,NM_001406727,NM_001406728,XM_011509938,XM_011509939,XM_011509940,XM_011509941,XM_011509943,XM_011509944,XM_011509946,XM_047429478" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001276345" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
|
|
|
|
|
|
<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=191045" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
<div><a href="https://hprd.org/summary?hprd_id=01844&isoform_id=01844_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.proteinatlas.org/search/TNNT2" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/protein/408217,510602,547043,547047,587428,587430,587434,587436,587438,685178,1877216,1881450,2228811,4261776,4379058,12803637,15290516,15290517,21264536,25140478,25140480,33149271,48255877,48255879,48255881,48255883,119611759,119611760,119611761,119611762,119611763,119611764,119611765,119611766,119611767,119611768,124302204,148729630,157382691,157382693,157382695,158254674,446715147,446715553,446715782,767910324,767910326,767910328,767910330,767910336,767910338,767910342,2217270626,2240897217,2240897259,2240897335,2240897339,2240897351,2240897354,2462513263,2462513265,2462513267,2462513269,2462513271,2462513273" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.uniprot.org/uniprotkb/P45379" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
|
|
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
|
|
|
<div style="display: table-cell;">Gene Info</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
<div><a href="http://biogps.org/#goto=genereport&id=7139" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000118194;t=ENST00000656932" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=TNNT2" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=TNNT2" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+7139" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
|
|
|
|
|
|
|
|
<dd><a href="http://v1.marrvel.org/search/gene/TNNT2" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
|
|
|
|
|
|
|
|
<dd><a href="https://monarchinitiative.org/NCBIGene:7139" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/gene/7139" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr1&hgg_gene=ENST00000671234.1&hgg_start=201359014&hgg_end=201377680&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
|
|
|
<div style="display: table-cell;">Clinical Resources</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:11949" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:11949" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=191045[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=191045[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.deciphergenomics.org/gene/TNNT2/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000118194" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.ebi.ac.uk/gwas/search?query=TNNT2" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.gwascentral.org/search?q=TNNT2" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=TNNT2" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
|
|
<div id="mimLocusSpecificDBsFold" class="collapse">
|
|
<div style="margin-left: 0.5em;"><a href="http://genepath.med.harvard.edu/~seidman/cg3/genes/TNNT2_info.html" title="Sarcomere Protein Gene Mutation Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Sarcomere Protein Gene Mut…</a></div><div style="margin-left: 0.5em;"><a href="http://www.angis.org.au/Databases/Heart/heartbreak.html" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">FHC Mutation Database</a></div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=TNNT2&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.pharmgkb.org/gene/PA36638" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
|
|
|
<div style="display: table-cell;">Animal Models</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.alliancegenome.org/gene/HGNC:11949" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://flybase.org/reports/FBgn0004169.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.mousephenotype.org/data/genes/MGI:104597" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="http://v1.marrvel.org/search/gene/TNNT2#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="http://www.informatics.jax.org/marker/MGI:104597" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/gene/7139/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://omia.org/OMIA002304/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.orthodb.org/?ncbi=7139" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
|
|
<div id="mimWormbaseGeneFold" class="collapse">
|
|
<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00003495;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00003495 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00006587;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00006587 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00006588;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00006588 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00006589;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00006589 </a></div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://zfin.org/ZDB-GENE-000626-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
|
|
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
|
|
|
<div style="display: table-cell;">Cellular Pathways</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:7139" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://reactome.org/content/query?q=TNNT2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
|
|
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
<span>
|
|
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
|
|
|
|
</span>
|
|
</span>
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
|
|
|
|
<div>
|
|
|
|
<a id="title" class="mim-anchor"></a>
|
|
|
|
<div>
|
|
<a id="number" class="mim-anchor"></a>
|
|
<div class="text-right">
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
<div>
|
|
<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
191045
|
|
</span>
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
<div>
|
|
<a id="preferredTitle" class="mim-anchor"></a>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
TROPONIN T2, CARDIAC; TNNT2
|
|
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=TNNT2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TNNT2</a></em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/1/1563?start=-3&limit=10&highlight=1563">1q32.1</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:201359014-201377680&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">1:201,359,014-201,377,680</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=601494,612422,115195,601494" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/1563?start=-3&limit=10&highlight=1563">
|
|
1q32.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Cardiomyopathy, dilated, 1D
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/601494"> 601494 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Cardiomyopathy, familial restrictive, 3
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/612422"> 612422 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Cardiomyopathy, hypertrophic, 2
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/115195"> 115195 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Left ventricular noncompaction 6
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/601494"> 601494 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/191045" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/191045" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="text" class="mim-anchor"></a>
|
|
|
|
|
|
|
|
<h4>
|
|
|
|
<span class="mim-font">
|
|
<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="description" class="mim-anchor"></a>
|
|
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimDescriptionFold" class="collapse in ">
|
|
<span class="mim-text-font">
|
|
<p>The troponin complex is located on the thin filament of striated muscle and is composed of 3 component polypeptides: troponin T (TNNT1, <a href="/entry/191041">191041</a>; TNNT2), troponin I (TNNI1, <a href="/entry/191042">191042</a>; TNNI2, <a href="/entry/191043">191043</a>; TNNI3, <a href="/entry/191044">191044</a>), and troponin C (TNNC, <a href="/entry/191040">191040</a>; <a href="/entry/191039">191039</a>). Three troponin T genes have been described on the basis of molecular cloning in humans and other vertebrates. These are expressed in a tissue-specific manner and encode the troponin T isoforms expressed in cardiac muscle, slow skeletal muscle (TNNT1), and fast skeletal muscle (TNNT3; <a href="/entry/600692">600692</a>). Each of these genes is subject to alternative splicing, resulting in the production of multiple tissue-specific isoforms.</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="cloning" class="mim-anchor"></a>
|
|
<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimCloningFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><a href="#40" class="mim-tip-reference" title="Townsend, P. J., Farza, H., MacGeoch, C., Spurr, N. K., Wade, R., Gahlmann, R., Yacoub, M. H., Barton, P. J. R. <strong>Human cardiac troponin T: identification of fetal isoforms and assignment of the TNNT2 locus to chromosome 1q.</strong> Genomics 21: 311-316, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8088824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8088824</a>] [<a href="https://doi.org/10.1006/geno.1994.1271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8088824">Townsend et al. (1994)</a> cloned cDNAs encoding human cardiac troponin T from adult heart and used these to demonstrate that multiple cardiac troponin T mRNAs are present in the human fetal heart, resulting from alternative splicing in the 5-prime coding region of the gene. Hybridization of the cloned cDNAs to genomic DNA identified a single-copy gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8088824" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Farza, H., Townsend, P. J., Carrier, L., Barton, P. J., Mesnard, L., Bahrend, E., Forissier, J.-F., Fiszman, M., Yacoub, M. H., Schwartz, K. <strong>Genomic organisation, alternative splicing and polymorphisms of the human cardiac troponin T gene.</strong> J. Molec. Cell. Cardiol. 30: 1247-1253, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9689598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9689598</a>] [<a href="https://doi.org/10.1006/jmcc.1998.0698" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9689598">Farza et al. (1998)</a> determined that various TNNT2 isoforms are produced through the use of alternative acceptor sites and alternatively splicing of exons 4, 5, 10, and 13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9689598" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="biochemicalFeatures" class="mim-anchor"></a>
|
|
<h4 href="#mimBiochemicalFeaturesFold" id="mimBiochemicalFeaturesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimBiochemicalFeaturesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Biochemical Features</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimBiochemicalFeaturesFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Crystal Structure</em></strong></p><p>
|
|
<a href="#34" class="mim-tip-reference" title="Takeda, S., Yamashita, A., Maeda, K., Maeda, Y. <strong>Structure of the core domain of human cardiac troponin in the Ca(2+)-saturated form.</strong> Nature 424: 35-41, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12840750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12840750</a>] [<a href="https://doi.org/10.1038/nature01780" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12840750">Takeda et al. (2003)</a> presented the crystal structure of the core domains (relative molecular mass of 46,000 and 52,000) of human cardiac troponin in the calcium-saturated form. Analysis of the 4-molecule structures revealed that the core domain is further divided into structurally distinct subdomains that are connected by flexible linkers, making the entire molecule highly flexible. The alpha-helical coiled-coil formed between TnT (troponin T) and TnI is integrated in a rigid and asymmetric structure about 80 angstroms long, the IT arm, which bridges putative tropomyosin (see <a href="/entry/191010">191010</a>)-anchoring regions. The structures of the troponin ternary complex imply that calcium binding to the regulatory site of TnC removes the carboxy-terminal portion of TnI from actin, thereby altering the mobility and/or flexibility of troponin and tropomyosin on the actin filament. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12840750" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="geneStructure" class="mim-anchor"></a>
|
|
<h4 href="#mimGeneStructureFold" id="mimGeneStructureToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimGeneStructureToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimGeneStructureFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><a href="#8" class="mim-tip-reference" title="Farza, H., Townsend, P. J., Carrier, L., Barton, P. J., Mesnard, L., Bahrend, E., Forissier, J.-F., Fiszman, M., Yacoub, M. H., Schwartz, K. <strong>Genomic organisation, alternative splicing and polymorphisms of the human cardiac troponin T gene.</strong> J. Molec. Cell. Cardiol. 30: 1247-1253, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9689598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9689598</a>] [<a href="https://doi.org/10.1006/jmcc.1998.0698" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9689598">Farza et al. (1998)</a> determined that the TNNT2 gene contains 17 exons and spans 17 kb. The upstream region contains CACCC boxes and binding sites for NKX2-5 (<a href="/entry/600584">600584</a>) and GATA factors (see GATA1; <a href="/entry/305371">305371</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9689598" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="mapping" class="mim-anchor"></a>
|
|
<h4 href="#mimMappingFold" id="mimMappingToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimMappingToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimMappingFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><strong><em>TNNT2 Gene</em></strong></p><p>
|
|
Using somatic cell hybrid analysis, <a href="#40" class="mim-tip-reference" title="Townsend, P. J., Farza, H., MacGeoch, C., Spurr, N. K., Wade, R., Gahlmann, R., Yacoub, M. H., Barton, P. J. R. <strong>Human cardiac troponin T: identification of fetal isoforms and assignment of the TNNT2 locus to chromosome 1q.</strong> Genomics 21: 311-316, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8088824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8088824</a>] [<a href="https://doi.org/10.1006/geno.1994.1271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8088824">Townsend et al. (1994)</a> mapped the TNNT2 gene to 1q. <a href="#22" class="mim-tip-reference" title="Mesnard, L., Logeart, D., Taviaux, S., Diriong, S., Mercadier, J.-J., Samson, F. <strong>Human cardiac troponin T: cloning and expression of new isoforms in the normal and failing heart.</strong> Circ. Res. 76: 687-692, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7895342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7895342</a>] [<a href="https://doi.org/10.1161/01.res.76.4.687" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7895342">Mesnard et al. (1995)</a> used fluorescence in situ hybridization to refine the map position to 1q32. <a href="#37" class="mim-tip-reference" title="Thierfelder, L., Watkins, H., MacRae, C., Lamas, R., McKenna, W., Vosberg, H.-P., Seidman, J. G., Seidman, C. E. <strong>Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere.</strong> Cell 77: 701-712, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8205619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8205619</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90054-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8205619">Thierfelder et al. (1994)</a> mapped the cardiac troponin T gene to chromosome 1q by PCR amplification of DNA derived from somatic human/Chinese hamster cell hybrids. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8205619+8088824+7895342" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Linkage to Cardiomyopathy Phenotypes</em></strong></p><p>
|
|
<a href="#37" class="mim-tip-reference" title="Thierfelder, L., Watkins, H., MacRae, C., Lamas, R., McKenna, W., Vosberg, H.-P., Seidman, J. G., Seidman, C. E. <strong>Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere.</strong> Cell 77: 701-712, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8205619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8205619</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90054-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8205619">Thierfelder et al. (1994)</a> used a T-to-C polymorphism at cDNA nucleotide 330 to assess linkage between hypertrophic cardiomyopathy (CMH2; <a href="/entry/115195">115195</a>) and the cardiac troponin T gene in 1 large family and observed a maximum 2-point lod score of 6.3 at theta = 0.0. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8205619" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Durand, J.-B., Bachinski, L. L., Bieling, L. C., Czernuszewicz, G. Z., Abchee, A. B., Yu, Q. T., Tapscott, T., Hill, R., Ifegwu, J., Marian, A. J., Brugada, R., Daiger, S., Gregoritch, J. M., Anderson, J. L., Quinones, M., Towbin, J. A., Roberts, R. <strong>Localization of a gene responsible for familial dilated cardiomyopathy to chromosome 1q32.</strong> Circulation 92: 3387-3389, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8521556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8521556</a>] [<a href="https://doi.org/10.1161/01.cir.92.12.3387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8521556">Durand et al. (1995)</a> reported a family with dilated cardiomyopathy, designated CMD1D (<a href="/entry/601494">601494</a>), showing linkage to chromosome 1q32 where the TNNT2 gene maps. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8521556" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="geneFunction" class="mim-anchor"></a>
|
|
<h4 href="#mimGeneFunctionFold" id="mimGeneFunctionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimGeneFunctionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimGeneFunctionFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><a href="#2" class="mim-tip-reference" title="Anderson, P. A. W., Greig, A., Mark, T. M., Malouf, N. N., Oakeley, A. E., Ungerleider, R. M., Allen, P. D., Kay, B. K. <strong>Molecular basis of human cardiac troponin T isoforms expressed in the developing, adult, and failing heart.</strong> Circ. Res. 76: 681-686, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7534662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7534662</a>] [<a href="https://doi.org/10.1161/01.res.76.4.681" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7534662">Anderson et al. (1995)</a> and <a href="#22" class="mim-tip-reference" title="Mesnard, L., Logeart, D., Taviaux, S., Diriong, S., Mercadier, J.-J., Samson, F. <strong>Human cardiac troponin T: cloning and expression of new isoforms in the normal and failing heart.</strong> Circ. Res. 76: 687-692, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7895342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7895342</a>] [<a href="https://doi.org/10.1161/01.res.76.4.687" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7895342">Mesnard et al. (1995)</a> each described multiple isoforms of cardiac troponin T that result from alternative splicing of adjacent 15-bp and 30-bp mini-exons in the 5-prime half of the coding region. Isoform cTnT1 contains both exons, cTnT2 lacks the 15-bp exon, cTnT3 lacks the 30-bp exon, and cTnT4 is missing them both. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7534662+7895342" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Inclusion of cardiac troponin T exon 5 in embryonic muscle requires conserved flanking intronic elements (MSEs). <a href="#5" class="mim-tip-reference" title="Charlet-B, N., Logan, P., Singh, G., Cooper, T. A. <strong>Dynamic antagonism between ETR-3 and PTB regulates cell type-specific alternative splicing.</strong> Molec. Cell 9: 649-658, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11931771/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11931771</a>] [<a href="https://doi.org/10.1016/s1097-2765(02)00479-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11931771">Charlet-B et al. (2002)</a> found that ETR3 (CUGBP2; <a href="/entry/602538">602538</a>), a member of the CELF family, binds U/G motifs in 2 MSEs and directly activates exon inclusion in vitro. They showed that binding and activation by ETR3 are directly antagonized by polypyrimidine tract-binding protein (PTB; <a href="/entry/600693">600693</a>). The use of dominant-negative mutants demonstrated that endogenous CELF and PTB activities are required for MSE-dependent activation and repression in muscle and nonmuscle cells, respectively. Combined use of CELF and PTB dominant-negative mutants provided an in vivo demonstration that antagonistic splicing activities exist within the same cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11931771" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Because it is not normally found in blood, cardiac troponin T in serum is a more sensitive indicator of myocardial cell injury than is serum creatine kinase MB activity, and its detection in the circulation may be a useful prognostic indicator in patients with unstable angina (<a href="#9" class="mim-tip-reference" title="Hamm, C. W., Ravkilde, J., Gerhardt, W., Jorgensen, P., Peheim, E., Ljungdahl, L., Goldmann, B., Katus, H. A. <strong>The prognostic value of serum troponin T in unstable angina.</strong> New Eng. J. Med. 327: 146-150, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1290492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1290492</a>] [<a href="https://doi.org/10.1056/NEJM199207163270302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1290492">Hamm et al., 1992</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1290492" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Sensitive and specific markers of myocardial cell necrosis, notably cardiac troponins, are valuable tools in the evaluation of patients with acute coronary syndromes. Troponins are not actively involved in the pathophysiology of acute coronary syndromes and, instead, represent a surrogate marker for the formation of fragile thrombi (<a href="#4" class="mim-tip-reference" title="Benamer, H., Steg, P. G., Benessiano, J., Vicaut, E., Gaultier, C. J., Aubry, P., Boudvillain, O., Sarfati, L., Brochet, E., Feldman, L. J., Himbert, D., Juliard, J.-M., Assayag, P. <strong>Elevated cardiac troponin I predicts a high-risk angiographic anatomy of the culprit lesion in unstable angina.</strong> Am. Heart J. 137: 815-820, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10220629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10220629</a>] [<a href="https://doi.org/10.1016/s0002-8703(99)70404-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10220629">Benamer et al., 1999</a>; <a href="#11" class="mim-tip-reference" title="Heeschen, C., van Den Brand, M. J., Hamm, C. W., Simoons, M. L. <strong>Angiographic findings in patients with refractory unstable angina according to troponin T status.</strong> Circulation 100: 1509-1514, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10510053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10510053</a>] [<a href="https://doi.org/10.1161/01.cir.100.14.1509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10510053">Heeschen et al., 1999</a>; <a href="#19" class="mim-tip-reference" title="Lindahl, B., Diderholm, E., Lagerqvist, B., Venge, P., Wallentin, L. <strong>Mechanisms behind the prognostic value of troponin T in unstable coronary artery disease: a FRISC II substudy.</strong> J. Am. Coll. Cardiol. 38: 979-986, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11583868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11583868</a>] [<a href="https://doi.org/10.1016/s0735-1097(01)01501-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11583868">Lindahl et al., 2001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10220629+10510053+11583868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Aviles, R. J., Askari, A. T., Lindahl, B., Wallentin, L., Jia, G., Ohman, E. M., Mahaffey, K. W., Newby, L. K., Califf, R. M., Simoons, M. L., Topol, E. J., Lauer, M. S. <strong>Troponin T levels in patients with acute coronary syndromes, with or without renal dysfunction.</strong> New Eng. J. Med. 346: 2047-2052, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12087140/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12087140</a>] [<a href="https://doi.org/10.1056/NEJMoa013456" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12087140">Aviles et al. (2002)</a> demonstrated that cardiac troponin T levels predict short-term prognosis in patients with acute coronary syndromes regardless of the level of creatinine clearance in the patient. The study had been undertaken because of concern that renal dysfunction might impair the prognostic value of the assay, because cardiac troponin T may be cleared by the kidney. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12087140" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 56 patients with chronic precapillary pulmonary hypertension, <a href="#39" class="mim-tip-reference" title="Torbicki, A., Kurzyna, M., Kuca, P., Fijalkowska, A., Sikora, J., Florczyk, M., Pruszczyk, P., Burakowski, J., Wawrzynska, L. <strong>Detectable serum cardiac troponin T as a marker of poor prognosis among patients with chronic precapillary pulmonary hypertension.</strong> Circulation 108: 844-848, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12900346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12900346</a>] [<a href="https://doi.org/10.1161/01.CIR.0000084544.54513.E2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12900346">Torbicki et al. (2003)</a> found that those with detectable cardiac troponin T had higher heart rates (p = 0.004), lower mixed venous oxygen saturation (p = 0.04), and higher serum N-terminal pro-B-type natriuretic peptide (<a href="/entry/600295">600295</a>) (p = 0.03); they also walked less during the 6-minute walk test (p = 0.02). Cumulative survival estimated by Kaplan-Meier curves was significantly worse at 24 months in cTnT-positive compared to cTnT-negative patients (log-rank test, p = 0.001), and multivariate analysis revealed cTnT status to be an independent marker of mortality. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12900346" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="molecularGenetics" class="mim-anchor"></a>
|
|
<h4 href="#mimMolecularGeneticsFold" id="mimMolecularGeneticsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimMolecularGeneticsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimMolecularGeneticsFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Familial Hypertrophic Cardiomyopathy 2</em></strong></p><p>
|
|
<a href="#37" class="mim-tip-reference" title="Thierfelder, L., Watkins, H., MacRae, C., Lamas, R., McKenna, W., Vosberg, H.-P., Seidman, J. G., Seidman, C. E. <strong>Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere.</strong> Cell 77: 701-712, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8205619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8205619</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90054-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8205619">Thierfelder et al. (1994)</a> demonstrated that affected individuals from 3 unrelated families with the form of familial hypertrophic cardiomyopathy linked to 1q (CMH2; <a href="/entry/115195">115195</a>) contained point mutations: missense mutations (ile79-to-asn, <a href="#0001">191045.0001</a>; arg92-to-gln, <a href="#0002">191045.0002</a>) in 2 of them and a mutation in the splice donor sequence of intron 15 in the third (<a href="#0003">191045.0003</a>). The abnormalities were demonstrated by screening by RNase A protection assays followed by sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8205619" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 3-generation family segregating autosomal dominant cardiomyopathy, in which the proband had a restrictive phenotype and relatives had clinical features of restrictive, hypertrophic, and/or dilated cardiomyopathy, <a href="#21" class="mim-tip-reference" title="Menon, S. C., Michels, V. V., Pellikka, P. A., Ballew, J. D., Karst, M. L., Herron, K. J., Nelson, S. M., Rodeheffer, R. J., Olson, T. M. <strong>Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology.</strong> Clin. Genet. 74: 445-454, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18651846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18651846</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18651846[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.01062.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18651846">Menon et al. (2008)</a> performed targeted linkage analysis for 9 sarcomeric genes and identified heterozygosity for the I79N mutation in the TNNT2 gene (<a href="#0001">191045.0001</a>) that segregated with the disease phenotype. The I79N mutation had previously been found in a family with CMH (<a href="#37" class="mim-tip-reference" title="Thierfelder, L., Watkins, H., MacRae, C., Lamas, R., McKenna, W., Vosberg, H.-P., Seidman, J. G., Seidman, C. E. <strong>Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere.</strong> Cell 77: 701-712, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8205619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8205619</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90054-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8205619">Thierfelder et al., 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8205619+18651846" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#35" class="mim-tip-reference" title="Tardiff, J. C., Factor, S. M., Tompkins, B. D., Hewett, T. E., Palmer, B. M., Moore, R. L., Schwartz, S., Robbins, J., Leinwand, L. A. <strong>A truncated cardiac troponin T molecule in transgenic mice suggests multiple cellular mechanisms for familial hypertrophic cardiomyopathy.</strong> J. Clin. Invest. 101: 2800-2811, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9637714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9637714</a>] [<a href="https://doi.org/10.1172/JCI2389" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9637714">Tardiff et al. (1998)</a> stated that 9 mutations had been described in the TNNT2 gene that cause familial hypertrophic cardiomyopathy, including 7 missense mutations, a deletion of an internal amino acid, and a splice site mutation that would result in the loss of either the 14 or 28 C-terminal residues with the addition of 7 non-TNNT2 amino acids in the latter case. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9637714" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Familial Dilated Cardiomyopathy 1D</em></strong></p><p>
