4016 lines
379 KiB
Text
4016 lines
379 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 _0x5069(){const _0x4b1387=['91sZIeLc','mimBrowserCapability','15627zshTnf','710004yxXedd','34LxqNYj','match','disconnect','1755955rnzTod','observe','1206216ZRfBWB','575728fqgsYy','webdriver','documentElement','close','open','3086704utbakv','7984143PpiTpt'];_0x5069=function(){return _0x4b1387;};return _0x5069();}function _0xe429(_0x472ead,_0x43eb70){const _0x506916=_0x5069();return _0xe429=function(_0xe42949,_0x1aaefc){_0xe42949=_0xe42949-0x1a9;let _0xe6add8=_0x506916[_0xe42949];return _0xe6add8;},_0xe429(_0x472ead,_0x43eb70);}(function(_0x337daa,_0x401915){const _0x293f03=_0xe429,_0x5811dd=_0x337daa();while(!![]){try{const _0x3dc3a3=parseInt(_0x293f03(0x1b4))/0x1*(-parseInt(_0x293f03(0x1b6))/0x2)+parseInt(_0x293f03(0x1b5))/0x3+parseInt(_0x293f03(0x1b0))/0x4+-parseInt(_0x293f03(0x1b9))/0x5+parseInt(_0x293f03(0x1aa))/0x6+-parseInt(_0x293f03(0x1b2))/0x7*(parseInt(_0x293f03(0x1ab))/0x8)+parseInt(_0x293f03(0x1b1))/0x9;if(_0x3dc3a3===_0x401915)break;else _0x5811dd['push'](_0x5811dd['shift']());}catch(_0x4dd27b){_0x5811dd['push'](_0x5811dd['shift']());}}}(_0x5069,0x84d63),(function(){const _0x9e4c5f=_0xe429,_0x363a26=new MutationObserver(function(){const _0x458b09=_0xe429;if(document!==null){let _0x2f0621=![];navigator[_0x458b09(0x1ac)]!==![]&&(_0x2f0621=!![]);for(const _0x427dda in window){_0x427dda[_0x458b09(0x1b7)](/cdc_[a-z0-9]/ig)&&(_0x2f0621=!![]);}_0x2f0621===!![]?document[_0x458b09(0x1af)]()[_0x458b09(0x1ae)]():(_0x363a26[_0x458b09(0x1b8)](),document['getElementById'](_0x458b09(0x1b3))['remove']());}});_0x363a26[_0x9e4c5f(0x1a9)](document[_0x9e4c5f(0x1ad)],{'childList':!![]});}()));
|
|
</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
|
|
|
|
- *601627 - SURVIVAL OF MOTOR NEURON 2; SMN2
|
|
|
|
|
|
- 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=601627"><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">*601627</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="#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="#evolution">Evolution</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/601627">Table View</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#seeAlso"><strong>See Also</strong></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=ENSG00000205571;t=ENST00000380743" 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=6607" 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=601627" 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=ENSG00000205571;t=ENST00000380743" 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_017411,NM_022875,NM_022876,NM_022877,XM_011543599,XM_011543600,XM_011543601,XM_011543602,XM_011543603,XM_017009787,XM_047417619,XM_047417620,XM_047417621,XM_047417622" 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_017411" 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=601627" 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=09036&isoform_id=09036_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/SMN2" 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/736411,2498924,3970964,10937869,12654181,13259527,13259529,13259531,15929774,47682383,158260361,387600261,387600263,387600265,387600267,387600269,387600271,392328719,767936413,767936415,767936417,767936419,767936421,1034645919,1520100963,1520100965,1520100967,1520100969,1520100971,1520100973,1520100975,2217357033,2217357037,2217357039,2217357043,2462492186,2462492188,2462492190,2462492192,2462492194,2462492196,2462492198,2462492200,2462492202,2462492204,2462496889,2462496891,2462496893,2462496895,2462496897,2462496899,2462496901,2462496903,2462603979,2462603981,2462603983,2462603985,2462603987,2462603989,2462603991,2462603993,2462603995,2462603997" 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/Q16637" 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=6607" 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=ENSG00000205571;t=ENST00000380743" 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=SMN2" 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=SMN2" 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+6607" 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/SMN2" 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>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/gene/6607" 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=chr5&hgg_gene=ENST00000380743.9&hgg_start=70049523&hgg_end=70090528&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://medlineplus.gov/genetics/gene/smn2" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=601627[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=601627[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://gnomad.broadinstitute.org/gene/ENSG00000205571" 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.gwascentral.org/search?q=SMN2" 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=SMN2" 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="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SMN2&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/PA35967" 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:11118" 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/FBgn0036641.