|
|
<a href="#14" class="mim-tip-reference" title="Kamisago, M., Sharma, S. D., DePalma, S. R., Solomon, S., Sharma, P., McDonough, B., Smoot, L., Mullen, M. P., Woolf, P. K., Wigle, E. D., Seidman, J. G., Seidman, C. E. <strong>Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy.</strong> New Eng. J. Med. 343: 1688-1696, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11106718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11106718</a>] [<a href="https://doi.org/10.1056/NEJM200012073432304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11106718">Kamisago et al. (2000)</a> identified a mutation in the TNNT2 gene (<a href="#0006">191045.0006</a>) as the cause of familial dilated cardiomyopathy (CMD1D; <a href="/entry/601494">601494</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11106718" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Mirza, M., Marston, S., Willott, R., Ashley, C., Mogensen, J., McKenna, W., Robinson, P., Redwood, C., Watkins, H. <strong>Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype.</strong> J. Biol. Chem. 280: 28498-28506, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15923195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15923195</a>] [<a href="https://doi.org/10.1074/jbc.M412281200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15923195">Mirza et al. (2005)</a> studied all 8 published mutations causing dilated cardiomyopathy (CMD), including 5 in the TNNT2 gene (lys210del, R141W, R131W, R205L, and D270N; <a href="#0006">191045.0006</a>-<a href="#0010">191045.0010</a>, respectively), 2 in the TPM1 gene (E54K, <a href="/entry/191010#0004">191010.0004</a>; and E40K, <a href="/entry/191010#0005">191010.0005</a>), and 1 in the TNNC1 gene (G159D; <a href="/entry/191040#0001">191040.0001</a>). Thin filaments, reconstituted with a 1:1 ratio of mutant:wildtype proteins, all showed reduced Ca(2+) sensitivity of activation in ATPase and motility assays, and, except for the E54K alpha-tropomyosin mutant which showed no effect, all showed lower maximum Ca(2+) activation. Incorporation of the TNNT2 mutations R141W and R205L into skinned guinea pig cardiac trabeculae also decreased Ca(2+) sensitivity of force generation. Thus, diverse thin filament CMD mutations appeared to affect different aspects of regulatory function yet change contractility in a consistent manner. <a href="#24" class="mim-tip-reference" title="Mirza, M., Marston, S., Willott, R., Ashley, C., Mogensen, J., McKenna, W., Robinson, P., Redwood, C., Watkins, H. <strong>Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype.</strong> J. Biol. Chem. 280: 28498-28506, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15923195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15923195</a>] [<a href="https://doi.org/10.1074/jbc.M412281200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15923195">Mirza et al. (2005)</a> stated that the CMD mutations depressed myofibrillar function, an effect opposite to that of CMH-causing thin filament mutations, and suggested that decreased contractility might trigger pathways that ultimately lead to the clinical phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15923195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Mogensen, J., Murphy, R. T., Shaw, T., Bahl, A., Redwood, C., Watkins, H., Burke, M., Elliott, P. M., McKenna, W. J. <strong>Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.</strong> J. Am. Coll. Cardiol. 44: 2033-2040, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15542288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15542288</a>] [<a href="https://doi.org/10.1016/j.jacc.2004.08.027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15542288">Mogensen et al. (2004)</a> analyzed the TNNT2 gene in 235 consecutive unrelated probands with dilated cardiomyopathy and identified 4 different mutations in 4 families, respectively (see <a href="#0006">191045.0006</a> and <a href="#0008">191045.0008</a>-<a href="#0010">191045.0010</a>). The mutations segregated with the disease in each family and were absent in 200 ethnically matched control chromosomes and 1,520 chromosomes from patients with hypertrophic cardiomyopathy. Functional studies showed significant impairment of mutated troponin interaction compared with wildtype control, indicating an altered regulation of myocardial contractility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15542288" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Familial Restrictive Cardiomyopathy 3</em></strong></p><p>
|
|
In a 12-month-old girl with restrictive cardiomyopathy (RCM3; <a href="/entry/612422">612422</a>), <a href="#28" class="mim-tip-reference" title="Peddy, S. B., Vricella, L. A., Crosson, J. E., Oswald, G. L., Cohn, R. D., Cameron, D. E., Valle, D., Loeys, B. L. <strong>Infantile restrictive cardiomyopathy resulting from a mutation in the cardiac troponin T gene.</strong> Pediatrics 117: 1830-1833, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16651346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16651346</a>] [<a href="https://doi.org/10.1542/peds.2005-2301" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16651346">Peddy et al. (2006)</a> performed direct sequencing of the 8 genes most commonly implicated in hypertrophic cardiomyopathy and identified a de novo 3-bp deletion in the TNNT2 gene (<a href="#0011">191045.0011</a>). The girl also carried a known MYBPC3 (<a href="/entry/600958">600958</a>) polymorphism, V896M, which was also found in her unaffected father; the authors suggested that the V896M variant may have acted as a modifier, exacerbating the phenotypic expression of the TNNT2 mutation and causing an unusually early onset of RMC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16651346" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Left Ventricular Noncompaction 6</em></strong></p><p>
|
|
In a 20-year-old woman with isolated left ventricular noncompaction (LVNC6; <a href="/entry/601494">601494</a>), <a href="#15" class="mim-tip-reference" title="Klaassen, S., Probst, S., Oechslin, E., Gerull, B., Krings, G., Schuler, P., Greutmann, M., Hurlimann, D., Yegibasi, M., Pons, L., Gramlich, M., Drenckhahn, J.-D., Heuser, A., Berger, F., Jenni, R., Thierfelder, L. <strong>Mutations in sarcomere protein genes in left ventricular noncompaction.</strong> Circulation 117: 2893-2901, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18506004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18506004</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.746164" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18506004">Klaassen et al. (2008)</a> identified heterozygosity for the R131W missense mutation in the TNNT2 gene (<a href="#0008">191045.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18506004" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 3-generation family with autosomal dominant left ventricular noncompaction of variable severity, <a href="#20" class="mim-tip-reference" title="Luedde, M., Ehlermann, P., Weichenhan, D., Will, R., Zeller, R., Rupp, S., Muller, A, Steen, H., Ivandic, B. T., Ulmer, H. E., Kern, M., Katus, H. A., Frey, N. <strong>Severe familial left ventricular non-compaction cardiomyopathy due to a novel troponin T (TNNT2) mutation.</strong> Cardiovasc. Res. 86: 452-460, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20083571/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20083571</a>] [<a href="https://doi.org/10.1093/cvr/cvq009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20083571">Luedde et al. (2010)</a> analyzed 6 cardiomyopathy-associated genes and identified a heterozygous missense mutation (E96K; <a href="#0012">191045.0012</a>) that segregated fully with disease. Transgenic mice with the E96K mutation developed left ventricular dysfunction and showed induction of marker genes of heart failure, including ANF (NPPA; <a href="/entry/108780">108780</a>), BNP (NPPB; <a href="/entry/600295">600295</a>), and beta-MHC (MYH7; <a href="/entry/160760">160760</a>), but LVNC was not observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20083571" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="genotypePhenotypeCorrelations" class="mim-anchor"></a>
|
|
<h4 href="#mimGenotypePhenotypeCorrelationsFold" id="mimGenotypePhenotypeCorrelationsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimGenotypePhenotypeCorrelationsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Genotype/Phenotype Correlations</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimGenotypePhenotypeCorrelationsFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><a href="#37" class="mim-tip-reference" title="Thierfelder, L., Watkins, H., MacRae, C., Lamas, R., McKenna, W., Vosberg, H.-P., Seidman, J. G., Seidman, C. E. <strong>Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere.</strong> Cell 77: 701-712, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8205619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8205619</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90054-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8205619">Thierfelder et al. (1994)</a> proposed that familial hypertrophic cardiomyopathy (CMH) is a disease of the sarcomere, since mutations in alpha-tropomyosin (TPM1; <a href="/entry/191010">191010</a>), cardiac troponin T, and beta-myosin heavy chain (MYH7; <a href="/entry/160760">160760</a>) all cause the same cardiac-specific phenotype (see their Figure 7). Because the cardiac troponin T isoform is not expressed in adult skeletal muscle, the tissue-specific effects of mutations in this thin filament protein were not unexpected. Although alpha-tropomyosin is expressed in many cell types, the mutations identified in exon 5 (<a href="/entry/191010#0001">191010.0001</a>; <a href="/entry/191010#0002">191010.0002</a>) produce clinically significant disease only in heart muscle. As a generalization, <a href="#37" class="mim-tip-reference" title="Thierfelder, L., Watkins, H., MacRae, C., Lamas, R., McKenna, W., Vosberg, H.-P., Seidman, J. G., Seidman, C. E. <strong>Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere.</strong> Cell 77: 701-712, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8205619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8205619</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90054-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8205619">Thierfelder et al. (1994)</a> proposed that CMH-causing mutations act by altering the stoichiometry of sarcomere components and that changes in gene expression perturbing the stoichiometry of sarcomere components may be a mechanism for secondary cardiac hypertrophy in response to various stimuli such as hypertension. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8205619" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#42" class="mim-tip-reference" title="Watkins, H., McKenna, W. J., Thierfelder, L., Suk, H. J., Anan, R., O'Donoghue, A., Spirito, P., Matsumori, A., Moravec, C. S., Seidman, J. G., Seidman, C. E. <strong>Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy.</strong> New Eng. J. Med. 332: 1058-1064, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7898523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7898523</a>] [<a href="https://doi.org/10.1056/NEJM199504203321603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7898523">Watkins et al. (1995)</a> concluded that mutations in the cardiac troponin T gene account for approximately 15% of cases of familial hypertrophic cardiomyopathy among patients seen in referral centers. These mutations, like those in alpha-tropomyosin, are characterized by relatively mild and sometimes subclinical hypertrophy but a high incidence of sudden death. Genetic testing may therefore be especially important in this group. In their Figure 2, <a href="#42" class="mim-tip-reference" title="Watkins, H., McKenna, W. J., Thierfelder, L., Suk, H. J., Anan, R., O'Donoghue, A., Spirito, P., Matsumori, A., Moravec, C. S., Seidman, J. G., Seidman, C. E. <strong>Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy.</strong> New Eng. J. Med. 332: 1058-1064, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7898523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7898523</a>] [<a href="https://doi.org/10.1056/NEJM199504203321603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7898523">Watkins et al. (1995)</a> diagrammed 8 mutations in the TNNT2 gene that cause CMH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7898523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Although mutations in either of the cardiac sarcomeric proteins myosin heavy chain and cardiac troponin T (as well as others) cause dominantly inherited hypertrophic cardiomyopathy, patients with mutations in these 2 genes have distinct clinical characteristics (<a href="#35" class="mim-tip-reference" title="Tardiff, J. C., Factor, S. M., Tompkins, B. D., Hewett, T. E., Palmer, B. M., Moore, R. L., Schwartz, S., Robbins, J., Leinwand, L. A. <strong>A truncated cardiac troponin T molecule in transgenic mice suggests multiple cellular mechanisms for familial hypertrophic cardiomyopathy.</strong> J. Clin. Invest. 101: 2800-2811, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9637714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9637714</a>] [<a href="https://doi.org/10.1172/JCI2389" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9637714">Tardiff et al., 1998</a>). Those with MYH7 mutations demonstrate more significant and uniform cardiac hypertrophy and a variable frequency of sudden death. Patients with TNNT2 mutations generally exhibit mild or no cardiac hypertrophy, but a high frequency of sudden death at an early age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9637714" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Rust, E. M., Albayya, F. P., Metzger, J. M. <strong>Identification of a contractile deficit in adult cardiac myocytes expressing hypertrophic cardiomyopathy-associated mutant troponin T proteins.</strong> J. Clin. Invest. 103: 1459-1467, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10330428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10330428</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10330428[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI6377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10330428">Rust et al. (1999)</a> stated that at least 7 different genetic loci had been identified as the cause of hypertrophic cardiomyopathy and that 11 mutations in the TNNT2 gene had been linked to CMH. Of these mutations, 9 were point mutations, 1 was a codon deletion that did not result in a frameshift, and 1 was a splice site mutation in intron 16 that was predicted to lead to production of a truncated protein. The 7 known disease genes share one common characteristic: they all encode key contractile or regulatory myofilament proteins. CMH is, therefore, a disease of cardiac sarcomere. To test the alternative molecular mechanisms of pathogenesis of troponin-related CMH, <a href="#30" class="mim-tip-reference" title="Rust, E. M., Albayya, F. P., Metzger, J. M. <strong>Identification of a contractile deficit in adult cardiac myocytes expressing hypertrophic cardiomyopathy-associated mutant troponin T proteins.</strong> J. Clin. Invest. 103: 1459-1467, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10330428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10330428</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10330428[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI6377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10330428">Rust et al. (1999)</a> studied single adult cardiomyocytes into which TNNT2 cDNAs carrying the I79N (<a href="#0001">191045.0001</a>) and R92Q (<a href="#0002">191045.0002</a>) mutations were transferred. They tested the hypothesis that the mutant TnT proteins would be expressed and incorporated into the cardiac sarcomere and would behave as dominant-negative proteins to alter directly the calcium-activated force generation at the level of the single cardiac myocyte. They found that under identical experimental conditions, the ectopic expression of the mutant TnTs was significantly less (less than 8% of total) than that obtained with expression of wildtype TnT (approximately 35%) in the myocytes. Confocal imaging of immunolabeled TnT showed a regular periodic pattern of localization of the ectopic mutant protein that was no different from that in normal controls, suggesting that the mutant protein incorporation had no deleterious effects on sarcomere architecture. Direct measurements of isometric force production in single cardiac myocytes demonstrated marked desensitization of submaximal calcium-activated tension, with unchanged maximum tension generation in mutant TnT-expressing myocytes compared with control myocytes. Collectively, these results demonstrated an impaired expression of the mutant protein and a disabling of cardiac contraction in the submaximal range of myoplasmic calcium concentrations. The functional results suggested that the development of new pharmacologic, chemical, or genetic approaches to sensitize the thin-filament regulatory protein system could ameliorate force deficits associated with expression of each of these 2 mutants in adult cardiac myocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10330428" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="animalModel" class="mim-anchor"></a>
|
|
<h4 href="#mimAnimalModelFold" id="mimAnimalModelToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimAnimalModelToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimAnimalModelFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><a href="#18" class="mim-tip-reference" title="Lin, D., Bobkova, A., Homsher, E., Tobacman, L. S. <strong>Altered cardiac troponin T in vitro function in the presence of a mutation implicated in familial hypertrophic cardiomyopathy.</strong> J. Clin. Invest. 97: 2842-2848, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8675696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8675696</a>] [<a href="https://doi.org/10.1172/JCI118740" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8675696">Lin et al. (1996)</a> studied the in vitro function of troponin containing an I91N mutation in rat cardiac TnT, corresponding to the human I79N mutation (<a href="#0001">191045.0001</a>) that causes familial hypertrophic cardiomyopathy (<a href="/entry/115195">115195</a>). The mutation had no effect on troponin's affinity for tropomyosin, troponin-induced binding of tropomyosin to actin, cooperative binding of myosin subfragment 1 to the thin filament, Ca(2+)-sensitive regulation of thin filament-myosin subfragment 1 ATPase activity, or the Ca(2+) concentration dependence of this regulation. However, in vitro motility assays showed that the mutation resulted in 50% faster thin filament movement over a surface coated with heavy meromyosin, suggesting an unexpected role for the N-terminal region of TnT in which this mutation occurs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8675696" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By creating transgenic mice expressing a Tnnt2 allele with a C-terminal truncation, <a href="#35" class="mim-tip-reference" title="Tardiff, J. C., Factor, S. M., Tompkins, B. D., Hewett, T. E., Palmer, B. M., Moore, R. L., Schwartz, S., Robbins, J., Leinwand, L. A. <strong>A truncated cardiac troponin T molecule in transgenic mice suggests multiple cellular mechanisms for familial hypertrophic cardiomyopathy.</strong> J. Clin. Invest. 101: 2800-2811, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9637714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9637714</a>] [<a href="https://doi.org/10.1172/JCI2389" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9637714">Tardiff et al. (1998)</a> showed that mice expressing the truncated protein at low (less than 5%) levels developed cardiomyopathy and that their hearts were significantly smaller than wildtype. These animals also exhibited significant diastolic dysfunction and milder systolic dysfunction. Animals expressing higher levels of transgene protein died within 24 hours of birth. Transgenic mouse hearts demonstrated myocellular disarray and had a reduced number of cardiac myocytes that were smaller in size. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9637714" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To ascertain the contractile phenotype resulting from mutations in the TNNT2 gene, either wildtype or mutant (ile79 to asn, arg92 to gln, or delta-glu160), human cardiac TNT cDNA constructs were transfected into quail myotubes for structural and contractile characterization by <a href="#32" class="mim-tip-reference" title="Sweeney, H. L., Feng, H. S., Yang, Z., Watkins, H. <strong>Functional analyses of troponin T mutations that cause hypertrophic cardiomyopathy: insights into disease pathogenesis and troponin function.</strong> Proc. Nat. Acad. Sci. 95: 14406-14410, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9826713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9826713</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9826713[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.24.14406" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9826713">Sweeney et al. (1998)</a>. All 3 mutants were found to decrease the calcium sensitivity of force production and the 2 missense mutations, I79N and R92Q, increased the unloaded shortening velocity nearly 2-fold. The data demonstrated that troponin T can alter the rate of myosin cross-bridge detachment, and thus the troponin complex plays a greater role in modulating muscle contractile performance than was previously recognized. The data suggested that these troponin T mutations may cause disease via an increased energetic load on the heart. This would represent a second paradigm for the pathogenesis of hypertrophic cardiomyopathy, the other being a dominant-negative effect of the mutant allele that blocks calcium activation of the thin filament. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9826713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Several mutations in cardiac troponin T can cause familial hypertrophic cardiomyopathy. However, patients with TNNT2 mutations generally exhibit mild or no ventricular hypertrophy, yet demonstrate a high frequency of early sudden death. To understand the functional basis of these phenotypes, <a href="#36" class="mim-tip-reference" title="Tardiff, J. C., Hewett, T. E., Palmer, B. M., Olsson, C., Factor, S. M., Moore, R. L., Robbins, J., Leinwand, L. A. <strong>Cardiac troponin T mutations result in allele-specific phenotypes in a mouse model for hypertrophic cardiomyopathy.</strong> J. Clin. Invest. 104: 469-481, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10449439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10449439</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10449439[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI6067" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10449439">Tardiff et al. (1999)</a> created transgenic mouse lines expressing 30%, 67%, and 92% of their total cardiac troponin as a missense allele analogous to one found in CMH: R92Q (<a href="#0002">191045.0002</a>). Similar to a mouse CMH model expressing a truncated TNNT2 protein, the left ventricles of all R92Q lines were smaller than those of wildtype. In striking contrast to truncation mice, however, the R92Q hearts demonstrated significant induction of atrial natriuretic factor and beta-myosin heavy chain (<a href="/entry/160760">160760</a>) transcripts, interstitial fibrosis, and mitochondrial pathology. Isolated cardiac myocytes from R92Q mice had increased basal sarcomeric activation, impaired relaxation, and shorter sarcomere lengths. Isolated working heart data were consistent, showing hypercontractility and diastolic dysfunction, both of which are common findings in patients with CMH. These mice represented the first disease model to exhibit hypercontractility, as well as a unique model system for exploring the cellular pathogenesis of CMH. The distinct phenotypes of mice with different TnT alleles suggested that the clinical heterogeneity of CMH is at least partially due to allele-specific mechanisms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10449439" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="Tobacman, L. S., Lin, D., Butters, C., Landis, C., Back, N., Pavlov, D., Homsher, E. <strong>Functional consequences of troponin T mutations found in hypertrophic cardiomyopathy.</strong> J. Biol. Chem. 274: 28363-28370, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10497196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10497196</a>] [<a href="https://doi.org/10.1074/jbc.274.40.28363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10497196">Tobacman et al. (1999)</a> introduced 5 mutations known to cause familial hypertrophic cardiomyopathy into bovine cardiac troponin T and found diverse functional defects: F110I (<a href="#0005">191045.0005</a>), E244D, and C-terminal truncation weakened the affinity of troponin for the thin filament; deletion of glu160 resulted in thin filaments with increased calcium affinity at the regulatory site of troponin C (<a href="/entry/191040">191040</a>); and R92Q and F110I resulted in impaired troponin solubility, suggesting abnormal protein folding. Depending on the mutation, the in vitro unloaded actin-myosin sliding speed showed small increases, small decreases, or was unchanged. C-terminal truncation resulted in a decreased thin filament myosin subfragment 1 MgATPase rate. <a href="#38" class="mim-tip-reference" title="Tobacman, L. S., Lin, D., Butters, C., Landis, C., Back, N., Pavlov, D., Homsher, E. <strong>Functional consequences of troponin T mutations found in hypertrophic cardiomyopathy.</strong> J. Biol. Chem. 274: 28363-28370, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10497196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10497196</a>] [<a href="https://doi.org/10.1074/jbc.274.40.28363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10497196">Tobacman et al. (1999)</a> noted that these mutations cause diverse immediate effects despite similarities in disease manifestations. Separable but repeatedly observed abnormalities resulting from CMH-related TnT mutations included increased unloaded sliding speed, increased or decreased Ca(2+) affinity, impairment of folding or sarcomeric integrity, and decreased force. Enhancement as well as impairment of contractile protein function was observed, suggesting that TnT, including the troponin tail region, modulates the regulation of cardiac contraction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10497196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In transgenic mice with the R92Q mutation, <a href="#13" class="mim-tip-reference" title="Javadpour, M. M., Tardiff, J. C., Pinz, I., Ingwall, J. S. <strong>Decreased energetics in murine hearts bearing the R92Q mutation in cardiac troponin T.</strong> J. Clin. Invest. 112: 768-775, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12952925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12952925</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12952925[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI15967" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12952925">Javadpour et al. (2003)</a> simultaneously measured cardiac energetics and contractile performance of the intact beating heart and found both a decrease in the free energy of ATP hydrolysis available to support contractile work and a marked inability to increase contractile performance upon acute inotropic challenge. <a href="#13" class="mim-tip-reference" title="Javadpour, M. M., Tardiff, J. C., Pinz, I., Ingwall, J. S. <strong>Decreased energetics in murine hearts bearing the R92Q mutation in cardiac troponin T.</strong> J. Clin. Invest. 112: 768-775, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12952925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12952925</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12952925[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI15967" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12952925">Javadpour et al. (2003)</a> concluded that alterations in thin filament protein structure and function can lead to significant defects in myocardial energetics and contractile reserve. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12952925" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To study the effect of troponin T mutations that cause familial hypertrophic cardiomyopathy on cardiac muscle contraction, <a href="#33" class="mim-tip-reference" title="Szczesna, D., Zhang, R., Zhao, J., Jones, M., Guzman, G., Potter, J. D. <strong>Altered regulation of cardiac muscle contraction by troponin T mutations that cause familial hypertrophic cardiomyopathy.</strong> J. Biol. Chem. 275: 624-630, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10617660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10617660</a>] [<a href="https://doi.org/10.1074/jbc.275.1.624" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10617660">Szczesna et al. (2000)</a> cloned and expressed the wildtype and several TNNT2 mutants, including I79N, R92Q, and R278C (<a href="#0004">191045.0004</a>). These mutants were reconstituted into skinned porcine cardiac muscle preparations and characterized for their effect on maximal steady-state force activation, inhibition, and the Ca(2+) sensitivity of force development. <a href="#33" class="mim-tip-reference" title="Szczesna, D., Zhang, R., Zhao, J., Jones, M., Guzman, G., Potter, J. D. <strong>Altered regulation of cardiac muscle contraction by troponin T mutations that cause familial hypertrophic cardiomyopathy.</strong> J. Biol. Chem. 275: 624-630, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10617660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10617660</a>] [<a href="https://doi.org/10.1074/jbc.275.1.624" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10617660">Szczesna et al. (2000)</a> observed changes in the Ca(2+) regulation of force development caused by these mutations. They interpreted the changes as likely causes of altered contractility leading to the development of hypertrophic cardiomyopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10617660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Miller, T., Szczesna, D., Housmans, P. R., Zhao, J., de Freitas, F., Gomes, A. V., Culbreath, L., McCue, J., Wang, Y., Xu, Y., Kerrick, W. G. L., Potter, J. D. <strong>Abnormal contractile function in transgenic mice expressing a familial hypertrophic cardiomyopathy-linked troponin T (I79N) mutation.</strong> J. Biol. Chem. 276: 3743-3755, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11060294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11060294</a>] [<a href="https://doi.org/10.1074/jbc.M006746200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11060294">Miller et al. (2001)</a> generated mice transgenic for wildtype human cardiac TNNT2 and for the I79N mutation driven by the murine alpha-myosin heavy chain promoter. Comparison of the transgenic I79N mice with transgenic wildtype mice and nontransgenic mice demonstrated normal survival and no cardiac hypertrophy even with chronic exercise in all groups. Mice carrying the mutant transgene, however, displayed increased Ca(2+) sensitivity of ATPase activity and force development in cardiac myofilaments. <a href="#23" class="mim-tip-reference" title="Miller, T., Szczesna, D., Housmans, P. R., Zhao, J., de Freitas, F., Gomes, A. V., Culbreath, L., McCue, J., Wang, Y., Xu, Y., Kerrick, W. G. L., Potter, J. D. <strong>Abnormal contractile function in transgenic mice expressing a familial hypertrophic cardiomyopathy-linked troponin T (I79N) mutation.</strong> J. Biol. Chem. 276: 3743-3755, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11060294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11060294</a>] [<a href="https://doi.org/10.1074/jbc.M006746200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11060294">Miller et al. (2001)</a> proposed that changes in calcium regulation of ATPase and changes in maximal force and rate of force activation could ultimately lead to catastrophic results and sudden death of individuals carrying the I79N mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11060294" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To study further the functional consequences of the I79N mutation, <a href="#16" class="mim-tip-reference" title="Knollmann, B. C., Blatt, S. A., Horton, K., de Freitas, F., Miller, T., Bell, M., Housmans, P. R., Weissman, N. J., Morad, M., Potter, J. D. <strong>Inotropic stimulation induces cardiac dysfunction in transgenic mice expressing a troponin T (I79N) mutation linked to familial hypertrophic cardiomyopathy.</strong> J. Biol. Chem. 276: 10039-10048, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11113119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11113119</a>] [<a href="https://doi.org/10.1074/jbc.M006745200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11113119">Knollmann et al. (2001)</a> compared cardiac performance of transgenic mice expressing either human TnT-I79N or human wildtype TnT. In isolated hearts, cardiac function was different depending on the calcium ion concentration of the perfusate. At higher calcium ion concentrations, systolic function was not different, but diastolic dysfunction became manifest as increased end-diastolic pressure and time to 90% relaxation. In vivo measurements by echocardiography and Doppler confirmed that baseline systolic function was significantly higher in the I79N mice without evidence for diastolic dysfunction. Inotropic stimulation with isoproterenol resulted only in a modest contractile response but caused significant mortality in the transgenic I79N mice. Doppler studies ruled out aortic outflow obstruction and were consistent with increased chamber stiffness. <a href="#16" class="mim-tip-reference" title="Knollmann, B. C., Blatt, S. A., Horton, K., de Freitas, F., Miller, T., Bell, M., Housmans, P. R., Weissman, N. J., Morad, M., Potter, J. D. <strong>Inotropic stimulation induces cardiac dysfunction in transgenic mice expressing a troponin T (I79N) mutation linked to familial hypertrophic cardiomyopathy.</strong> J. Biol. Chem. 276: 10039-10048, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11113119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11113119</a>] [<a href="https://doi.org/10.1074/jbc.M006745200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11113119">Knollmann et al. (2001)</a> concluded that in vivo the increased myofilament calcium ion sensitivity due to the I79N mutation enhances baseline contractility but leads to cardiac dysfunction during inotropic stimulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11113119" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Mutations in the TNNT2 gene, encoding the thin-filament contractile protein cardiac troponin T, are responsible for 15% of all cases of familial hypertrophic cardiomyopathy. Mutant proteins are thought to act through a dominant-negative mode that impairs function of heart muscle. <a href="#31" class="mim-tip-reference" title="Sehnert, A. J., Huq, A., Weinstein, B. M., Walker, C., Fishman, M., Stainier, D. Y. R. <strong>Cardiac troponin T is essential in sarcomere assembly and cardiac contractility.</strong> Nature Genet. 31: 106-110, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11967535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11967535</a>] [<a href="https://doi.org/10.1038/ng875" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11967535">Sehnert et al. (2002)</a> pointed out that, despite the importance of cardiac troponin T in human disease, its loss-of-function phenotype had not been described. They showed that the zebrafish 'silent heart' (sih) mutation affects the tnnt2 gene. They characterized 2 mutated alleles of sih that severely reduce tnnt2 expression: one affects mRNA splicing, and the other affects gene transcription. Tnnt2, together with alpha-tropomyosin (TPM1; <a href="/entry/191010">191010</a>) and cardiac troponins C and I (TNNI3; <a href="/entry/191044">191044</a>), forms a calcium-sensitive regulatory complex within sarcomeres. Unexpectedly, in addition to loss of Tnnt2 expression in sih mutant hearts, <a href="#31" class="mim-tip-reference" title="Sehnert, A. J., Huq, A., Weinstein, B. M., Walker, C., Fishman, M., Stainier, D. Y. R. <strong>Cardiac troponin T is essential in sarcomere assembly and cardiac contractility.</strong> Nature Genet. 31: 106-110, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11967535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11967535</a>] [<a href="https://doi.org/10.1038/ng875" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11967535">Sehnert et al. (2002)</a> observed a significant reduction in Tpm1 and Tnni3 and, consequently, severe sarcomere defects. This interdependence of thin-filament protein expression led them to postulate that some mutations in tnnt2 may trigger misregulation of thin-filament protein expression, resulting in sarcomere loss and myocyte disarray, the life-threatening hallmarks of TNNT2 mutations in mice and humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11967535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Harada, K., Potter, J. D. <strong>Familial hypertrophic cardiomyopathy mutations from different functional regions of troponin T result in different effects on the pH and Ca(2+) sensitivity of cardiac muscle contraction.</strong> J. Biol. Chem. 279: 14488-14495, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14722098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14722098</a>] [<a href="https://doi.org/10.1074/jbc.M309355200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14722098">Harada and Potter (2004)</a> incorporated 8 CMH-linked TnT mutations into porcine skinned cardiac fibers and found that all 8 mutants altered the contractile properties of the skinned cardiac fibers: E244D potentiated the maximum force development without changing Ca(2+) sensitivity, whereas the other 7 mutants increased the Ca(2+) sensitivity of force development but not the maximal force. Mutations in a region including residues 91 to 94 also decreased the change in Ca(2+) sensitivity of force development observed upon lowering pH from 7 to 6.5 compared with wildtype. <a href="#10" class="mim-tip-reference" title="Harada, K., Potter, J. D. <strong>Familial hypertrophic cardiomyopathy mutations from different functional regions of troponin T result in different effects on the pH and Ca(2+) sensitivity of cardiac muscle contraction.</strong> J. Biol. Chem. 279: 14488-14495, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14722098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14722098</a>] [<a href="https://doi.org/10.1074/jbc.M309355200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14722098">Harada and Potter (2004)</a> suggested that different regions of TnT may contribute to the pathogenesis of TnT-linked familial CMH through different mechanisms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14722098" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Hernandez, O. M., Szczesna-Cordary, D., Knollmann, B. C., Miller, T., Bell, M., Zhao, J., Sirenko, S. G., Diaz, Z., Guzman, G., Xu, Y., Wang, Y., Kerrick, W. G. L., Potter, J. D. <strong>F110I and R278C troponin T mutations that cause familial hypertrophic cardiomyopathy affect muscle contraction in transgenic mice and reconstituted human cardiac fibers.</strong> J. Biol. Chem. 280: 37183-37194, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16115869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16115869</a>] [<a href="https://doi.org/10.1074/jbc.M508114200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16115869">Hernandez et al. (2005)</a> studied cardiac muscle fibers from transgenic mice expressing the F110I (<a href="#0005">191045.0005</a>) and R278C mutations and observed an increased Ca(2+) sensitivity of force and ATPase activity in the F110I mutant fibers compared to the R278C fibers. Similar changes were seen in human cardiac fibers reconstituted with the TNNT2 mutants. In both sets of transgenic mice the maximal level of force was markedly decreased, although the maximal ATPase was not; thus their ratios of ATPase/force (energy cost) at all Ca(2+) concentrations were dramatically higher than wildtype. <a href="#12" class="mim-tip-reference" title="Hernandez, O. M., Szczesna-Cordary, D., Knollmann, B. C., Miller, T., Bell, M., Zhao, J., Sirenko, S. G., Diaz, Z., Guzman, G., Xu, Y., Wang, Y., Kerrick, W. G. L., Potter, J. D. <strong>F110I and R278C troponin T mutations that cause familial hypertrophic cardiomyopathy affect muscle contraction in transgenic mice and reconstituted human cardiac fibers.</strong> J. Biol. Chem. 280: 37183-37194, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16115869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16115869</a>] [<a href="https://doi.org/10.1074/jbc.M508114200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16115869">Hernandez et al. (2005)</a> suggested that the combination of increased Ca(2+) sensitivity and energy cost in the F110I hearts may account for the greater severity of this phenotype compared to the R278C mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16115869" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Du, C.-K., Morimoto, S., Nishii, K., Minakami, R., Ohta, M., Tadano, N., Lu, Q.-W., Wang, Y.-Y., Zhan, D.-Y., Mochizuki, M., Kita, S., Miwa, Y., Takahashi-Yanaga, F., Iwamoto, T., Ohtsuki, I., Sasaguri, T. <strong>Knock-in mouse model of dilated cardiomyopathy caused by troponin mutation.</strong> Circ. Res. 101: 185-194, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17556660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17556660</a>] [<a href="https://doi.org/10.1161/CIRCRESAHA.106.146670" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17556660">Du et al. (2007)</a> generated knockin mice with a Tnnt2 K210del mutation (<a href="#0006">191045.0006</a>) and found that cardiac muscle fibers from mutant mice showed significantly lower Ca(2+) sensitivity in force generation than those from wildtype mice. The peak amplitude of Ca(2+) transient in mutant cardiomyocytes was increased, although the maximum isometric force produced by intact cardiac muscle fibers of mutant mice was not significantly different from wildtype, suggesting that the Ca(2+) transient was augmented to compensate for decreased myofilament Ca(2+) sensitivity. Mutant mice developed marked cardiac enlargement, heart failure, and frequent sudden death, recapitulating the phenotype of dilated cardiomyopathy patients. Administration of pimobendan, a positive inotropic agent that directly increases myofilament Ca(2+) sensitivity, prevented cardiac enlargement, heart failure, and sudden death. <a href="#6" class="mim-tip-reference" title="Du, C.-K., Morimoto, S., Nishii, K., Minakami, R., Ohta, M., Tadano, N., Lu, Q.-W., Wang, Y.-Y., Zhan, D.-Y., Mochizuki, M., Kita, S., Miwa, Y., Takahashi-Yanaga, F., Iwamoto, T., Ohtsuki, I., Sasaguri, T. <strong>Knock-in mouse model of dilated cardiomyopathy caused by troponin mutation.</strong> Circ. Res. 101: 185-194, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17556660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17556660</a>] [<a href="https://doi.org/10.1161/CIRCRESAHA.106.146670" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17556660">Du et al. (2007)</a> concluded that Ca(2+) desensitization of the cardiac myofilament is the underlying cause of the dilated cardiomyopathy associated with the K210del mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17556660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="allelicVariants" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<span href="#mimAllelicVariantsFold" id="mimAllelicVariantsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimAllelicVariantsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
|
|
</span>
|
|
<strong>12 Selected Examples</a>):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div id="mimAllelicVariantsFold" class="collapse in mimTextToggleFold">
|
|
<div>
|
|
<a href="/allelicVariants/191045" class="btn btn-default" role="button"> Table View </a>
|
|
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=191045[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
|
|
|
|
</div>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0001" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
CARDIOMYOPATHY, DILATED, 1D, INCLUDED<br />
|
|
CARDIOMYOPATHY, FAMILIAL, RESTRICTIVE, 3, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
TNNT2, ILE79ASN
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121964855 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121964855;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121964855?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121964855" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121964855" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013217 OR RCV000013218 OR RCV000013219 OR RCV000159272 OR RCV000211864 OR RCV000243910 OR RCV000684789 OR RCV001171170" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013217, RCV000013218, RCV000013219, RCV000159272, RCV000211864, RCV000243910, RCV000684789, RCV001171170" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013217...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In members of family AW afflicted with the form of familial hypertrophic cardiomyopathy (CMH2; <a href="/entry/115195">115195</a>) linked to chromosome 1, <a href="#37" class="mim-tip-reference" title="Thierfelder, L., Watkins, H., MacRae, C., Lamas, R., McKenna, W., Vosberg, H.-P., Seidman, J. G., Seidman, C. E. <strong>Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere.</strong> Cell 77: 701-712, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8205619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8205619</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90054-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8205619">Thierfelder et al. (1994)</a> found heterozygosity for a 248T-A transversion in the TNNT2 gene, changing codon 79 from ATC to AAC and replacing the normal nonpolar isoleucine with a polar asparagine residue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8205619" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a 3-generation family segregating autosomal dominant cardiomyopathy, in which the proband had a restrictive phenotype (RCM3; <a href="/entry/612422">612422</a>) and relatives had clinical features of restrictive, hypertrophic, and/or dilated (CMD1D; <a href="/entry/601494">601494</a>) cardiomyopathy, <a href="#21" class="mim-tip-reference" title="Menon, S. C., Michels, V. V., Pellikka, P. A., Ballew, J. D., Karst, M. L., Herron, K. J., Nelson, S. M., Rodeheffer, R. J., Olson, T. M. <strong>Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology.</strong> Clin. Genet. 74: 445-454, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18651846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18651846</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18651846[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.01062.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18651846">Menon et al. (2008)</a> identified heterozygosity for the I79N mutation in the TNNT2 gene. The mutation was not found in unaffected individuals. Despite the variable morphology, all affected members of the family exhibited restrictive physiology. There was a high incidence of atrial tachyarrhythmia but no significant ventricular arrhythmia or sudden death in affected members of this family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18651846" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0002" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
TNNT2, ARG92GLN
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121964856 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121964856;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121964856" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121964856" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013220 OR RCV000159281 OR RCV000211865 OR RCV000621709 OR RCV000627784 OR RCV003450625 OR RCV003450626" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013220, RCV000159281, RCV000211865, RCV000621709, RCV000627784, RCV003450625, RCV003450626" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013220...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In members of family BA with the form of familial hypertrophic cardiomyopathy (CMH2; <a href="/entry/115195">115195</a>) linked to chromosome 1, <a href="#37" class="mim-tip-reference" title="Thierfelder, L., Watkins, H., MacRae, C., Lamas, R., McKenna, W., Vosberg, H.-P., Seidman, J. G., Seidman, C. E. <strong>Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere.</strong> Cell 77: 701-712, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8205619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8205619</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90054-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8205619">Thierfelder et al. (1994)</a> identified heterozygosity for a 287G-A transition in the TNNT2 gene, changing codon 92 from CGG to CAG and predicting the replacement of a positively charged arginine with a neutral glutamine (R92Q). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8205619" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0003" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
TNNT2, IVS15, G-A, +1
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs111377893 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111377893;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs111377893" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs111377893" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000036621 OR RCV001233169 OR RCV001787036 OR RCV001798106 OR RCV002426558 OR RCV003445106 OR RCV003445107 OR RCV004808562" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000036621, RCV001233169, RCV001787036, RCV001798106, RCV002426558, RCV003445106, RCV003445107, RCV004808562" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000036621...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In family AU in which <a href="#41" class="mim-tip-reference" title="Watkins, H., MacRae, C., Thierfelder, L., Chou, Y.-H., Frenneaux, M., McKenna, W., Seidman, J. G., Seidman, C. E. <strong>A disease locus for familial hypertrophic cardiomyopathy maps to chromosome 1q3.</strong> Nature Genet. 3: 333-337, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7981753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7981753</a>] [<a href="https://doi.org/10.1038/ng0493-333" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7981753">Watkins et al. (1993)</a> found that familial hypertrophic cardiomyopathy (CMH2; <a href="/entry/115195">115195</a>) was linked to 1q, <a href="#37" class="mim-tip-reference" title="Thierfelder, L., Watkins, H., MacRae, C., Lamas, R., McKenna, W., Vosberg, H.-P., Seidman, J. G., Seidman, C. E. <strong>Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere.</strong> Cell 77: 701-712, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8205619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8205619</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90054-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8205619">Thierfelder et al. (1994)</a> found that the clinical disorder was linked to a T-to-C polymorphism at nucleotide 330 of the cDNA of cardiac troponin T. Furthermore, they showed that affected individuals had 2 aberrant splice products. A change from GT to AT in the exon 15 splice donor site resulted in skipping of exon 15 and a shorter cardiac troponin T cDNA. Activation of a cryptic splice site in intron 15 caused the insertion of the first 13 nucleotides of intron 15 into the cDNA sequence and resulted in the longer product. The mutation was identified in all affected adults in family AU and in 3 clinically unaffected adults who were known to carry the disease haplotype at multiple polymorphic markers. It was not present in other clinically unaffected adults or in over 200 chromosomes 1 derived from unrelated normal individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8205619+7981753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The other mutations in the TNNT2 gene and in alpha-tropomyosin that had been demonstrated as causes of CMH were missense mutations. This mutation is expected to cause a truncated TnT peptide lacking the conserved C terminus. <a href="#43" class="mim-tip-reference" title="Watkins, H., Seidman, C. E., Seidman, J. G., Feng, H. S., Sweeney, H. L. <strong>Expression and functional assessment of a truncated cardiac troponin T that causes hypertrophic cardiomyopathy: evidence for a dominant negative action.</strong> J. Clin. Invest. 98: 2456-2461, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8958207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8958207</a>] [<a href="https://doi.org/10.1172/JCI119063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8958207">Watkins et al. (1996)</a> devised a series of experiments designed to test whether the mutated TNNT2 functioned as a null allele or produced a 'poison peptide.' The missense mutations all result in altered polypeptides which, after they incorporate into the sarcomere, are dominant over the normal protein encoded by the remaining, wildtype allele. <a href="#43" class="mim-tip-reference" title="Watkins, H., Seidman, C. E., Seidman, J. G., Feng, H. S., Sweeney, H. L. <strong>Expression and functional assessment of a truncated cardiac troponin T that causes hypertrophic cardiomyopathy: evidence for a dominant negative action.</strong> J. Clin. Invest. 98: 2456-2461, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8958207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8958207</a>] [<a href="https://doi.org/10.1172/JCI119063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8958207">Watkins et al. (1996)</a> used a quail myoblast-to-myotube system in which the mutant cardiac troponin was expressed and thereby determined the functional consequences. The data showed that the mutated gene is not a null allele but rather produces a stable, truncated polypeptide that accumulates in the myotube and is subsequently incorporated into the sarcomere. This protein displayed a dominant-negative effect on sarcomeric function, as evidenced by greatly diminished force production, even when it was coexpressed with the wildtype sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8958207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0004" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
TNNT2, ARG278CYS
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121964857 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121964857;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121964857?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121964857" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121964857" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013222 OR RCV000036622 OR RCV000148898 OR RCV000157540 OR RCV000159322 OR RCV000162331 OR RCV000203739 OR RCV000248304 OR RCV000755702 OR RCV000768493 OR RCV000771167" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013222, RCV000036622, RCV000148898, RCV000157540, RCV000159322, RCV000162331, RCV000203739, RCV000248304, RCV000755702, RCV000768493, RCV000771167" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013222...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p><a href="#42" class="mim-tip-reference" title="Watkins, H., McKenna, W. J., Thierfelder, L., Suk, H. J., Anan, R., O'Donoghue, A., Spirito, P., Matsumori, A., Moravec, C. S., Seidman, J. G., Seidman, C. E. <strong>Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy.</strong> New Eng. J. Med. 332: 1058-1064, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7898523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7898523</a>] [<a href="https://doi.org/10.1056/NEJM199504203321603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7898523">Watkins et al. (1995)</a> identified an arg278-to-cys mutation of the TNNT2 gene as a cause of familial hypertrophic cardiomyopathy (CMH2; <a href="/entry/115195">115195</a>). The mutation occurred in a C-terminal region of TNNT2 that is highly homologous to a C-terminal region of fast skeletal troponin T (TNNT3; <a href="/entry/600692">600692</a>) that had been shown to have an important role in tropomyosin binding and thus in the calcium ion regulation of contraction (<a href="#27" class="mim-tip-reference" title="Onoyama, Y., Ohtsuki, I. <strong>Effect of chymotryptic troponin T subfragments on the calcium ion-sensitivity of ATPase and superprecipitation of actomyosin.</strong> J. Biochem. 100: 517-519, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2946667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2946667</a>] [<a href="https://doi.org/10.1093/oxfordjournals.jbchem.a121742" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2946667">Onoyama and Ohtsuki, 1986</a>). <a href="#26" class="mim-tip-reference" title="Morimoto, S., Nakaura, H., Yanaga, F., Ohtsuki, I. <strong>Functional consequences of a carboxy terminal missense mutation arg278cys in human cardiac troponin T.</strong> Biochem. Biophys. Res. Commun. 261: 79-82, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10405326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10405326</a>] [<a href="https://doi.org/10.1006/bbrc.1999.1000" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10405326">Morimoto et al. (1999)</a> presented evidence that the C-terminal region of TNNT2 plays an important role, probably through its interaction with tropomyosin, in allowing troponin complex to inhibit the muscle contraction at low levels of calcium ion, in agreement with the hypothesis deduced from the previous studies on fast skeletal troponin T. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2946667+10405326+7898523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0005" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
TNNT2, PHE110ILE
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121964858 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121964858;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121964858" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121964858" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013223 OR RCV000223682 OR RCV000709767 OR RCV001804727 OR RCV003450627 OR RCV004802934" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013223, RCV000223682, RCV000709767, RCV001804727, RCV003450627, RCV004802934" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013223...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected members of a family with hypertrophic cardiomyopathy (CMH2; <a href="/entry/115195">115195</a>), <a href="#42" class="mim-tip-reference" title="Watkins, H., McKenna, W. J., Thierfelder, L., Suk, H. J., Anan, R., O'Donoghue, A., Spirito, P., Matsumori, A., Moravec, C. S., Seidman, J. G., Seidman, C. E. <strong>Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy.</strong> New Eng. J. Med. 332: 1058-1064, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7898523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7898523</a>] [<a href="https://doi.org/10.1056/NEJM199504203321603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7898523">Watkins et al. (1995)</a> identified a missense 340T-A transversion in the TNNT2 gene, resulting in a phe110-to-ile (F110I) substitution. <a href="#1" class="mim-tip-reference" title="Anan, R., Shono, H., Kisanuki, A., Arima, S., Nakao, S., Tanaka, H. <strong>Patients with familial hypertrophic cardiomyopathy caused by a phe110ile missense mutation in the cardiac troponin T gene have variable cardiac morphologies and a favorable prognosis.</strong> Circulation 98: 391-397, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9714088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9714088</a>] [<a href="https://doi.org/10.1161/01.cir.98.5.391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9714088">Anan et al. (1998)</a> found the same mutation in 6 of 46 unrelated Japanese probands with familial CMH. Haplotype analysis supported a founder effect in 2 families, whereas the others had independent mutations. The authors suggested that residue 340 in the TNNT2 gene may represent a mutation hotspot. There was considerable inter- and intra-familial phenotypic variability, with apical hypertrophy alone in 2 unrelated families. In contrast to other reported TNNT2 mutations, F110I appeared to show a favorable prognosis, with Kaplan-Meier product-limit survival curves similar to those seen in patients with phe513-to-cys beta-myosin heavy chain mutations (<a href="/entry/160760#0016">160760.0016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9714088+7898523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0006" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 CARDIOMYOPATHY, DILATED, 1D</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
TNNT2, LYS210DEL
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121964859 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121964859;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121964859" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121964859" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs45578238 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs45578238;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs45578238" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs45578238" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000036607 OR RCV000211868 OR RCV000223828 OR RCV000247384 OR RCV000524543 OR RCV001798105 OR RCV002051803 OR RCV003450713 OR RCV004737177" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000036607, RCV000211868, RCV000223828, RCV000247384, RCV000524543, RCV001798105, RCV002051803, RCV003450713, RCV004737177" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000036607...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated families with dilated cardiomyopathy (CMD1D; <a href="/entry/601494">601494</a>), <a href="#14" class="mim-tip-reference" title="Kamisago, M., Sharma, S. D., DePalma, S. R., Solomon, S., Sharma, P., McDonough, B., Smoot, L., Mullen, M. P., Woolf, P. K., Wigle, E. D., Seidman, J. G., Seidman, C. E. <strong>Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy.</strong> New Eng. J. Med. 343: 1688-1696, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11106718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11106718</a>] [<a href="https://doi.org/10.1056/NEJM200012073432304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11106718">Kamisago et al. (2000)</a> discovered a deletion of 3 nucleotides (AGA) of the cardiac troponin T gene. This deletion is predicted to eliminate 1 of 4 lysine residues encoded in tandem in exon 13 (designated lys210del, according to the numbering of <a href="#40" class="mim-tip-reference" title="Townsend, P. J., Farza, H., MacGeoch, C., Spurr, N. K., Wade, R., Gahlmann, R., Yacoub, M. H., Barton, P. J. R. <strong>Human cardiac troponin T: identification of fetal isoforms and assignment of the TNNT2 locus to chromosome 1q.</strong> Genomics 21: 311-316, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8088824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8088824</a>] [<a href="https://doi.org/10.1006/geno.1994.1271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8088824">Townsend et al. (1994)</a>). Haplotype analyses indicated that each mutation arose independently in these families. In one family, sudden death occurred in a 26- and a 27-year-old as well as in a 1- and an 8-month-old, both of whom had a clinical diagnosis of infantile cardiomyopathy. In the other family, a 19-year-old female had postpartum congestive heart failure, resulting in sudden death. A 17-year-old sister had died of congestive heart failure, and postmortem showed marked dilatation of the right and left ventricles with histologic findings of increased interstitial fibrosis without myocyte disarray. A nephew died of congestive heart failure at the age of 15 years; postmortem showed marked right ventricular dilatation and normal cardiac ultrastructure. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11106718+8088824" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 affected members of a family with CMD, <a href="#25" class="mim-tip-reference" title="Mogensen, J., Murphy, R. T., Shaw, T., Bahl, A., Redwood, C., Watkins, H., Burke, M., Elliott, P. M., McKenna, W. J. <strong>Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.</strong> J. Am. Coll. Cardiol. 44: 2033-2040, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15542288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15542288</a>] [<a href="https://doi.org/10.1016/j.jacc.2004.08.027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15542288">Mogensen et al. (2004)</a> identified heterozygosity for the lys120del mutation. The proband died at age 26 years from heart failure; his 2 brothers also had CMD, the younger undergoing cardiac transplantation at age 22 years. Their father had an unexplained sudden death at age 36 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15542288" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0007" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 CARDIOMYOPATHY, DILATED, 1D</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
TNNT2, ARG141TRP
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315379 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315379;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315379?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs74315380 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315380;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013225 OR RCV000157537 OR RCV000159296 OR RCV000211866 OR RCV000524542 OR RCV000710045 OR RCV001375512 OR RCV003450628 OR RCV003450629 OR RCV004991970" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013225, RCV000157537, RCV000159296, RCV000211866, RCV000524542, RCV000710045, RCV001375512, RCV003450628, RCV003450629, RCV004991970" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013225...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p><a href="#17" class="mim-tip-reference" title="Li, D., Czernuszewicz, G. Z., Gonzalez, O., Tapscott, T., Karibe, A., Durand, J.-B., Brugada, R., Hill, R., Gregoritch, J. M., Anderson, J. L., Quinones, M., Bachinski, L. L., Roberts, R. <strong>Novel cardiac troponin T mutation as a cause of familial dilated cardiomyopathy.</strong> Circulation 104: 2188-2193, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11684629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11684629</a>] [<a href="https://doi.org/10.1161/hc4301.098285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11684629">Li et al. (2001)</a> found a C-to-T transition at nucleotide position 471 of the TNNT2 gene, which was predicted to change the highly conserved basic amino acid arginine at residue 141 to the polar-neutral tryptophan (arg141 to trp; R141W). This sequence change cosegregated with dilated cardiomyopathy (CMD1D; <a href="/entry/601494">601494</a>) in the family, with 5 phenotypically normal mutation carriers in addition to 14 affected individuals. Evaluation of 200 control chromosomes and 219 individuals with familial hypertrophic cardiomyopathy failed to detect the variation, leading the authors to conclude that this was a pathogenic mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11684629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0008" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 CARDIOMYOPATHY, DILATED, 1D</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
LEFT VENTRICULAR NONCOMPACTION 6, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
TNNT2, ARG131TRP
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315379 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315379;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74315379?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs74315380 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315380;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74315380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013226 OR RCV000030567 OR RCV000159291 OR RCV000524541 OR RCV000588329 OR RCV003450630 OR RCV003450631" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013226, RCV000030567, RCV000159291, RCV000524541, RCV000588329, RCV003450630, RCV003450631" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013226...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Dilated Cardiomyopathy 1D</em></strong></p><p>
|
|
In a 28-year-old woman with dilated cardiomyopathy (CMD1D; <a href="/entry/601494">601494</a>), <a href="#25" class="mim-tip-reference" title="Mogensen, J., Murphy, R. T., Shaw, T., Bahl, A., Redwood, C., Watkins, H., Burke, M., Elliott, P. M., McKenna, W. J. <strong>Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.</strong> J. Am. Coll. Cardiol. 44: 2033-2040, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15542288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15542288</a>] [<a href="https://doi.org/10.1016/j.jacc.2004.08.027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15542288">Mogensen et al. (2004)</a> identified heterozygosity for an arg131-to-trp (R131W) substitution at a conserved residue in exon 10 of the TNNT2 gene. An older brother had died suddenly at 16 years of age; their mother had CMD and died of heart failure at 34 years of age. The mutation was not found in her unaffected older brother or father, or in 200 ethnically matched control chromosomes. Functional studies showed significant impairment of mutated troponin interaction compared with wildtype control, indicating an altered regulation of myocardial contractility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15542288" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Left Ventricular Noncompaction 6</em></strong></p><p>
|
|
In a 20-year-old woman who presented in cardiogenic shock and was diagnosed with isolated left ventricular noncompaction (LVNC6; see <a href="/entry/601494">601494</a>), <a href="#15" class="mim-tip-reference" title="Klaassen, S., Probst, S., Oechslin, E., Gerull, B., Krings, G., Schuler, P., Greutmann, M., Hurlimann, D., Yegibasi, M., Pons, L., Gramlich, M., Drenckhahn, J.-D., Heuser, A., Berger, F., Jenni, R., Thierfelder, L. <strong>Mutations in sarcomere protein genes in left ventricular noncompaction.</strong> Circulation 117: 2893-2901, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18506004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18506004</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.746164" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18506004">Klaassen et al. (2008)</a> identified heterozygosity for the R131W mutation in TNNT2. The patient had primarily midlateral and midinferior LVNC, left ventricular dilation, and impaired left ventricular systolic function. The de novo mutation was not present in her unaffected parents, and was not found in 360 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18506004" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Variant Function</em></strong></p><p>
|
|
<a href="#24" class="mim-tip-reference" title="Mirza, M., Marston, S., Willott, R., Ashley, C., Mogensen, J., McKenna, W., Robinson, P., Redwood, C., Watkins, H. <strong>Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype.</strong> J. Biol. Chem. 280: 28498-28506, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15923195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15923195</a>] [<a href="https://doi.org/10.1074/jbc.M412281200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15923195">Mirza et al. (2005)</a> studied the R131W mutation and found that thin filaments reconstituted with a 1:1 ratio of mutant:wildtype proteins showed reduced Ca(2+) sensitivity of activation in ATPase and motility assays and a lower maximum Ca(2+) activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15923195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0009" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 CARDIOMYOPATHY, DILATED, 1D</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
TNNT2, ARG205LEU
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121964860 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121964860;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121964860" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121964860" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013228" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013228" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013228</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 affected members of a 3-generation family with dilated cardiomyopathy (CMD1D; <a href="/entry/601494">601494</a>), <a href="#25" class="mim-tip-reference" title="Mogensen, J., Murphy, R. T., Shaw, T., Bahl, A., Redwood, C., Watkins, H., Burke, M., Elliott, P. M., McKenna, W. J. <strong>Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.</strong> J. Am. Coll. Cardiol. 44: 2033-2040, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15542288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15542288</a>] [<a href="https://doi.org/10.1016/j.jacc.2004.08.027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15542288">Mogensen et al. (2004)</a> identified heterozygosity for an arg205-to-leu (R205L) substitution at a conserved residue in exon 13 of the TNNT2 gene. The proband, who underwent cardiac transplantation at 16 years of age, had a younger sister with CMD who died of heart failure at age 20 years. Their affected mother was alive at 48 years of age; their maternal grandmother had an unexplained sudden death at 24 years of age. The mutation was not found in 2 younger unaffected sisters or the unaffected maternal grandfather, or in 200 ethnically matched control chromosomes. Functional studies showed significant impairment of mutated troponin interaction compared with wildtype control, indicating an altered regulation of myocardial contractility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15542288" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0010" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 CARDIOMYOPATHY, DILATED, 1D</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
TNNT2, ASP270ASN
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121964861 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121964861;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121964861?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121964861" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121964861" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013229 OR RCV001851816 OR RCV002415410 OR RCV003450632 OR RCV003450633 OR RCV004802935" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013229, RCV001851816, RCV002415410, RCV003450632, RCV003450633, RCV004802935" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013229...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected members of a family with dilated cardiomyopathy (CMD1D; <a href="/entry/601494">601494</a>), <a href="#25" class="mim-tip-reference" title="Mogensen, J., Murphy, R. T., Shaw, T., Bahl, A., Redwood, C., Watkins, H., Burke, M., Elliott, P. M., McKenna, W. J. <strong>Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.</strong> J. Am. Coll. Cardiol. 44: 2033-2040, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15542288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15542288</a>] [<a href="https://doi.org/10.1016/j.jacc.2004.08.027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15542288">Mogensen et al. (2004)</a> identified heterozygosity for an asp270-to-asn (D270N) substitution at a conserved residue in exon 15 of the TNNT2 gene. The proband underwent cardiac transplantation at 38 years of age and died at age 44; his affected son was alive at 21 years of age. The mutation was not found in 2 unaffected children or in 200 ethnically matched control chromosomes. Functional studies showed significant impairment of mutated troponin interaction compared with wildtype control, indicating an altered regulation of myocardial contractility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15542288" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0011" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 CARDIOMYOPATHY, FAMILIAL, RESTRICTIVE, 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
TNNT2, 3-BP DEL, 285GGA
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs727504277 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs727504277;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs727504277" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs727504277" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000154282 OR RCV003388923" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000154282, RCV003388923" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000154282...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Restrictive Cardiomyopathy 3</em></strong></p><p>
|
|
In a 12-month-old girl with restrictive cardiomyopathy (RCM3; <a href="/entry/612422">612422</a>), <a href="#28" class="mim-tip-reference" title="Peddy, S. B., Vricella, L. A., Crosson, J. E., Oswald, G. L., Cohn, R. D., Cameron, D. E., Valle, D., Loeys, B. L. <strong>Infantile restrictive cardiomyopathy resulting from a mutation in the cardiac troponin T gene.</strong> Pediatrics 117: 1830-1833, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16651346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16651346</a>] [<a href="https://doi.org/10.1542/peds.2005-2301" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16651346">Peddy et al. (2006)</a> identified a 3-bp deletion (285delGGA) in exon 9 the TNNT2 gene, resulting in the deletion of glutamic acid at codon 96 (glu96del) in a highly conserved segment of the main tropomyosin-binding region in the N-terminal half of troponin T. The deletion was not found in either parent, who had normal echocardiograms at ages 28 and 34 years, respectively. The girl also carried a known MYBPC3 (<a href="/entry/600958">600958</a>) polymorphism, V896M, which was also found in her unaffected father; the authors suggested that the V896M variant may have acted as a modifier, exacerbating the phenotypic expression of the TNNT2 mutation and causing an unusually early onset of RMC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16651346" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Variant Function</em></strong></p><p>
|
|
<a href="#29" class="mim-tip-reference" title="Pinto, J. R., Parvatiyar, M. S., Jones, M. A., Liang, J., Potter, J. D. <strong>A troponin T mutation that causes infantile restrictive cardiomyopathy increases Ca(2+) sensitivity of force development and impairs the inhibitory properties of troponin.</strong> J. Biol. Chem. 283: 2156-2166, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18032382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18032382</a>] [<a href="https://doi.org/10.1074/jbc.M707066200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18032382">Pinto et al. (2008)</a> analyzed the effects of the 3-bp TNNT2 deletion in both the adult and fetal human cardiac TNNT2 isoforms, in order to evaluate the disease progression after birth when the isoform switch occurs. Both mutant isoforms showed a large increase in Ca(2+) sensitivity compared to their respective wildtypes, but there was no significant change in force recovery in any of the experiments. Both mutants showed an impaired ability to inhibit actomyosin ATPase activity, and the capacity of troponin complexes to fully relax fibers after troponin T displacement was also compromised. Experiments with fetal troponin isoforms showed a less severe impact compared with adult isoforms, consistent with a cardioprotective role for slow skeletal isoforms and with the rapid onset of RCM after birth following the isoform switch. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18032382" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0012" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 LEFT VENTRICULAR NONCOMPACTION 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
TNNT2, GLU96LYS
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs869312881 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869312881;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs869312881" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs869312881" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000210349 OR RCV001798699 OR RCV001853371 OR RCV004589904" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000210349, RCV001798699, RCV001853371, RCV004589904" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000210349...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 affected members across 3 generations of a family with left ventricular noncompaction of variable severity (LVNC6; <a href="/entry/601494">601494</a>), <a href="#20" class="mim-tip-reference" title="Luedde, M., Ehlermann, P., Weichenhan, D., Will, R., Zeller, R., Rupp, S., Muller, A, Steen, H., Ivandic, B. T., Ulmer, H. E., Kern, M., Katus, H. A., Frey, N. <strong>Severe familial left ventricular non-compaction cardiomyopathy due to a novel troponin T (TNNT2) mutation.</strong> Cardiovasc. Res. 86: 452-460, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20083571/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20083571</a>] [<a href="https://doi.org/10.1093/cvr/cvq009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20083571">Luedde et al. (2010)</a> identified heterozygosity for a G-A transition in exon 10 of the TNNT2 gene, resulting in a glu96-to-lys (E96K) substitution at a highly conserved residue. The mutation was not found in unaffected family members. Chorionic villus biopsy of a subsequent pregnancy in the family showed that the fetus carried the mutation, and soon after birth the infant boy showed clinical signs of heart failure as well as decreased left ventricular function on echocardiography. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20083571" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="references"class="mim-anchor"></a>
|
|
<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span class="mim-font">
|
|
<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div id="mimReferencesFold" class="collapse in mimTextToggleFold">
|
|
<ol>
|
|
|
|
<li>
|
|
<a id="1" class="mim-anchor"></a>
|
|
<a id="Anan1998" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Anan, R., Shono, H., Kisanuki, A., Arima, S., Nakao, S., Tanaka, H.
|
|
<strong>Patients with familial hypertrophic cardiomyopathy caused by a phe110ile missense mutation in the cardiac troponin T gene have variable cardiac morphologies and a favorable prognosis.</strong>
|
|
Circulation 98: 391-397, 1998.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9714088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9714088</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9714088" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1161/01.cir.98.5.391" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="2" class="mim-anchor"></a>
|
|
<a id="Anderson1995" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Anderson, P. A. W., Greig, A., Mark, T. M., Malouf, N. N., Oakeley, A. E., Ungerleider, R. M., Allen, P. D., Kay, B. K.
|
|
<strong>Molecular basis of human cardiac troponin T isoforms expressed in the developing, adult, and failing heart.</strong>
|
|
Circ. Res. 76: 681-686, 1995.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7534662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7534662</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7534662" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1161/01.res.76.4.681" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="3" class="mim-anchor"></a>
|
|
<a id="Aviles2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Aviles, R. J., Askari, A. T., Lindahl, B., Wallentin, L., Jia, G., Ohman, E. M., Mahaffey, K. W., Newby, L. K., Califf, R. M., Simoons, M. L., Topol, E. J., Lauer, M. S.
|
|
<strong>Troponin T levels in patients with acute coronary syndromes, with or without renal dysfunction.</strong>
|
|
New Eng. J. Med. 346: 2047-2052, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12087140/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12087140</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12087140" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1056/NEJMoa013456" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="4" class="mim-anchor"></a>
|
|
<a id="Benamer1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Benamer, H., Steg, P. G., Benessiano, J., Vicaut, E., Gaultier, C. J., Aubry, P., Boudvillain, O., Sarfati, L., Brochet, E., Feldman, L. J., Himbert, D., Juliard, J.-M., Assayag, P.
|
|
<strong>Elevated cardiac troponin I predicts a high-risk angiographic anatomy of the culprit lesion in unstable angina.</strong>
|
|
Am. Heart J. 137: 815-820, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10220629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10220629</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10220629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/s0002-8703(99)70404-7" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="5" class="mim-anchor"></a>
|
|
<a id="Charlet-B2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Charlet-B, N., Logan, P., Singh, G., Cooper, T. A.
|
|
<strong>Dynamic antagonism between ETR-3 and PTB regulates cell type-specific alternative splicing.</strong>
|
|
Molec. Cell 9: 649-658, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11931771/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11931771</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11931771" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/s1097-2765(02)00479-3" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="6" class="mim-anchor"></a>
|
|
<a id="Du2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Du, C.-K., Morimoto, S., Nishii, K., Minakami, R., Ohta, M., Tadano, N., Lu, Q.-W., Wang, Y.-Y., Zhan, D.-Y., Mochizuki, M., Kita, S., Miwa, Y., Takahashi-Yanaga, F., Iwamoto, T., Ohtsuki, I., Sasaguri, T.
|
|
<strong>Knock-in mouse model of dilated cardiomyopathy caused by troponin mutation.</strong>
|
|
Circ. Res. 101: 185-194, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17556660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17556660</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17556660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1161/CIRCRESAHA.106.146670" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="7" class="mim-anchor"></a>
|
|
<a id="Durand1995" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Durand, J.-B., Bachinski, L. L., Bieling, L. C., Czernuszewicz, G. Z., Abchee, A. B., Yu, Q. T., Tapscott, T., Hill, R., Ifegwu, J., Marian, A. J., Brugada, R., Daiger, S., Gregoritch, J. M., Anderson, J. L., Quinones, M., Towbin, J. A., Roberts, R.
|
|
<strong>Localization of a gene responsible for familial dilated cardiomyopathy to chromosome 1q32.</strong>
|
|
Circulation 92: 3387-3389, 1995.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8521556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8521556</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8521556" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1161/01.cir.92.12.3387" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="8" class="mim-anchor"></a>
|
|
<a id="Farza1998" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Farza, H., Townsend, P. J., Carrier, L., Barton, P. J., Mesnard, L., Bahrend, E., Forissier, J.-F., Fiszman, M., Yacoub, M. H., Schwartz, K.
|
|
<strong>Genomic organisation, alternative splicing and polymorphisms of the human cardiac troponin T gene.</strong>
|
|
J. Molec. Cell. Cardiol. 30: 1247-1253, 1998.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9689598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9689598</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9689598" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1006/jmcc.1998.0698" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="9" class="mim-anchor"></a>
|
|
<a id="Hamm1992" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Hamm, C. W., Ravkilde, J., Gerhardt, W., Jorgensen, P., Peheim, E., Ljungdahl, L., Goldmann, B., Katus, H. A.
|
|
<strong>The prognostic value of serum troponin T in unstable angina.</strong>
|
|
New Eng. J. Med. 327: 146-150, 1992.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1290492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1290492</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1290492" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1056/NEJM199207163270302" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="10" class="mim-anchor"></a>
|
|
<a id="Harada2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Harada, K., Potter, J. D.
|
|
<strong>Familial hypertrophic cardiomyopathy mutations from different functional regions of troponin T result in different effects on the pH and Ca(2+) sensitivity of cardiac muscle contraction.</strong>
|
|
J. Biol. Chem. 279: 14488-14495, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14722098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14722098</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14722098" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1074/jbc.M309355200" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="11" class="mim-anchor"></a>
|
|
<a id="Heeschen1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Heeschen, C., van Den Brand, M. J., Hamm, C. W., Simoons, M. L.
|
|
<strong>Angiographic findings in patients with refractory unstable angina according to troponin T status.</strong>
|
|
Circulation 100: 1509-1514, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10510053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10510053</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10510053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1161/01.cir.100.14.1509" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="12" class="mim-anchor"></a>
|
|
<a id="Hernandez2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Hernandez, O. M., Szczesna-Cordary, D., Knollmann, B. C., Miller, T., Bell, M., Zhao, J., Sirenko, S. G., Diaz, Z., Guzman, G., Xu, Y., Wang, Y., Kerrick, W. G. L., Potter, J. D.
|
|
<strong>F110I and R278C troponin T mutations that cause familial hypertrophic cardiomyopathy affect muscle contraction in transgenic mice and reconstituted human cardiac fibers.</strong>
|
|
J. Biol. Chem. 280: 37183-37194, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16115869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16115869</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16115869" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1074/jbc.M508114200" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="13" class="mim-anchor"></a>
|
|
<a id="Javadpour2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Javadpour, M. M., Tardiff, J. C., Pinz, I., Ingwall, J. S.
|
|
<strong>Decreased energetics in murine hearts bearing the R92Q mutation in cardiac troponin T.</strong>
|
|
J. Clin. Invest. 112: 768-775, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12952925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12952925</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12952925[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12952925" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1172/JCI15967" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="14" class="mim-anchor"></a>
|
|
<a id="Kamisago2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Kamisago, M., Sharma, S. D., DePalma, S. R., Solomon, S., Sharma, P., McDonough, B., Smoot, L., Mullen, M. P., Woolf, P. K., Wigle, E. D., Seidman, J. G., Seidman, C. E.
|
|
<strong>Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy.</strong>
|
|
New Eng. J. Med. 343: 1688-1696, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11106718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11106718</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11106718" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1056/NEJM200012073432304" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="15" class="mim-anchor"></a>
|
|
<a id="Klaassen2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Klaassen, S., Probst, S., Oechslin, E., Gerull, B., Krings, G., Schuler, P., Greutmann, M., Hurlimann, D., Yegibasi, M., Pons, L., Gramlich, M., Drenckhahn, J.-D., Heuser, A., Berger, F., Jenni, R., Thierfelder, L.
|
|
<strong>Mutations in sarcomere protein genes in left ventricular noncompaction.</strong>
|
|
Circulation 117: 2893-2901, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18506004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18506004</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18506004" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.746164" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="16" class="mim-anchor"></a>
|
|
<a id="Knollmann2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Knollmann, B. C., Blatt, S. A., Horton, K., de Freitas, F., Miller, T., Bell, M., Housmans, P. R., Weissman, N. J., Morad, M., Potter, J. D.
|
|
<strong>Inotropic stimulation induces cardiac dysfunction in transgenic mice expressing a troponin T (I79N) mutation linked to familial hypertrophic cardiomyopathy.</strong>
|
|
J. Biol. Chem. 276: 10039-10048, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11113119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11113119</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11113119" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1074/jbc.M006745200" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="17" class="mim-anchor"></a>
|
|
<a id="Li2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Li, D., Czernuszewicz, G. Z., Gonzalez, O., Tapscott, T., Karibe, A., Durand, J.-B., Brugada, R., Hill, R., Gregoritch, J. M., Anderson, J. L., Quinones, M., Bachinski, L. L., Roberts, R.
|
|
<strong>Novel cardiac troponin T mutation as a cause of familial dilated cardiomyopathy.</strong>
|
|
Circulation 104: 2188-2193, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11684629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11684629</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11684629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1161/hc4301.098285" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="18" class="mim-anchor"></a>
|
|
<a id="Lin1996" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Lin, D., Bobkova, A., Homsher, E., Tobacman, L. S.
|
|
<strong>Altered cardiac troponin T in vitro function in the presence of a mutation implicated in familial hypertrophic cardiomyopathy.</strong>
|
|
J. Clin. Invest. 97: 2842-2848, 1996.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8675696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8675696</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8675696" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1172/JCI118740" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="19" class="mim-anchor"></a>
|
|
<a id="Lindahl2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Lindahl, B., Diderholm, E., Lagerqvist, B., Venge, P., Wallentin, L.
|
|
<strong>Mechanisms behind the prognostic value of troponin T in unstable coronary artery disease: a FRISC II substudy.</strong>
|
|
J. Am. Coll. Cardiol. 38: 979-986, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11583868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11583868</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11583868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/s0735-1097(01)01501-7" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="20" class="mim-anchor"></a>
|
|
<a id="Luedde2010" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Luedde, M., Ehlermann, P., Weichenhan, D., Will, R., Zeller, R., Rupp, S., Muller, A, Steen, H., Ivandic, B. T., Ulmer, H. E., Kern, M., Katus, H. A., Frey, N.
|
|
<strong>Severe familial left ventricular non-compaction cardiomyopathy due to a novel troponin T (TNNT2) mutation.</strong>
|
|
Cardiovasc. Res. 86: 452-460, 2010.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20083571/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20083571</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20083571" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/cvr/cvq009" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="21" class="mim-anchor"></a>
|
|
<a id="Menon2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Menon, S. C., Michels, V. V., Pellikka, P. A., Ballew, J. D., Karst, M. L., Herron, K. J., Nelson, S. M., Rodeheffer, R. J., Olson, T. M.
|
|
<strong>Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology.</strong>
|
|
Clin. Genet. 74: 445-454, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18651846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18651846</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18651846[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18651846" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1111/j.1399-0004.2008.01062.x" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="22" class="mim-anchor"></a>
|
|
<a id="Mesnard1995" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Mesnard, L., Logeart, D., Taviaux, S., Diriong, S., Mercadier, J.-J., Samson, F.
|
|
<strong>Human cardiac troponin T: cloning and expression of new isoforms in the normal and failing heart.</strong>
|
|
Circ. Res. 76: 687-692, 1995.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7895342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7895342</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7895342" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1161/01.res.76.4.687" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="23" class="mim-anchor"></a>
|
|
<a id="Miller2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Miller, T., Szczesna, D., Housmans, P. R., Zhao, J., de Freitas, F., Gomes, A. V., Culbreath, L., McCue, J., Wang, Y., Xu, Y., Kerrick, W. G. L., Potter, J. D.
|
|
<strong>Abnormal contractile function in transgenic mice expressing a familial hypertrophic cardiomyopathy-linked troponin T (I79N) mutation.</strong>
|
|
J. Biol. Chem. 276: 3743-3755, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11060294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11060294</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11060294" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1074/jbc.M006746200" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="24" class="mim-anchor"></a>
|
|
<a id="Mirza2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Mirza, M., Marston, S., Willott, R., Ashley, C., Mogensen, J., McKenna, W., Robinson, P., Redwood, C., Watkins, H.
|
|
<strong>Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype.</strong>
|
|
J. Biol. Chem. 280: 28498-28506, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15923195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15923195</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15923195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1074/jbc.M412281200" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="25" class="mim-anchor"></a>
|
|
<a id="Mogensen2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Mogensen, J., Murphy, R. T., Shaw, T., Bahl, A., Redwood, C., Watkins, H., Burke, M., Elliott, P. M., McKenna, W. J.
|
|
<strong>Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.</strong>
|
|
J. Am. Coll. Cardiol. 44: 2033-2040, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15542288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15542288</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15542288" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/j.jacc.2004.08.027" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="26" class="mim-anchor"></a>
|
|
<a id="Morimoto1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Morimoto, S., Nakaura, H., Yanaga, F., Ohtsuki, I.
|
|
<strong>Functional consequences of a carboxy terminal missense mutation arg278cys in human cardiac troponin T.</strong>
|
|
Biochem. Biophys. Res. Commun. 261: 79-82, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10405326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10405326</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10405326" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1006/bbrc.1999.1000" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="27" class="mim-anchor"></a>
|
|
<a id="Onoyama1986" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Onoyama, Y., Ohtsuki, I.
|
|
<strong>Effect of chymotryptic troponin T subfragments on the calcium ion-sensitivity of ATPase and superprecipitation of actomyosin.</strong>
|
|
J. Biochem. 100: 517-519, 1986.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2946667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2946667</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2946667" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/oxfordjournals.jbchem.a121742" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="28" class="mim-anchor"></a>
|
|
<a id="Peddy2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Peddy, S. B., Vricella, L. A., Crosson, J. E., Oswald, G. L., Cohn, R. D., Cameron, D. E., Valle, D., Loeys, B. L.
|
|
<strong>Infantile restrictive cardiomyopathy resulting from a mutation in the cardiac troponin T gene.</strong>
|
|
Pediatrics 117: 1830-1833, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16651346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16651346</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16651346" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1542/peds.2005-2301" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="29" class="mim-anchor"></a>
|
|
<a id="Pinto2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Pinto, J. R., Parvatiyar, M. S., Jones, M. A., Liang, J., Potter, J. D.
|
|
<strong>A troponin T mutation that causes infantile restrictive cardiomyopathy increases Ca(2+) sensitivity of force development and impairs the inhibitory properties of troponin.</strong>
|
|
J. Biol. Chem. 283: 2156-2166, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18032382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18032382</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18032382" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1074/jbc.M707066200" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="30" class="mim-anchor"></a>
|
|
<a id="Rust1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Rust, E. M., Albayya, F. P., Metzger, J. M.
|
|
<strong>Identification of a contractile deficit in adult cardiac myocytes expressing hypertrophic cardiomyopathy-associated mutant troponin T proteins.</strong>
|
|
J. Clin. Invest. 103: 1459-1467, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10330428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10330428</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10330428[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10330428" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1172/JCI6377" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="31" class="mim-anchor"></a>
|
|
<a id="Sehnert2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Sehnert, A. J., Huq, A., Weinstein, B. M., Walker, C., Fishman, M., Stainier, D. Y. R.
|
|
<strong>Cardiac troponin T is essential in sarcomere assembly and cardiac contractility.</strong>
|
|
Nature Genet. 31: 106-110, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11967535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11967535</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11967535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/ng875" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="32" class="mim-anchor"></a>
|
|
<a id="Sweeney1998" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Sweeney, H. L., Feng, H. S., Yang, Z., Watkins, H.
|
|
<strong>Functional analyses of troponin T mutations that cause hypertrophic cardiomyopathy: insights into disease pathogenesis and troponin function.</strong>
|
|
Proc. Nat. Acad. Sci. 95: 14406-14410, 1998.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9826713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9826713</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9826713[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9826713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1073/pnas.95.24.14406" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="33" class="mim-anchor"></a>
|
|
<a id="Szczesna2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Szczesna, D., Zhang, R., Zhao, J., Jones, M., Guzman, G., Potter, J. D.
|
|
<strong>Altered regulation of cardiac muscle contraction by troponin T mutations that cause familial hypertrophic cardiomyopathy.</strong>
|
|
J. Biol. Chem. 275: 624-630, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10617660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10617660</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10617660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1074/jbc.275.1.624" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="34" class="mim-anchor"></a>
|
|
<a id="Takeda2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Takeda, S., Yamashita, A., Maeda, K., Maeda, Y.
|
|
<strong>Structure of the core domain of human cardiac troponin in the Ca(2+)-saturated form.</strong>
|
|
Nature 424: 35-41, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12840750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12840750</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12840750" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature01780" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="35" class="mim-anchor"></a>
|
|
<a id="Tardiff1998" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Tardiff, J. C., Factor, S. M., Tompkins, B. D., Hewett, T. E., Palmer, B. M., Moore, R. L., Schwartz, S., Robbins, J., Leinwand, L. A.
|
|
<strong>A truncated cardiac troponin T molecule in transgenic mice suggests multiple cellular mechanisms for familial hypertrophic cardiomyopathy.</strong>
|
|
J. Clin. Invest. 101: 2800-2811, 1998.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9637714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9637714</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9637714" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1172/JCI2389" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="36" class="mim-anchor"></a>
|
|
<a id="Tardiff1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Tardiff, J. C., Hewett, T. E., Palmer, B. M., Olsson, C., Factor, S. M., Moore, R. L., Robbins, J., Leinwand, L. A.
|
|
<strong>Cardiac troponin T mutations result in allele-specific phenotypes in a mouse model for hypertrophic cardiomyopathy.</strong>
|
|
J. Clin. Invest. 104: 469-481, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10449439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10449439</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10449439[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10449439" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1172/JCI6067" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="37" class="mim-anchor"></a>
|
|
<a id="Thierfelder1994" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Thierfelder, L., Watkins, H., MacRae, C., Lamas, R., McKenna, W., Vosberg, H.-P., Seidman, J. G., Seidman, C. E.
|
|
<strong>Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere.</strong>
|
|
Cell 77: 701-712, 1994.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8205619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8205619</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8205619" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/0092-8674(94)90054-x" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="38" class="mim-anchor"></a>
|
|
<a id="Tobacman1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Tobacman, L. S., Lin, D., Butters, C., Landis, C., Back, N., Pavlov, D., Homsher, E.
|
|
<strong>Functional consequences of troponin T mutations found in hypertrophic cardiomyopathy.</strong>
|
|
J. Biol. Chem. 274: 28363-28370, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10497196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10497196</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10497196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1074/jbc.274.40.28363" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="39" class="mim-anchor"></a>
|
|
<a id="Torbicki2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Torbicki, A., Kurzyna, M., Kuca, P., Fijalkowska, A., Sikora, J., Florczyk, M., Pruszczyk, P., Burakowski, J., Wawrzynska, L.
|
|
<strong>Detectable serum cardiac troponin T as a marker of poor prognosis among patients with chronic precapillary pulmonary hypertension.</strong>
|
|
Circulation 108: 844-848, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12900346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12900346</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12900346" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1161/01.CIR.0000084544.54513.E2" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="40" class="mim-anchor"></a>
|
|
<a id="Townsend1994" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Townsend, P. J., Farza, H., MacGeoch, C., Spurr, N. K., Wade, R., Gahlmann, R., Yacoub, M. H., Barton, P. J. R.
|
|
<strong>Human cardiac troponin T: identification of fetal isoforms and assignment of the TNNT2 locus to chromosome 1q.</strong>
|
|
Genomics 21: 311-316, 1994.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8088824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8088824</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8088824" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1006/geno.1994.1271" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="41" class="mim-anchor"></a>
|
|
<a id="Watkins1993" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Watkins, H., MacRae, C., Thierfelder, L., Chou, Y.-H., Frenneaux, M., McKenna, W., Seidman, J. G., Seidman, C. E.
|
|
<strong>A disease locus for familial hypertrophic cardiomyopathy maps to chromosome 1q3.</strong>
|
|
Nature Genet. 3: 333-337, 1993.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7981753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7981753</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7981753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/ng0493-333" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="42" class="mim-anchor"></a>
|
|
<a id="Watkins1995" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Watkins, H., McKenna, W. J., Thierfelder, L., Suk, H. J., Anan, R., O'Donoghue, A., Spirito, P., Matsumori, A., Moravec, C. S., Seidman, J. G., Seidman, C. E.
|
|
<strong>Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy.</strong>
|
|
New Eng. J. Med. 332: 1058-1064, 1995.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7898523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7898523</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7898523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1056/NEJM199504203321603" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="43" class="mim-anchor"></a>
|
|
<a id="Watkins1996" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Watkins, H., Seidman, C. E., Seidman, J. G., Feng, H. S., Sweeney, H. L.
|
|
<strong>Expression and functional assessment of a truncated cardiac troponin T that causes hypertrophic cardiomyopathy: evidence for a dominant negative action.</strong>
|
|
J. Clin. Invest. 98: 2456-2461, 1996.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8958207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8958207</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8958207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1172/JCI119063" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
</ol>
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="contributors" class="mim-anchor"></a>
|
|
|
|
<div class="row">
|
|
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
|
<span class="mim-text-font">
|
|
<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Marla J. F. O'Neill - updated : 9/9/2013
|
|
</span>
|
|
</div>
|
|
</div>
|
|
<div class="row collapse" id="mimCollapseContributors">
|
|
<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Marla J. F. O'Neill - updated : 6/7/2010<br>Marla J. F. O'Neill - updated : 3/5/2009<br>Patricia A. Hartz - updated : 1/30/2009<br>Marla J. F. O'Neill - updated : 12/2/2008<br>Marla J. F. O'Neill - updated : 11/20/2008<br>Marla J. F. O'Neill - updated : 3/7/2008<br>Marla J. F. O'Neill - updated : 3/6/2008<br>Marla J. F. O'Neill - updated : 3/30/2006<br>Marla J. F. O'Neill - updated : 10/20/2004<br>Marla J. F. O'Neill - updated : 5/7/2004<br>Ada Hamosh - updated : 7/7/2003<br>Victor A. McKusick - updated : 4/17/2003<br>Stylianos E. Antonarakis - updated : 9/23/2002<br>Victor A. McKusick - updated : 7/1/2002<br>Victor A. McKusick - updated : 5/6/2002<br>Paul Brennan - updated : 4/29/2002<br>Paul J. Converse - updated : 5/14/2001<br>Victor A. McKusick - updated : 4/12/2001<br>Victor A. McKusick - updated : 1/4/2001<br>Paul Brennan - updated : 2/18/2000<br>Victor A. McKusick - updated : 1/13/2000<br>Victor A. McKusick - updated : 11/8/1999<br>Victor A. McKusick - updated : 10/26/1999<br>Victor A. McKusick - updated : 7/6/1999<br>Victor A. McKusick - updated : 12/10/1998<br>Victor A. McKusick - updated : 9/3/1998<br>Alan F. Scott - updated : 7/27/1995
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="creationDate" class="mim-anchor"></a>
|
|
<div class="row">
|
|
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
|
<span class="text-nowrap mim-text-font">
|
|
Creation Date:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Victor A. McKusick : 6/17/1994
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="editHistory" class="mim-anchor"></a>
|
|
|
|
<div class="row">
|
|
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
|
<span class="text-nowrap mim-text-font">
|
|
<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
carol : 07/13/2023
|
|
</span>
|
|
</div>
|
|
</div>
|
|
<div class="row collapse" id="mimCollapseEditHistory">
|
|
<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
carol : 01/11/2023<br>carol : 01/10/2023<br>carol : 03/28/2016<br>tpirozzi : 9/9/2013<br>terry : 11/3/2010<br>terry : 9/9/2010<br>carol : 6/7/2010<br>wwang : 3/9/2009<br>terry : 3/5/2009<br>mgross : 1/30/2009<br>wwang : 12/4/2008<br>wwang : 12/3/2008<br>terry : 12/2/2008<br>carol : 11/20/2008<br>terry : 11/20/2008<br>carol : 3/7/2008<br>carol : 3/6/2008<br>wwang : 4/3/2006<br>terry : 3/30/2006<br>joanna : 1/20/2006<br>carol : 10/20/2004<br>carol : 5/7/2004<br>carol : 5/7/2004<br>terry : 5/7/2004<br>joanna : 9/30/2003<br>terry : 7/31/2003<br>alopez : 7/9/2003<br>alopez : 7/9/2003<br>terry : 7/7/2003<br>tkritzer : 4/24/2003<br>terry : 4/17/2003<br>mgross : 9/23/2002<br>cwells : 7/3/2002<br>terry : 7/1/2002<br>alopez : 5/6/2002<br>alopez : 5/6/2002<br>alopez : 4/29/2002<br>alopez : 4/29/2002<br>alopez : 4/26/2002<br>carol : 12/19/2001<br>mgross : 5/14/2001<br>mcapotos : 4/18/2001<br>terry : 4/12/2001<br>carol : 1/11/2001<br>cwells : 1/11/2001<br>cwells : 1/10/2001<br>cwells : 1/10/2001<br>terry : 1/4/2001<br>terry : 1/4/2001<br>alopez : 2/21/2000<br>alopez : 2/18/2000<br>mcapotos : 1/14/2000<br>mcapotos : 1/14/2000<br>mcapotos : 1/14/2000<br>terry : 1/13/2000<br>mgross : 11/8/1999<br>carol : 10/28/1999<br>terry : 10/26/1999<br>jlewis : 7/15/1999<br>terry : 7/6/1999<br>carol : 12/16/1998<br>terry : 12/10/1998<br>alopez : 9/16/1998<br>dkim : 9/11/1998<br>carol : 9/3/1998<br>terry : 6/1/1998<br>mark : 12/26/1996<br>terry : 12/17/1996<br>mark : 5/9/1995<br>carol : 6/21/1994<br>jason : 6/17/1994
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div class="container visible-print-block">
|
|
|
|
<div class="row">
|
|
|
|
|
|
|
|
<div class="col-md-8 col-md-offset-1">
|
|
|
|
<div>
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
<strong>*</strong> 191045
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
TROPONIN T2, CARDIAC; TNNT2
|
|
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: TNNT2</em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 1q32.1
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 1:201,359,014-201,377,680 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
1q32.1
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Cardiomyopathy, dilated, 1D
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
601494
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Cardiomyopathy, familial restrictive, 3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
612422
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Cardiomyopathy, hypertrophic, 2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
115195
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Left ventricular noncompaction 6
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
601494
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>The troponin complex is located on the thin filament of striated muscle and is composed of 3 component polypeptides: troponin T (TNNT1, 191041; TNNT2), troponin I (TNNI1, 191042; TNNI2, 191043; TNNI3, 191044), and troponin C (TNNC, 191040; 191039). Three troponin T genes have been described on the basis of molecular cloning in humans and other vertebrates. These are expressed in a tissue-specific manner and encode the troponin T isoforms expressed in cardiac muscle, slow skeletal muscle (TNNT1), and fast skeletal muscle (TNNT3; 600692). Each of these genes is subject to alternative splicing, resulting in the production of multiple tissue-specific isoforms.</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Townsend et al. (1994) cloned cDNAs encoding human cardiac troponin T from adult heart and used these to demonstrate that multiple cardiac troponin T mRNAs are present in the human fetal heart, resulting from alternative splicing in the 5-prime coding region of the gene. Hybridization of the cloned cDNAs to genomic DNA identified a single-copy gene. </p><p>Farza et al. (1998) determined that various TNNT2 isoforms are produced through the use of alternative acceptor sites and alternatively splicing of exons 4, 5, 10, and 13. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Biochemical Features</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Crystal Structure</em></strong></p><p>
|
|
Takeda et al. (2003) presented the crystal structure of the core domains (relative molecular mass of 46,000 and 52,000) of human cardiac troponin in the calcium-saturated form. Analysis of the 4-molecule structures revealed that the core domain is further divided into structurally distinct subdomains that are connected by flexible linkers, making the entire molecule highly flexible. The alpha-helical coiled-coil formed between TnT (troponin T) and TnI is integrated in a rigid and asymmetric structure about 80 angstroms long, the IT arm, which bridges putative tropomyosin (see 191010)-anchoring regions. The structures of the troponin ternary complex imply that calcium binding to the regulatory site of TnC removes the carboxy-terminal portion of TnI from actin, thereby altering the mobility and/or flexibility of troponin and tropomyosin on the actin filament. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Farza et al. (1998) determined that the TNNT2 gene contains 17 exons and spans 17 kb. The upstream region contains CACCC boxes and binding sites for NKX2-5 (600584) and GATA factors (see GATA1; 305371). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>TNNT2 Gene</em></strong></p><p>
|
|
Using somatic cell hybrid analysis, Townsend et al. (1994) mapped the TNNT2 gene to 1q. Mesnard et al. (1995) used fluorescence in situ hybridization to refine the map position to 1q32. Thierfelder et al. (1994) mapped the cardiac troponin T gene to chromosome 1q by PCR amplification of DNA derived from somatic human/Chinese hamster cell hybrids. </p><p><strong><em>Linkage to Cardiomyopathy Phenotypes</em></strong></p><p>
|
|
Thierfelder et al. (1994) used a T-to-C polymorphism at cDNA nucleotide 330 to assess linkage between hypertrophic cardiomyopathy (CMH2; 115195) and the cardiac troponin T gene in 1 large family and observed a maximum 2-point lod score of 6.3 at theta = 0.0. </p><p>Durand et al. (1995) reported a family with dilated cardiomyopathy, designated CMD1D (601494), showing linkage to chromosome 1q32 where the TNNT2 gene maps. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Anderson et al. (1995) and Mesnard et al. (1995) each described multiple isoforms of cardiac troponin T that result from alternative splicing of adjacent 15-bp and 30-bp mini-exons in the 5-prime half of the coding region. Isoform cTnT1 contains both exons, cTnT2 lacks the 15-bp exon, cTnT3 lacks the 30-bp exon, and cTnT4 is missing them both. </p><p>Inclusion of cardiac troponin T exon 5 in embryonic muscle requires conserved flanking intronic elements (MSEs). Charlet-B et al. (2002) found that ETR3 (CUGBP2; 602538), a member of the CELF family, binds U/G motifs in 2 MSEs and directly activates exon inclusion in vitro. They showed that binding and activation by ETR3 are directly antagonized by polypyrimidine tract-binding protein (PTB; 600693). The use of dominant-negative mutants demonstrated that endogenous CELF and PTB activities are required for MSE-dependent activation and repression in muscle and nonmuscle cells, respectively. Combined use of CELF and PTB dominant-negative mutants provided an in vivo demonstration that antagonistic splicing activities exist within the same cells. </p><p>Because it is not normally found in blood, cardiac troponin T in serum is a more sensitive indicator of myocardial cell injury than is serum creatine kinase MB activity, and its detection in the circulation may be a useful prognostic indicator in patients with unstable angina (Hamm et al., 1992). </p><p>Sensitive and specific markers of myocardial cell necrosis, notably cardiac troponins, are valuable tools in the evaluation of patients with acute coronary syndromes. Troponins are not actively involved in the pathophysiology of acute coronary syndromes and, instead, represent a surrogate marker for the formation of fragile thrombi (Benamer et al., 1999; Heeschen et al., 1999; Lindahl et al., 2001). </p><p>Aviles et al. (2002) demonstrated that cardiac troponin T levels predict short-term prognosis in patients with acute coronary syndromes regardless of the level of creatinine clearance in the patient. The study had been undertaken because of concern that renal dysfunction might impair the prognostic value of the assay, because cardiac troponin T may be cleared by the kidney. </p><p>In 56 patients with chronic precapillary pulmonary hypertension, Torbicki et al. (2003) found that those with detectable cardiac troponin T had higher heart rates (p = 0.004), lower mixed venous oxygen saturation (p = 0.04), and higher serum N-terminal pro-B-type natriuretic peptide (600295) (p = 0.03); they also walked less during the 6-minute walk test (p = 0.02). Cumulative survival estimated by Kaplan-Meier curves was significantly worse at 24 months in cTnT-positive compared to cTnT-negative patients (log-rank test, p = 0.001), and multivariate analysis revealed cTnT status to be an independent marker of mortality. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Familial Hypertrophic Cardiomyopathy 2</em></strong></p><p>
|
|
Thierfelder et al. (1994) demonstrated that affected individuals from 3 unrelated families with the form of familial hypertrophic cardiomyopathy linked to 1q (CMH2; 115195) contained point mutations: missense mutations (ile79-to-asn, 191045.0001; arg92-to-gln, 191045.0002) in 2 of them and a mutation in the splice donor sequence of intron 15 in the third (191045.0003). The abnormalities were demonstrated by screening by RNase A protection assays followed by sequencing. </p><p>In a 3-generation family segregating autosomal dominant cardiomyopathy, in which the proband had a restrictive phenotype and relatives had clinical features of restrictive, hypertrophic, and/or dilated cardiomyopathy, Menon et al. (2008) performed targeted linkage analysis for 9 sarcomeric genes and identified heterozygosity for the I79N mutation in the TNNT2 gene (191045.0001) that segregated with the disease phenotype. The I79N mutation had previously been found in a family with CMH (Thierfelder et al., 1994). </p><p>Tardiff et al. (1998) stated that 9 mutations had been described in the TNNT2 gene that cause familial hypertrophic cardiomyopathy, including 7 missense mutations, a deletion of an internal amino acid, and a splice site mutation that would result in the loss of either the 14 or 28 C-terminal residues with the addition of 7 non-TNNT2 amino acids in the latter case. </p><p><strong><em>Familial Dilated Cardiomyopathy 1D</em></strong></p><p>
|
|
Kamisago et al. (2000) identified a mutation in the TNNT2 gene (191045.0006) as the cause of familial dilated cardiomyopathy (CMD1D; 601494). </p><p>Mirza et al. (2005) studied all 8 published mutations causing dilated cardiomyopathy (CMD), including 5 in the TNNT2 gene (lys210del, R141W, R131W, R205L, and D270N; 191045.0006-191045.0010, respectively), 2 in the TPM1 gene (E54K, 191010.0004; and E40K, 191010.0005), and 1 in the TNNC1 gene (G159D; 191040.0001). Thin filaments, reconstituted with a 1:1 ratio of mutant:wildtype proteins, all showed reduced Ca(2+) sensitivity of activation in ATPase and motility assays, and, except for the E54K alpha-tropomyosin mutant which showed no effect, all showed lower maximum Ca(2+) activation. Incorporation of the TNNT2 mutations R141W and R205L into skinned guinea pig cardiac trabeculae also decreased Ca(2+) sensitivity of force generation. Thus, diverse thin filament CMD mutations appeared to affect different aspects of regulatory function yet change contractility in a consistent manner. Mirza et al. (2005) stated that the CMD mutations depressed myofibrillar function, an effect opposite to that of CMH-causing thin filament mutations, and suggested that decreased contractility might trigger pathways that ultimately lead to the clinical phenotype. </p><p>Mogensen et al. (2004) analyzed the TNNT2 gene in 235 consecutive unrelated probands with dilated cardiomyopathy and identified 4 different mutations in 4 families, respectively (see 191045.0006 and 191045.0008-191045.0010). The mutations segregated with the disease in each family and were absent in 200 ethnically matched control chromosomes and 1,520 chromosomes from patients with hypertrophic cardiomyopathy. Functional studies showed significant impairment of mutated troponin interaction compared with wildtype control, indicating an altered regulation of myocardial contractility. </p><p><strong><em>Familial Restrictive Cardiomyopathy 3</em></strong></p><p>
|
|
In a 12-month-old girl with restrictive cardiomyopathy (RCM3; 612422), Peddy et al. (2006) performed direct sequencing of the 8 genes most commonly implicated in hypertrophic cardiomyopathy and identified a de novo 3-bp deletion in the TNNT2 gene (191045.0011). The girl also carried a known MYBPC3 (600958) polymorphism, V896M, which was also found in her unaffected father; the authors suggested that the V896M variant may have acted as a modifier, exacerbating the phenotypic expression of the TNNT2 mutation and causing an unusually early onset of RMC. </p><p><strong><em>Left Ventricular Noncompaction 6</em></strong></p><p>
|
|
In a 20-year-old woman with isolated left ventricular noncompaction (LVNC6; 601494), Klaassen et al. (2008) identified heterozygosity for the R131W missense mutation in the TNNT2 gene (191045.0008). </p><p>In a 3-generation family with autosomal dominant left ventricular noncompaction of variable severity, Luedde et al. (2010) analyzed 6 cardiomyopathy-associated genes and identified a heterozygous missense mutation (E96K; 191045.0012) that segregated fully with disease. Transgenic mice with the E96K mutation developed left ventricular dysfunction and showed induction of marker genes of heart failure, including ANF (NPPA; 108780), BNP (NPPB; 600295), and beta-MHC (MYH7; 160760), but LVNC was not observed. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Genotype/Phenotype Correlations</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Thierfelder et al. (1994) proposed that familial hypertrophic cardiomyopathy (CMH) is a disease of the sarcomere, since mutations in alpha-tropomyosin (TPM1; 191010), cardiac troponin T, and beta-myosin heavy chain (MYH7; 160760) all cause the same cardiac-specific phenotype (see their Figure 7). Because the cardiac troponin T isoform is not expressed in adult skeletal muscle, the tissue-specific effects of mutations in this thin filament protein were not unexpected. Although alpha-tropomyosin is expressed in many cell types, the mutations identified in exon 5 (191010.0001; 191010.0002) produce clinically significant disease only in heart muscle. As a generalization, Thierfelder et al. (1994) proposed that CMH-causing mutations act by altering the stoichiometry of sarcomere components and that changes in gene expression perturbing the stoichiometry of sarcomere components may be a mechanism for secondary cardiac hypertrophy in response to various stimuli such as hypertension. </p><p>Watkins et al. (1995) concluded that mutations in the cardiac troponin T gene account for approximately 15% of cases of familial hypertrophic cardiomyopathy among patients seen in referral centers. These mutations, like those in alpha-tropomyosin, are characterized by relatively mild and sometimes subclinical hypertrophy but a high incidence of sudden death. Genetic testing may therefore be especially important in this group. In their Figure 2, Watkins et al. (1995) diagrammed 8 mutations in the TNNT2 gene that cause CMH. </p><p>Although mutations in either of the cardiac sarcomeric proteins myosin heavy chain and cardiac troponin T (as well as others) cause dominantly inherited hypertrophic cardiomyopathy, patients with mutations in these 2 genes have distinct clinical characteristics (Tardiff et al., 1998). Those with MYH7 mutations demonstrate more significant and uniform cardiac hypertrophy and a variable frequency of sudden death. Patients with TNNT2 mutations generally exhibit mild or no cardiac hypertrophy, but a high frequency of sudden death at an early age. </p><p>Rust et al. (1999) stated that at least 7 different genetic loci had been identified as the cause of hypertrophic cardiomyopathy and that 11 mutations in the TNNT2 gene had been linked to CMH. Of these mutations, 9 were point mutations, 1 was a codon deletion that did not result in a frameshift, and 1 was a splice site mutation in intron 16 that was predicted to lead to production of a truncated protein. The 7 known disease genes share one common characteristic: they all encode key contractile or regulatory myofilament proteins. CMH is, therefore, a disease of cardiac sarcomere. To test the alternative molecular mechanisms of pathogenesis of troponin-related CMH, Rust et al. (1999) studied single adult cardiomyocytes into which TNNT2 cDNAs carrying the I79N (191045.0001) and R92Q (191045.0002) mutations were transferred. They tested the hypothesis that the mutant TnT proteins would be expressed and incorporated into the cardiac sarcomere and would behave as dominant-negative proteins to alter directly the calcium-activated force generation at the level of the single cardiac myocyte. They found that under identical experimental conditions, the ectopic expression of the mutant TnTs was significantly less (less than 8% of total) than that obtained with expression of wildtype TnT (approximately 35%) in the myocytes. Confocal imaging of immunolabeled TnT showed a regular periodic pattern of localization of the ectopic mutant protein that was no different from that in normal controls, suggesting that the mutant protein incorporation had no deleterious effects on sarcomere architecture. Direct measurements of isometric force production in single cardiac myocytes demonstrated marked desensitization of submaximal calcium-activated tension, with unchanged maximum tension generation in mutant TnT-expressing myocytes compared with control myocytes. Collectively, these results demonstrated an impaired expression of the mutant protein and a disabling of cardiac contraction in the submaximal range of myoplasmic calcium concentrations. The functional results suggested that the development of new pharmacologic, chemical, or genetic approaches to sensitize the thin-filament regulatory protein system could ameliorate force deficits associated with expression of each of these 2 mutants in adult cardiac myocytes. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Lin et al. (1996) studied the in vitro function of troponin containing an I91N mutation in rat cardiac TnT, corresponding to the human I79N mutation (191045.0001) that causes familial hypertrophic cardiomyopathy (115195). The mutation had no effect on troponin's affinity for tropomyosin, troponin-induced binding of tropomyosin to actin, cooperative binding of myosin subfragment 1 to the thin filament, Ca(2+)-sensitive regulation of thin filament-myosin subfragment 1 ATPase activity, or the Ca(2+) concentration dependence of this regulation. However, in vitro motility assays showed that the mutation resulted in 50% faster thin filament movement over a surface coated with heavy meromyosin, suggesting an unexpected role for the N-terminal region of TnT in which this mutation occurs. </p><p>By creating transgenic mice expressing a Tnnt2 allele with a C-terminal truncation, Tardiff et al. (1998) showed that mice expressing the truncated protein at low (less than 5%) levels developed cardiomyopathy and that their hearts were significantly smaller than wildtype. These animals also exhibited significant diastolic dysfunction and milder systolic dysfunction. Animals expressing higher levels of transgene protein died within 24 hours of birth. Transgenic mouse hearts demonstrated myocellular disarray and had a reduced number of cardiac myocytes that were smaller in size. </p><p>To ascertain the contractile phenotype resulting from mutations in the TNNT2 gene, either wildtype or mutant (ile79 to asn, arg92 to gln, or delta-glu160), human cardiac TNT cDNA constructs were transfected into quail myotubes for structural and contractile characterization by Sweeney et al. (1998). All 3 mutants were found to decrease the calcium sensitivity of force production and the 2 missense mutations, I79N and R92Q, increased the unloaded shortening velocity nearly 2-fold. The data demonstrated that troponin T can alter the rate of myosin cross-bridge detachment, and thus the troponin complex plays a greater role in modulating muscle contractile performance than was previously recognized. The data suggested that these troponin T mutations may cause disease via an increased energetic load on the heart. This would represent a second paradigm for the pathogenesis of hypertrophic cardiomyopathy, the other being a dominant-negative effect of the mutant allele that blocks calcium activation of the thin filament. </p><p>Several mutations in cardiac troponin T can cause familial hypertrophic cardiomyopathy. However, patients with TNNT2 mutations generally exhibit mild or no ventricular hypertrophy, yet demonstrate a high frequency of early sudden death. To understand the functional basis of these phenotypes, Tardiff et al. (1999) created transgenic mouse lines expressing 30%, 67%, and 92% of their total cardiac troponin as a missense allele analogous to one found in CMH: R92Q (191045.0002). Similar to a mouse CMH model expressing a truncated TNNT2 protein, the left ventricles of all R92Q lines were smaller than those of wildtype. In striking contrast to truncation mice, however, the R92Q hearts demonstrated significant induction of atrial natriuretic factor and beta-myosin heavy chain (160760) transcripts, interstitial fibrosis, and mitochondrial pathology. Isolated cardiac myocytes from R92Q mice had increased basal sarcomeric activation, impaired relaxation, and shorter sarcomere lengths. Isolated working heart data were consistent, showing hypercontractility and diastolic dysfunction, both of which are common findings in patients with CMH. These mice represented the first disease model to exhibit hypercontractility, as well as a unique model system for exploring the cellular pathogenesis of CMH. The distinct phenotypes of mice with different TnT alleles suggested that the clinical heterogeneity of CMH is at least partially due to allele-specific mechanisms. </p><p>Tobacman et al. (1999) introduced 5 mutations known to cause familial hypertrophic cardiomyopathy into bovine cardiac troponin T and found diverse functional defects: F110I (191045.0005), E244D, and C-terminal truncation weakened the affinity of troponin for the thin filament; deletion of glu160 resulted in thin filaments with increased calcium affinity at the regulatory site of troponin C (191040); and R92Q and F110I resulted in impaired troponin solubility, suggesting abnormal protein folding. Depending on the mutation, the in vitro unloaded actin-myosin sliding speed showed small increases, small decreases, or was unchanged. C-terminal truncation resulted in a decreased thin filament myosin subfragment 1 MgATPase rate. Tobacman et al. (1999) noted that these mutations cause diverse immediate effects despite similarities in disease manifestations. Separable but repeatedly observed abnormalities resulting from CMH-related TnT mutations included increased unloaded sliding speed, increased or decreased Ca(2+) affinity, impairment of folding or sarcomeric integrity, and decreased force. Enhancement as well as impairment of contractile protein function was observed, suggesting that TnT, including the troponin tail region, modulates the regulation of cardiac contraction. </p><p>In transgenic mice with the R92Q mutation, Javadpour et al. (2003) simultaneously measured cardiac energetics and contractile performance of the intact beating heart and found both a decrease in the free energy of ATP hydrolysis available to support contractile work and a marked inability to increase contractile performance upon acute inotropic challenge. Javadpour et al. (2003) concluded that alterations in thin filament protein structure and function can lead to significant defects in myocardial energetics and contractile reserve. </p><p>To study the effect of troponin T mutations that cause familial hypertrophic cardiomyopathy on cardiac muscle contraction, Szczesna et al. (2000) cloned and expressed the wildtype and several TNNT2 mutants, including I79N, R92Q, and R278C (191045.0004). These mutants were reconstituted into skinned porcine cardiac muscle preparations and characterized for their effect on maximal steady-state force activation, inhibition, and the Ca(2+) sensitivity of force development. Szczesna et al. (2000) observed changes in the Ca(2+) regulation of force development caused by these mutations. They interpreted the changes as likely causes of altered contractility leading to the development of hypertrophic cardiomyopathy. </p><p>Miller et al. (2001) generated mice transgenic for wildtype human cardiac TNNT2 and for the I79N mutation driven by the murine alpha-myosin heavy chain promoter. Comparison of the transgenic I79N mice with transgenic wildtype mice and nontransgenic mice demonstrated normal survival and no cardiac hypertrophy even with chronic exercise in all groups. Mice carrying the mutant transgene, however, displayed increased Ca(2+) sensitivity of ATPase activity and force development in cardiac myofilaments. Miller et al. (2001) proposed that changes in calcium regulation of ATPase and changes in maximal force and rate of force activation could ultimately lead to catastrophic results and sudden death of individuals carrying the I79N mutation. </p><p>To study further the functional consequences of the I79N mutation, Knollmann et al. (2001) compared cardiac performance of transgenic mice expressing either human TnT-I79N or human wildtype TnT. In isolated hearts, cardiac function was different depending on the calcium ion concentration of the perfusate. At higher calcium ion concentrations, systolic function was not different, but diastolic dysfunction became manifest as increased end-diastolic pressure and time to 90% relaxation. In vivo measurements by echocardiography and Doppler confirmed that baseline systolic function was significantly higher in the I79N mice without evidence for diastolic dysfunction. Inotropic stimulation with isoproterenol resulted only in a modest contractile response but caused significant mortality in the transgenic I79N mice. Doppler studies ruled out aortic outflow obstruction and were consistent with increased chamber stiffness. Knollmann et al. (2001) concluded that in vivo the increased myofilament calcium ion sensitivity due to the I79N mutation enhances baseline contractility but leads to cardiac dysfunction during inotropic stimulation. </p><p>Mutations in the TNNT2 gene, encoding the thin-filament contractile protein cardiac troponin T, are responsible for 15% of all cases of familial hypertrophic cardiomyopathy. Mutant proteins are thought to act through a dominant-negative mode that impairs function of heart muscle. Sehnert et al. (2002) pointed out that, despite the importance of cardiac troponin T in human disease, its loss-of-function phenotype had not been described. They showed that the zebrafish 'silent heart' (sih) mutation affects the tnnt2 gene. They characterized 2 mutated alleles of sih that severely reduce tnnt2 expression: one affects mRNA splicing, and the other affects gene transcription. Tnnt2, together with alpha-tropomyosin (TPM1; 191010) and cardiac troponins C and I (TNNI3; 191044), forms a calcium-sensitive regulatory complex within sarcomeres. Unexpectedly, in addition to loss of Tnnt2 expression in sih mutant hearts, Sehnert et al. (2002) observed a significant reduction in Tpm1 and Tnni3 and, consequently, severe sarcomere defects. This interdependence of thin-filament protein expression led them to postulate that some mutations in tnnt2 may trigger misregulation of thin-filament protein expression, resulting in sarcomere loss and myocyte disarray, the life-threatening hallmarks of TNNT2 mutations in mice and humans. </p><p>Harada and Potter (2004) incorporated 8 CMH-linked TnT mutations into porcine skinned cardiac fibers and found that all 8 mutants altered the contractile properties of the skinned cardiac fibers: E244D potentiated the maximum force development without changing Ca(2+) sensitivity, whereas the other 7 mutants increased the Ca(2+) sensitivity of force development but not the maximal force. Mutations in a region including residues 91 to 94 also decreased the change in Ca(2+) sensitivity of force development observed upon lowering pH from 7 to 6.5 compared with wildtype. Harada and Potter (2004) suggested that different regions of TnT may contribute to the pathogenesis of TnT-linked familial CMH through different mechanisms. </p><p>Hernandez et al. (2005) studied cardiac muscle fibers from transgenic mice expressing the F110I (191045.0005) and R278C mutations and observed an increased Ca(2+) sensitivity of force and ATPase activity in the F110I mutant fibers compared to the R278C fibers. Similar changes were seen in human cardiac fibers reconstituted with the TNNT2 mutants. In both sets of transgenic mice the maximal level of force was markedly decreased, although the maximal ATPase was not; thus their ratios of ATPase/force (energy cost) at all Ca(2+) concentrations were dramatically higher than wildtype. Hernandez et al. (2005) suggested that the combination of increased Ca(2+) sensitivity and energy cost in the F110I hearts may account for the greater severity of this phenotype compared to the R278C mutation. </p><p>Du et al. (2007) generated knockin mice with a Tnnt2 K210del mutation (191045.0006) and found that cardiac muscle fibers from mutant mice showed significantly lower Ca(2+) sensitivity in force generation than those from wildtype mice. The peak amplitude of Ca(2+) transient in mutant cardiomyocytes was increased, although the maximum isometric force produced by intact cardiac muscle fibers of mutant mice was not significantly different from wildtype, suggesting that the Ca(2+) transient was augmented to compensate for decreased myofilament Ca(2+) sensitivity. Mutant mice developed marked cardiac enlargement, heart failure, and frequent sudden death, recapitulating the phenotype of dilated cardiomyopathy patients. Administration of pimobendan, a positive inotropic agent that directly increases myofilament Ca(2+) sensitivity, prevented cardiac enlargement, heart failure, and sudden death. Du et al. (2007) concluded that Ca(2+) desensitization of the cardiac myofilament is the underlying cause of the dilated cardiomyopathy associated with the K210del mutation. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>12 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
CARDIOMYOPATHY, DILATED, 1D, INCLUDED<br />
|
|
CARDIOMYOPATHY, FAMILIAL, RESTRICTIVE, 3, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TNNT2, ILE79ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121964855,
|
|
|
|
|
|
gnomAD: rs121964855,
|
|
|
|
|
|
ClinVar: RCV000013217, RCV000013218, RCV000013219, RCV000159272, RCV000211864, RCV000243910, RCV000684789, RCV001171170
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In members of family AW afflicted with the form of familial hypertrophic cardiomyopathy (CMH2; 115195) linked to chromosome 1, Thierfelder et al. (1994) found heterozygosity for a 248T-A transversion in the TNNT2 gene, changing codon 79 from ATC to AAC and replacing the normal nonpolar isoleucine with a polar asparagine residue. </p><p>In affected members of a 3-generation family segregating autosomal dominant cardiomyopathy, in which the proband had a restrictive phenotype (RCM3; 612422) and relatives had clinical features of restrictive, hypertrophic, and/or dilated (CMD1D; 601494) cardiomyopathy, Menon et al. (2008) identified heterozygosity for the I79N mutation in the TNNT2 gene. The mutation was not found in unaffected individuals. Despite the variable morphology, all affected members of the family exhibited restrictive physiology. There was a high incidence of atrial tachyarrhythmia but no significant ventricular arrhythmia or sudden death in affected members of this family. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TNNT2, ARG92GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121964856,
|
|
|
|
|
|
|
|
ClinVar: RCV000013220, RCV000159281, RCV000211865, RCV000621709, RCV000627784, RCV003450625, RCV003450626
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In members of family BA with the form of familial hypertrophic cardiomyopathy (CMH2; 115195) linked to chromosome 1, Thierfelder et al. (1994) identified heterozygosity for a 287G-A transition in the TNNT2 gene, changing codon 92 from CGG to CAG and predicting the replacement of a positively charged arginine with a neutral glutamine (R92Q). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TNNT2, IVS15, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs111377893,
|
|
|
|
|
|
|
|
ClinVar: RCV000036621, RCV001233169, RCV001787036, RCV001798106, RCV002426558, RCV003445106, RCV003445107, RCV004808562
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In family AU in which Watkins et al. (1993) found that familial hypertrophic cardiomyopathy (CMH2; 115195) was linked to 1q, Thierfelder et al. (1994) found that the clinical disorder was linked to a T-to-C polymorphism at nucleotide 330 of the cDNA of cardiac troponin T. Furthermore, they showed that affected individuals had 2 aberrant splice products. A change from GT to AT in the exon 15 splice donor site resulted in skipping of exon 15 and a shorter cardiac troponin T cDNA. Activation of a cryptic splice site in intron 15 caused the insertion of the first 13 nucleotides of intron 15 into the cDNA sequence and resulted in the longer product. The mutation was identified in all affected adults in family AU and in 3 clinically unaffected adults who were known to carry the disease haplotype at multiple polymorphic markers. It was not present in other clinically unaffected adults or in over 200 chromosomes 1 derived from unrelated normal individuals. </p><p>The other mutations in the TNNT2 gene and in alpha-tropomyosin that had been demonstrated as causes of CMH were missense mutations. This mutation is expected to cause a truncated TnT peptide lacking the conserved C terminus. Watkins et al. (1996) devised a series of experiments designed to test whether the mutated TNNT2 functioned as a null allele or produced a 'poison peptide.' The missense mutations all result in altered polypeptides which, after they incorporate into the sarcomere, are dominant over the normal protein encoded by the remaining, wildtype allele. Watkins et al. (1996) used a quail myoblast-to-myotube system in which the mutant cardiac troponin was expressed and thereby determined the functional consequences. The data showed that the mutated gene is not a null allele but rather produces a stable, truncated polypeptide that accumulates in the myotube and is subsequently incorporated into the sarcomere. This protein displayed a dominant-negative effect on sarcomeric function, as evidenced by greatly diminished force production, even when it was coexpressed with the wildtype sequence. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TNNT2, ARG278CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121964857,
|
|
|
|
|
|
gnomAD: rs121964857,
|
|
|
|
|
|
ClinVar: RCV000013222, RCV000036622, RCV000148898, RCV000157540, RCV000159322, RCV000162331, RCV000203739, RCV000248304, RCV000755702, RCV000768493, RCV000771167
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Watkins et al. (1995) identified an arg278-to-cys mutation of the TNNT2 gene as a cause of familial hypertrophic cardiomyopathy (CMH2; 115195). The mutation occurred in a C-terminal region of TNNT2 that is highly homologous to a C-terminal region of fast skeletal troponin T (TNNT3; 600692) that had been shown to have an important role in tropomyosin binding and thus in the calcium ion regulation of contraction (Onoyama and Ohtsuki, 1986). Morimoto et al. (1999) presented evidence that the C-terminal region of TNNT2 plays an important role, probably through its interaction with tropomyosin, in allowing troponin complex to inhibit the muscle contraction at low levels of calcium ion, in agreement with the hypothesis deduced from the previous studies on fast skeletal troponin T. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TNNT2, PHE110ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121964858,
|
|
|
|
|
|
|
|
ClinVar: RCV000013223, RCV000223682, RCV000709767, RCV001804727, RCV003450627, RCV004802934
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected members of a family with hypertrophic cardiomyopathy (CMH2; 115195), Watkins et al. (1995) identified a missense 340T-A transversion in the TNNT2 gene, resulting in a phe110-to-ile (F110I) substitution. Anan et al. (1998) found the same mutation in 6 of 46 unrelated Japanese probands with familial CMH. Haplotype analysis supported a founder effect in 2 families, whereas the others had independent mutations. The authors suggested that residue 340 in the TNNT2 gene may represent a mutation hotspot. There was considerable inter- and intra-familial phenotypic variability, with apical hypertrophy alone in 2 unrelated families. In contrast to other reported TNNT2 mutations, F110I appeared to show a favorable prognosis, with Kaplan-Meier product-limit survival curves similar to those seen in patients with phe513-to-cys beta-myosin heavy chain mutations (160760.0016). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 CARDIOMYOPATHY, DILATED, 1D</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TNNT2, LYS210DEL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121964859, rs45578238,
|
|
|
|
|
|
|
|
ClinVar: RCV000036607, RCV000211868, RCV000223828, RCV000247384, RCV000524543, RCV001798105, RCV002051803, RCV003450713, RCV004737177
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated families with dilated cardiomyopathy (CMD1D; 601494), Kamisago et al. (2000) discovered a deletion of 3 nucleotides (AGA) of the cardiac troponin T gene. This deletion is predicted to eliminate 1 of 4 lysine residues encoded in tandem in exon 13 (designated lys210del, according to the numbering of Townsend et al. (1994)). Haplotype analyses indicated that each mutation arose independently in these families. In one family, sudden death occurred in a 26- and a 27-year-old as well as in a 1- and an 8-month-old, both of whom had a clinical diagnosis of infantile cardiomyopathy. In the other family, a 19-year-old female had postpartum congestive heart failure, resulting in sudden death. A 17-year-old sister had died of congestive heart failure, and postmortem showed marked dilatation of the right and left ventricles with histologic findings of increased interstitial fibrosis without myocyte disarray. A nephew died of congestive heart failure at the age of 15 years; postmortem showed marked right ventricular dilatation and normal cardiac ultrastructure. </p><p>In 3 affected members of a family with CMD, Mogensen et al. (2004) identified heterozygosity for the lys120del mutation. The proband died at age 26 years from heart failure; his 2 brothers also had CMD, the younger undergoing cardiac transplantation at age 22 years. Their father had an unexplained sudden death at age 36 years. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 CARDIOMYOPATHY, DILATED, 1D</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TNNT2, ARG141TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315379, rs74315380,
|
|
|
|
|
|
gnomAD: rs74315379,
|
|
|
|
|
|
ClinVar: RCV000013225, RCV000157537, RCV000159296, RCV000211866, RCV000524542, RCV000710045, RCV001375512, RCV003450628, RCV003450629, RCV004991970
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Li et al. (2001) found a C-to-T transition at nucleotide position 471 of the TNNT2 gene, which was predicted to change the highly conserved basic amino acid arginine at residue 141 to the polar-neutral tryptophan (arg141 to trp; R141W). This sequence change cosegregated with dilated cardiomyopathy (CMD1D; 601494) in the family, with 5 phenotypically normal mutation carriers in addition to 14 affected individuals. Evaluation of 200 control chromosomes and 219 individuals with familial hypertrophic cardiomyopathy failed to detect the variation, leading the authors to conclude that this was a pathogenic mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 CARDIOMYOPATHY, DILATED, 1D</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
LEFT VENTRICULAR NONCOMPACTION 6, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TNNT2, ARG131TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315379, rs74315380,
|
|
|
|
|
|
gnomAD: rs74315379,
|
|
|
|
|
|
ClinVar: RCV000013226, RCV000030567, RCV000159291, RCV000524541, RCV000588329, RCV003450630, RCV003450631
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Dilated Cardiomyopathy 1D</em></strong></p><p>
|
|
In a 28-year-old woman with dilated cardiomyopathy (CMD1D; 601494), Mogensen et al. (2004) identified heterozygosity for an arg131-to-trp (R131W) substitution at a conserved residue in exon 10 of the TNNT2 gene. An older brother had died suddenly at 16 years of age; their mother had CMD and died of heart failure at 34 years of age. The mutation was not found in her unaffected older brother or father, or in 200 ethnically matched control chromosomes. Functional studies showed significant impairment of mutated troponin interaction compared with wildtype control, indicating an altered regulation of myocardial contractility. </p><p><strong><em>Left Ventricular Noncompaction 6</em></strong></p><p>
|
|
In a 20-year-old woman who presented in cardiogenic shock and was diagnosed with isolated left ventricular noncompaction (LVNC6; see 601494), Klaassen et al. (2008) identified heterozygosity for the R131W mutation in TNNT2. The patient had primarily midlateral and midinferior LVNC, left ventricular dilation, and impaired left ventricular systolic function. The de novo mutation was not present in her unaffected parents, and was not found in 360 control chromosomes. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
Mirza et al. (2005) studied the R131W mutation and found that thin filaments reconstituted with a 1:1 ratio of mutant:wildtype proteins showed reduced Ca(2+) sensitivity of activation in ATPase and motility assays and a lower maximum Ca(2+) activation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 CARDIOMYOPATHY, DILATED, 1D</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TNNT2, ARG205LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121964860,
|
|
|
|
|
|
|
|
ClinVar: RCV000013228
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 affected members of a 3-generation family with dilated cardiomyopathy (CMD1D; 601494), Mogensen et al. (2004) identified heterozygosity for an arg205-to-leu (R205L) substitution at a conserved residue in exon 13 of the TNNT2 gene. The proband, who underwent cardiac transplantation at 16 years of age, had a younger sister with CMD who died of heart failure at age 20 years. Their affected mother was alive at 48 years of age; their maternal grandmother had an unexplained sudden death at 24 years of age. The mutation was not found in 2 younger unaffected sisters or the unaffected maternal grandfather, or in 200 ethnically matched control chromosomes. Functional studies showed significant impairment of mutated troponin interaction compared with wildtype control, indicating an altered regulation of myocardial contractility. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 CARDIOMYOPATHY, DILATED, 1D</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TNNT2, ASP270ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121964861,
|
|
|
|
|
|
gnomAD: rs121964861,
|
|
|
|
|
|
ClinVar: RCV000013229, RCV001851816, RCV002415410, RCV003450632, RCV003450633, RCV004802935
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected members of a family with dilated cardiomyopathy (CMD1D; 601494), Mogensen et al. (2004) identified heterozygosity for an asp270-to-asn (D270N) substitution at a conserved residue in exon 15 of the TNNT2 gene. The proband underwent cardiac transplantation at 38 years of age and died at age 44; his affected son was alive at 21 years of age. The mutation was not found in 2 unaffected children or in 200 ethnically matched control chromosomes. Functional studies showed significant impairment of mutated troponin interaction compared with wildtype control, indicating an altered regulation of myocardial contractility. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 CARDIOMYOPATHY, FAMILIAL, RESTRICTIVE, 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TNNT2, 3-BP DEL, 285GGA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs727504277,
|
|
|
|
|
|
|
|
ClinVar: RCV000154282, RCV003388923
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Restrictive Cardiomyopathy 3</em></strong></p><p>
|
|
In a 12-month-old girl with restrictive cardiomyopathy (RCM3; 612422), Peddy et al. (2006) identified a 3-bp deletion (285delGGA) in exon 9 the TNNT2 gene, resulting in the deletion of glutamic acid at codon 96 (glu96del) in a highly conserved segment of the main tropomyosin-binding region in the N-terminal half of troponin T. The deletion was not found in either parent, who had normal echocardiograms at ages 28 and 34 years, respectively. The girl also carried a known MYBPC3 (600958) polymorphism, V896M, which was also found in her unaffected father; the authors suggested that the V896M variant may have acted as a modifier, exacerbating the phenotypic expression of the TNNT2 mutation and causing an unusually early onset of RMC. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
Pinto et al. (2008) analyzed the effects of the 3-bp TNNT2 deletion in both the adult and fetal human cardiac TNNT2 isoforms, in order to evaluate the disease progression after birth when the isoform switch occurs. Both mutant isoforms showed a large increase in Ca(2+) sensitivity compared to their respective wildtypes, but there was no significant change in force recovery in any of the experiments. Both mutants showed an impaired ability to inhibit actomyosin ATPase activity, and the capacity of troponin complexes to fully relax fibers after troponin T displacement was also compromised. Experiments with fetal troponin isoforms showed a less severe impact compared with adult isoforms, consistent with a cardioprotective role for slow skeletal isoforms and with the rapid onset of RCM after birth following the isoform switch. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 LEFT VENTRICULAR NONCOMPACTION 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TNNT2, GLU96LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs869312881,
|
|
|
|
|
|
|
|
ClinVar: RCV000210349, RCV001798699, RCV001853371, RCV004589904
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 affected members across 3 generations of a family with left ventricular noncompaction of variable severity (LVNC6; 601494), Luedde et al. (2010) identified heterozygosity for a G-A transition in exon 10 of the TNNT2 gene, resulting in a glu96-to-lys (E96K) substitution at a highly conserved residue. The mutation was not found in unaffected family members. Chorionic villus biopsy of a subsequent pregnancy in the family showed that the fetus carried the mutation, and soon after birth the infant boy showed clinical signs of heart failure as well as decreased left ventricular function on echocardiography. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Anan, R., Shono, H., Kisanuki, A., Arima, S., Nakao, S., Tanaka, H.
|
|
<strong>Patients with familial hypertrophic cardiomyopathy caused by a phe110ile missense mutation in the cardiac troponin T gene have variable cardiac morphologies and a favorable prognosis.</strong>
|
|
Circulation 98: 391-397, 1998.
|
|
|
|
|
|
[PubMed: 9714088]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1161/01.cir.98.5.391]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Anderson, P. A. W., Greig, A., Mark, T. M., Malouf, N. N., Oakeley, A. E., Ungerleider, R. M., Allen, P. D., Kay, B. K.
|
|
<strong>Molecular basis of human cardiac troponin T isoforms expressed in the developing, adult, and failing heart.</strong>
|
|
Circ. Res. 76: 681-686, 1995.
|
|
|
|
|
|
[PubMed: 7534662]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1161/01.res.76.4.681]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Aviles, R. J., Askari, A. T., Lindahl, B., Wallentin, L., Jia, G., Ohman, E. M., Mahaffey, K. W., Newby, L. K., Califf, R. M., Simoons, M. L., Topol, E. J., Lauer, M. S.
|
|
<strong>Troponin T levels in patients with acute coronary syndromes, with or without renal dysfunction.</strong>
|
|
New Eng. J. Med. 346: 2047-2052, 2002.
|
|
|
|
|
|
[PubMed: 12087140]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1056/NEJMoa013456]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Benamer, H., Steg, P. G., Benessiano, J., Vicaut, E., Gaultier, C. J., Aubry, P., Boudvillain, O., Sarfati, L., Brochet, E., Feldman, L. J., Himbert, D., Juliard, J.-M., Assayag, P.
|
|
<strong>Elevated cardiac troponin I predicts a high-risk angiographic anatomy of the culprit lesion in unstable angina.</strong>
|
|
Am. Heart J. 137: 815-820, 1999.
|
|
|
|
|
|
[PubMed: 10220629]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0002-8703(99)70404-7]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Charlet-B, N., Logan, P., Singh, G., Cooper, T. A.
|
|
<strong>Dynamic antagonism between ETR-3 and PTB regulates cell type-specific alternative splicing.</strong>
|
|
Molec. Cell 9: 649-658, 2002.
|
|
|
|
|
|
[PubMed: 11931771]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s1097-2765(02)00479-3]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Du, C.-K., Morimoto, S., Nishii, K., Minakami, R., Ohta, M., Tadano, N., Lu, Q.-W., Wang, Y.-Y., Zhan, D.-Y., Mochizuki, M., Kita, S., Miwa, Y., Takahashi-Yanaga, F., Iwamoto, T., Ohtsuki, I., Sasaguri, T.
|
|
<strong>Knock-in mouse model of dilated cardiomyopathy caused by troponin mutation.</strong>
|
|
Circ. Res. 101: 185-194, 2007.
|
|
|
|
|
|
[PubMed: 17556660]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1161/CIRCRESAHA.106.146670]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Durand, J.-B., Bachinski, L. L., Bieling, L. C., Czernuszewicz, G. Z., Abchee, A. B., Yu, Q. T., Tapscott, T., Hill, R., Ifegwu, J., Marian, A. J., Brugada, R., Daiger, S., Gregoritch, J. M., Anderson, J. L., Quinones, M., Towbin, J. A., Roberts, R.
|
|
<strong>Localization of a gene responsible for familial dilated cardiomyopathy to chromosome 1q32.</strong>
|
|
Circulation 92: 3387-3389, 1995.
|
|
|
|
|
|
[PubMed: 8521556]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1161/01.cir.92.12.3387]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Farza, H., Townsend, P. J., Carrier, L., Barton, P. J., Mesnard, L., Bahrend, E., Forissier, J.-F., Fiszman, M., Yacoub, M. H., Schwartz, K.
|
|
<strong>Genomic organisation, alternative splicing and polymorphisms of the human cardiac troponin T gene.</strong>
|
|
J. Molec. Cell. Cardiol. 30: 1247-1253, 1998.
|
|
|
|
|
|
[PubMed: 9689598]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1006/jmcc.1998.0698]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hamm, C. W., Ravkilde, J., Gerhardt, W., Jorgensen, P., Peheim, E., Ljungdahl, L., Goldmann, B., Katus, H. A.
|
|
<strong>The prognostic value of serum troponin T in unstable angina.</strong>
|
|
New Eng. J. Med. 327: 146-150, 1992.
|
|
|
|
|
|
[PubMed: 1290492]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1056/NEJM199207163270302]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Harada, K., Potter, J. D.
|
|
<strong>Familial hypertrophic cardiomyopathy mutations from different functional regions of troponin T result in different effects on the pH and Ca(2+) sensitivity of cardiac muscle contraction.</strong>
|
|
J. Biol. Chem. 279: 14488-14495, 2004.
|
|
|
|
|
|
[PubMed: 14722098]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.M309355200]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Heeschen, C., van Den Brand, M. J., Hamm, C. W., Simoons, M. L.
|
|
<strong>Angiographic findings in patients with refractory unstable angina according to troponin T status.</strong>
|
|
Circulation 100: 1509-1514, 1999.
|
|
|
|
|
|
[PubMed: 10510053]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1161/01.cir.100.14.1509]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hernandez, O. M., Szczesna-Cordary, D., Knollmann, B. C., Miller, T., Bell, M., Zhao, J., Sirenko, S. G., Diaz, Z., Guzman, G., Xu, Y., Wang, Y., Kerrick, W. G. L., Potter, J. D.
|
|
<strong>F110I and R278C troponin T mutations that cause familial hypertrophic cardiomyopathy affect muscle contraction in transgenic mice and reconstituted human cardiac fibers.</strong>
|
|
J. Biol. Chem. 280: 37183-37194, 2005.
|
|
|
|
|
|
[PubMed: 16115869]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.M508114200]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Javadpour, M. M., Tardiff, J. C., Pinz, I., Ingwall, J. S.
|
|
<strong>Decreased energetics in murine hearts bearing the R92Q mutation in cardiac troponin T.</strong>
|
|
J. Clin. Invest. 112: 768-775, 2003.
|
|
|
|
|
|
[PubMed: 12952925]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1172/JCI15967]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kamisago, M., Sharma, S. D., DePalma, S. R., Solomon, S., Sharma, P., McDonough, B., Smoot, L., Mullen, M. P., Woolf, P. K., Wigle, E. D., Seidman, J. G., Seidman, C. E.
|
|
<strong>Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy.</strong>
|
|
New Eng. J. Med. 343: 1688-1696, 2000.
|
|
|
|
|
|
[PubMed: 11106718]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1056/NEJM200012073432304]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Klaassen, S., Probst, S., Oechslin, E., Gerull, B., Krings, G., Schuler, P., Greutmann, M., Hurlimann, D., Yegibasi, M., Pons, L., Gramlich, M., Drenckhahn, J.-D., Heuser, A., Berger, F., Jenni, R., Thierfelder, L.
|
|
<strong>Mutations in sarcomere protein genes in left ventricular noncompaction.</strong>
|
|
Circulation 117: 2893-2901, 2008.
|
|
|
|
|
|
[PubMed: 18506004]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1161/CIRCULATIONAHA.107.746164]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Knollmann, B. C., Blatt, S. A., Horton, K., de Freitas, F., Miller, T., Bell, M., Housmans, P. R., Weissman, N. J., Morad, M., Potter, J. D.
|
|
<strong>Inotropic stimulation induces cardiac dysfunction in transgenic mice expressing a troponin T (I79N) mutation linked to familial hypertrophic cardiomyopathy.</strong>
|
|
J. Biol. Chem. 276: 10039-10048, 2001.
|
|
|
|
|
|
[PubMed: 11113119]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.M006745200]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Li, D., Czernuszewicz, G. Z., Gonzalez, O., Tapscott, T., Karibe, A., Durand, J.-B., Brugada, R., Hill, R., Gregoritch, J. M., Anderson, J. L., Quinones, M., Bachinski, L. L., Roberts, R.
|
|
<strong>Novel cardiac troponin T mutation as a cause of familial dilated cardiomyopathy.</strong>
|
|
Circulation 104: 2188-2193, 2001.
|
|
|
|
|
|
[PubMed: 11684629]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1161/hc4301.098285]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lin, D., Bobkova, A., Homsher, E., Tobacman, L. S.
|
|
<strong>Altered cardiac troponin T in vitro function in the presence of a mutation implicated in familial hypertrophic cardiomyopathy.</strong>
|
|
J. Clin. Invest. 97: 2842-2848, 1996.
|
|
|
|
|
|
[PubMed: 8675696]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1172/JCI118740]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lindahl, B., Diderholm, E., Lagerqvist, B., Venge, P., Wallentin, L.
|
|
<strong>Mechanisms behind the prognostic value of troponin T in unstable coronary artery disease: a FRISC II substudy.</strong>
|
|
J. Am. Coll. Cardiol. 38: 979-986, 2001.
|
|
|
|
|
|
[PubMed: 11583868]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0735-1097(01)01501-7]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Luedde, M., Ehlermann, P., Weichenhan, D., Will, R., Zeller, R., Rupp, S., Muller, A, Steen, H., Ivandic, B. T., Ulmer, H. E., Kern, M., Katus, H. A., Frey, N.
|
|
<strong>Severe familial left ventricular non-compaction cardiomyopathy due to a novel troponin T (TNNT2) mutation.</strong>
|
|
Cardiovasc. Res. 86: 452-460, 2010.
|
|
|
|
|
|
[PubMed: 20083571]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/cvr/cvq009]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Menon, S. C., Michels, V. V., Pellikka, P. A., Ballew, J. D., Karst, M. L., Herron, K. J., Nelson, S. M., Rodeheffer, R. J., Olson, T. M.
|
|
<strong>Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology.</strong>
|
|
Clin. Genet. 74: 445-454, 2008.
|
|
|
|
|
|
[PubMed: 18651846]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1111/j.1399-0004.2008.01062.x]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Mesnard, L., Logeart, D., Taviaux, S., Diriong, S., Mercadier, J.-J., Samson, F.
|
|
<strong>Human cardiac troponin T: cloning and expression of new isoforms in the normal and failing heart.</strong>
|
|
Circ. Res. 76: 687-692, 1995.
|
|
|
|
|
|
[PubMed: 7895342]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1161/01.res.76.4.687]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Miller, T., Szczesna, D., Housmans, P. R., Zhao, J., de Freitas, F., Gomes, A. V., Culbreath, L., McCue, J., Wang, Y., Xu, Y., Kerrick, W. G. L., Potter, J. D.
|
|
<strong>Abnormal contractile function in transgenic mice expressing a familial hypertrophic cardiomyopathy-linked troponin T (I79N) mutation.</strong>
|
|
J. Biol. Chem. 276: 3743-3755, 2001.
|
|
|
|
|
|
[PubMed: 11060294]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.M006746200]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Mirza, M., Marston, S., Willott, R., Ashley, C., Mogensen, J., McKenna, W., Robinson, P., Redwood, C., Watkins, H.
|
|
<strong>Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype.</strong>
|
|
J. Biol. Chem. 280: 28498-28506, 2005.
|
|
|
|
|
|
[PubMed: 15923195]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.M412281200]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Mogensen, J., Murphy, R. T., Shaw, T., Bahl, A., Redwood, C., Watkins, H., Burke, M., Elliott, P. M., McKenna, W. J.
|
|
<strong>Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.</strong>
|
|
J. Am. Coll. Cardiol. 44: 2033-2040, 2004.
|
|
|
|
|
|
[PubMed: 15542288]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.jacc.2004.08.027]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Morimoto, S., Nakaura, H., Yanaga, F., Ohtsuki, I.
|
|
<strong>Functional consequences of a carboxy terminal missense mutation arg278cys in human cardiac troponin T.</strong>
|
|
Biochem. Biophys. Res. Commun. 261: 79-82, 1999.
|
|
|
|
|
|
[PubMed: 10405326]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1006/bbrc.1999.1000]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Onoyama, Y., Ohtsuki, I.
|
|
<strong>Effect of chymotryptic troponin T subfragments on the calcium ion-sensitivity of ATPase and superprecipitation of actomyosin.</strong>
|
|
J. Biochem. 100: 517-519, 1986.
|
|
|
|
|
|
[PubMed: 2946667]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/oxfordjournals.jbchem.a121742]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Peddy, S. B., Vricella, L. A., Crosson, J. E., Oswald, G. L., Cohn, R. D., Cameron, D. E., Valle, D., Loeys, B. L.
|
|
<strong>Infantile restrictive cardiomyopathy resulting from a mutation in the cardiac troponin T gene.</strong>
|
|
Pediatrics 117: 1830-1833, 2006.
|
|
|
|
|
|
[PubMed: 16651346]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1542/peds.2005-2301]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Pinto, J. R., Parvatiyar, M. S., Jones, M. A., Liang, J., Potter, J. D.
|
|
<strong>A troponin T mutation that causes infantile restrictive cardiomyopathy increases Ca(2+) sensitivity of force development and impairs the inhibitory properties of troponin.</strong>
|
|
J. Biol. Chem. 283: 2156-2166, 2008.
|
|
|
|
|
|
[PubMed: 18032382]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.M707066200]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Rust, E. M., Albayya, F. P., Metzger, J. M.
|
|
<strong>Identification of a contractile deficit in adult cardiac myocytes expressing hypertrophic cardiomyopathy-associated mutant troponin T proteins.</strong>
|
|
J. Clin. Invest. 103: 1459-1467, 1999.
|
|
|
|
|
|
[PubMed: 10330428]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1172/JCI6377]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Sehnert, A. J., Huq, A., Weinstein, B. M., Walker, C., Fishman, M., Stainier, D. Y. R.
|
|
<strong>Cardiac troponin T is essential in sarcomere assembly and cardiac contractility.</strong>
|
|
Nature Genet. 31: 106-110, 2002.
|
|
|
|
|
|
[PubMed: 11967535]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng875]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Sweeney, H. L., Feng, H. S., Yang, Z., Watkins, H.
|
|
<strong>Functional analyses of troponin T mutations that cause hypertrophic cardiomyopathy: insights into disease pathogenesis and troponin function.</strong>
|
|
Proc. Nat. Acad. Sci. 95: 14406-14410, 1998.
|
|
|
|
|
|
[PubMed: 9826713]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.95.24.14406]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Szczesna, D., Zhang, R., Zhao, J., Jones, M., Guzman, G., Potter, J. D.
|
|
<strong>Altered regulation of cardiac muscle contraction by troponin T mutations that cause familial hypertrophic cardiomyopathy.</strong>
|
|
J. Biol. Chem. 275: 624-630, 2000.
|
|
|
|
|
|
[PubMed: 10617660]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.275.1.624]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Takeda, S., Yamashita, A., Maeda, K., Maeda, Y.
|
|
<strong>Structure of the core domain of human cardiac troponin in the Ca(2+)-saturated form.</strong>
|
|
Nature 424: 35-41, 2003.
|
|
|
|
|
|
[PubMed: 12840750]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature01780]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Tardiff, J. C., Factor, S. M., Tompkins, B. D., Hewett, T. E., Palmer, B. M., Moore, R. L., Schwartz, S., Robbins, J., Leinwand, L. A.
|
|
<strong>A truncated cardiac troponin T molecule in transgenic mice suggests multiple cellular mechanisms for familial hypertrophic cardiomyopathy.</strong>
|
|
J. Clin. Invest. 101: 2800-2811, 1998.
|
|
|
|
|
|
[PubMed: 9637714]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1172/JCI2389]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Tardiff, J. C., Hewett, T. E., Palmer, B. M., Olsson, C., Factor, S. M., Moore, R. L., Robbins, J., Leinwand, L. A.
|
|
<strong>Cardiac troponin T mutations result in allele-specific phenotypes in a mouse model for hypertrophic cardiomyopathy.</strong>
|
|
J. Clin. Invest. 104: 469-481, 1999.
|
|
|
|
|
|
[PubMed: 10449439]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1172/JCI6067]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Thierfelder, L., Watkins, H., MacRae, C., Lamas, R., McKenna, W., Vosberg, H.-P., Seidman, J. G., Seidman, C. E.
|
|
<strong>Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere.</strong>
|
|
Cell 77: 701-712, 1994.
|
|
|
|
|
|
[PubMed: 8205619]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/0092-8674(94)90054-x]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Tobacman, L. S., Lin, D., Butters, C., Landis, C., Back, N., Pavlov, D., Homsher, E.
|
|
<strong>Functional consequences of troponin T mutations found in hypertrophic cardiomyopathy.</strong>
|
|
J. Biol. Chem. 274: 28363-28370, 1999.
|
|
|
|
|
|
[PubMed: 10497196]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.274.40.28363]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Torbicki, A., Kurzyna, M., Kuca, P., Fijalkowska, A., Sikora, J., Florczyk, M., Pruszczyk, P., Burakowski, J., Wawrzynska, L.
|
|
<strong>Detectable serum cardiac troponin T as a marker of poor prognosis among patients with chronic precapillary pulmonary hypertension.</strong>
|
|
Circulation 108: 844-848, 2003.
|
|
|
|
|
|
[PubMed: 12900346]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1161/01.CIR.0000084544.54513.E2]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Townsend, P. J., Farza, H., MacGeoch, C., Spurr, N. K., Wade, R., Gahlmann, R., Yacoub, M. H., Barton, P. J. R.
|
|
<strong>Human cardiac troponin T: identification of fetal isoforms and assignment of the TNNT2 locus to chromosome 1q.</strong>
|
|
Genomics 21: 311-316, 1994.
|
|
|
|
|
|
[PubMed: 8088824]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1006/geno.1994.1271]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Watkins, H., MacRae, C., Thierfelder, L., Chou, Y.-H., Frenneaux, M., McKenna, W., Seidman, J. G., Seidman, C. E.
|
|
<strong>A disease locus for familial hypertrophic cardiomyopathy maps to chromosome 1q3.</strong>
|
|
Nature Genet. 3: 333-337, 1993.
|
|
|
|
|
|
[PubMed: 7981753]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng0493-333]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Watkins, H., McKenna, W. J., Thierfelder, L., Suk, H. J., Anan, R., O'Donoghue, A., Spirito, P., Matsumori, A., Moravec, C. S., Seidman, J. G., Seidman, C. E.
|
|
<strong>Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy.</strong>
|
|
New Eng. J. Med. 332: 1058-1064, 1995.
|
|
|
|
|
|
[PubMed: 7898523]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1056/NEJM199504203321603]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Watkins, H., Seidman, C. E., Seidman, J. G., Feng, H. S., Sweeney, H. L.
|
|
<strong>Expression and functional assessment of a truncated cardiac troponin T that causes hypertrophic cardiomyopathy: evidence for a dominant negative action.</strong>
|
|
J. Clin. Invest. 98: 2456-2461, 1996.
|
|
|
|
|
|
[PubMed: 8958207]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1172/JCI119063]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
</ol>
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div class="row">
|
|
<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
|
<span class="text-nowrap mim-text-font">
|
|
Contributors:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Marla J. F. O'Neill - updated : 9/9/2013<br>Marla J. F. O'Neill - updated : 6/7/2010<br>Marla J. F. O'Neill - updated : 3/5/2009<br>Patricia A. Hartz - updated : 1/30/2009<br>Marla J. F. O'Neill - updated : 12/2/2008<br>Marla J. F. O'Neill - updated : 11/20/2008<br>Marla J. F. O'Neill - updated : 3/7/2008<br>Marla J. F. O'Neill - updated : 3/6/2008<br>Marla J. F. O'Neill - updated : 3/30/2006<br>Marla J. F. O'Neill - updated : 10/20/2004<br>Marla J. F. O'Neill - updated : 5/7/2004<br>Ada Hamosh - updated : 7/7/2003<br>Victor A. McKusick - updated : 4/17/2003<br>Stylianos E. Antonarakis - updated : 9/23/2002<br>Victor A. McKusick - updated : 7/1/2002<br>Victor A. McKusick - updated : 5/6/2002<br>Paul Brennan - updated : 4/29/2002<br>Paul J. Converse - updated : 5/14/2001<br>Victor A. McKusick - updated : 4/12/2001<br>Victor A. McKusick - updated : 1/4/2001<br>Paul Brennan - updated : 2/18/2000<br>Victor A. McKusick - updated : 1/13/2000<br>Victor A. McKusick - updated : 11/8/1999<br>Victor A. McKusick - updated : 10/26/1999<br>Victor A. McKusick - updated : 7/6/1999<br>Victor A. McKusick - updated : 12/10/1998<br>Victor A. McKusick - updated : 9/3/1998<br>Alan F. Scott - updated : 7/27/1995
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div class="row">
|
|
<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
|
<span class="text-nowrap mim-text-font">
|
|
Creation Date:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Victor A. McKusick : 6/17/1994
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div class="row">
|
|
<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
|
<span class="text-nowrap mim-text-font">
|
|
Edit History:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
carol : 07/13/2023<br>carol : 01/11/2023<br>carol : 01/10/2023<br>carol : 03/28/2016<br>tpirozzi : 9/9/2013<br>terry : 11/3/2010<br>terry : 9/9/2010<br>carol : 6/7/2010<br>wwang : 3/9/2009<br>terry : 3/5/2009<br>mgross : 1/30/2009<br>wwang : 12/4/2008<br>wwang : 12/3/2008<br>terry : 12/2/2008<br>carol : 11/20/2008<br>terry : 11/20/2008<br>carol : 3/7/2008<br>carol : 3/6/2008<br>wwang : 4/3/2006<br>terry : 3/30/2006<br>joanna : 1/20/2006<br>carol : 10/20/2004<br>carol : 5/7/2004<br>carol : 5/7/2004<br>terry : 5/7/2004<br>joanna : 9/30/2003<br>terry : 7/31/2003<br>alopez : 7/9/2003<br>alopez : 7/9/2003<br>terry : 7/7/2003<br>tkritzer : 4/24/2003<br>terry : 4/17/2003<br>mgross : 9/23/2002<br>cwells : 7/3/2002<br>terry : 7/1/2002<br>alopez : 5/6/2002<br>alopez : 5/6/2002<br>alopez : 4/29/2002<br>alopez : 4/29/2002<br>alopez : 4/26/2002<br>carol : 12/19/2001<br>mgross : 5/14/2001<br>mcapotos : 4/18/2001<br>terry : 4/12/2001<br>carol : 1/11/2001<br>cwells : 1/11/2001<br>cwells : 1/10/2001<br>cwells : 1/10/2001<br>terry : 1/4/2001<br>terry : 1/4/2001<br>alopez : 2/21/2000<br>alopez : 2/18/2000<br>mcapotos : 1/14/2000<br>mcapotos : 1/14/2000<br>mcapotos : 1/14/2000<br>terry : 1/13/2000<br>mgross : 11/8/1999<br>carol : 10/28/1999<br>terry : 10/26/1999<br>jlewis : 7/15/1999<br>terry : 7/6/1999<br>carol : 12/16/1998<br>terry : 12/10/1998<br>alopez : 9/16/1998<br>dkim : 9/11/1998<br>carol : 9/3/1998<br>terry : 6/1/1998<br>mark : 12/26/1996<br>terry : 12/17/1996<br>mark : 5/9/1995<br>carol : 6/21/1994<br>jason : 6/17/1994
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div id="mimFooter">
|
|
|
|
|
|
<div class="container ">
|
|
<div class="row">
|
|
<br />
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div class="hidden-print mim-footer">
|
|
<div class="container">
|
|
<div class="row">
|
|
<p />
|
|
</div>
|
|
<div class="row text-center small">
|
|
NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers,
|
|
and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal
|
|
medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
|
|
<br />
|
|
OMIM<sup>®</sup> and Online Mendelian Inheritance in Man<sup>®</sup> are registered trademarks of the Johns Hopkins University.
|
|
<br />
|
|
Copyright<sup>®</sup> 1966-2025 Johns Hopkins University.
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div class="visible-print-block mim-footer" style="position: relative;">
|
|
<div class="container">
|
|
<div class="row">
|
|
<p />
|
|
</div>
|
|
<div class="row text-center small">
|
|
NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers,
|
|
and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal
|
|
medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
|
|
<br />
|
|
OMIM<sup>®</sup> and Online Mendelian Inheritance in Man<sup>®</sup> are registered trademarks of the Johns Hopkins University.
|
|
<br />
|
|
Copyright<sup>®</sup> 1966-2025 Johns Hopkins University.
|
|
<br />
|
|
Printed: March 14, 2025
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="modal fade" id="mimDonationPopupModal" tabindex="-1" role="dialog" aria-labelledby="mimDonationPopupModalTitle">
|
|
<div class="modal-dialog" role="document">
|
|
<div class="modal-content">
|
|
<div class="modal-header">
|
|
<button type="button" id="mimDonationPopupCancel" class="close" data-dismiss="modal" aria-label="Close"><span aria-hidden="true">×</span></button>
|
|
<h4 class="modal-title" id="mimDonationPopupModalTitle">
|
|
OMIM Donation:
|
|
</h4>
|
|
</div>
|
|
<div class="modal-body">
|
|
<div class="row">
|
|
<div class="col-lg-offset-1 col-md-offset-1 col-sm-offset-1 col-xs-offset-1 col-lg-10 col-md-10 col-sm-10 col-xs-10">
|
|
<p>
|
|
Dear OMIM User,
|
|
</p>
|
|
</div>
|
|
</div>
|
|
<div class="row">
|
|
<div class="col-lg-offset-1 col-md-offset-1 col-sm-offset-1 col-xs-offset-1 col-lg-10 col-md-10 col-sm-10 col-xs-10">
|
|
<p>
|
|
To ensure long-term funding for the OMIM project, we have diversified
|
|
our revenue stream. We are determined to keep this website freely
|
|
accessible. Unfortunately, it is not free to produce. Expert curators
|
|
review the literature and organize it to facilitate your work. Over 90%
|
|
of the OMIM's operating expenses go to salary support for MD and PhD
|
|
science writers and biocurators. Please join your colleagues by making a
|
|
donation now and again in the future. Donations are an important
|
|
component of our efforts to ensure long-term funding to provide you the
|
|
information that you need at your fingertips.
|
|
</p>
|
|
</div>
|
|
</div>
|
|
<div class="row">
|
|
<div class="col-lg-offset-1 col-md-offset-1 col-sm-offset-1 col-xs-offset-1 col-lg-10 col-md-10 col-sm-10 col-xs-10">
|
|
<p>
|
|
Thank you in advance for your generous support, <br />
|
|
Ada Hamosh, MD, MPH <br />
|
|
Scientific Director, OMIM <br />
|
|
</p>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div class="modal-footer">
|
|
<button type="button" id="mimDonationPopupDonate" class="btn btn-success btn-block" data-dismiss="modal"> Donate To OMIM! </button>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
</body>
|
|
|
|
</html>
|
|
|
|
|