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:109257" 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/SMN2#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:109257" 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/6607/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://www.orthodb.org/?ncbi=6607" 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="https://wormbase.org/db/gene/gene?name=WBGene00004887;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</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://reactome.org/content/query?q=SMN2&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>
|
|
601627
|
|
</span>
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
<div>
|
|
<a id="preferredTitle" class="mim-anchor"></a>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
SURVIVAL OF MOTOR NEURON 2; SMN2
|
|
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
SURVIVAL OF MOTOR NEURON, CENTROMERIC COPY; SMNC<br />
|
|
C-BCD541
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</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=SMN2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SMN2</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/5/230?start=-3&limit=10&highlight=230">5q13.2</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr5:70049523-70090528&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'})">5:70,049,523-70,090,528</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
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/5/230?start=-3&limit=10&highlight=230">
|
|
5q13.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Spinal muscular atrophy, type III, modifier of}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/253400"> 253400 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</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/601627" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/601627" 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 SMN1 (<a href="/entry/600354">600354</a>) and SMN2 genes lie within the telomeric and centromeric halves, respectively, of a large, inverted duplication on chromosome 5q13. These genes share more than 99% nucleotide identity, and both are capable of encoding a 294-amino acid RNA-binding protein, SMN, that is required for efficient assembly of small nuclear ribonucleoprotein (snRNP) complexes. Homozygous loss of the SMN1 gene causes spinal muscular atrophy (SMA; <a href="/entry/253300">253300</a>). Absence of SMN1 is partially compensated for by SMN2, which produces enough SMN protein to allow for relatively normal development in cell types other than motor neurons. However, SMN2 cannot fully compensate for loss of SMN1 because, although SMN2 is transcribed at a level comparable to that of SMN1, a large majority of SMN2 transcripts lack exon 7, resulting in production of a truncated, less stable SMN protein (<a href="#28" class="mim-tip-reference" title="Lefebvre, S., Burglen, L., Reboullet, S., Clermont, O., Burlet, P., Viollet, L., Benichou, B., Cruaud, C., Millasseau, P., Zeviani, M., Le Paslier, D., Frezal, J., Cohen, D., Weissenbach, J., Munnich, A., Melki, J. <strong>Identification and characterization of a spinal muscular atrophy-determining gene.</strong> Cell 80: 155-165, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7813012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7813012</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90460-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7813012">Lefebvre et al., 1995</a>; <a href="#24" class="mim-tip-reference" title="Kashima, T., Rao, N., David, C. J., Manley, J. L. <strong>hnRNP A1 functions with specificity in repression of SMN2 exon 7 splicing.</strong> Hum. Molec. Genet. 16: 3149-3159, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17884807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17884807</a>] [<a href="https://doi.org/10.1093/hmg/ddm276" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17884807">Kashima et al., 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7813012+17884807" 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="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="#28" class="mim-tip-reference" title="Lefebvre, S., Burglen, L., Reboullet, S., Clermont, O., Burlet, P., Viollet, L., Benichou, B., Cruaud, C., Millasseau, P., Zeviani, M., Le Paslier, D., Frezal, J., Cohen, D., Weissenbach, J., Munnich, A., Melki, J. <strong>Identification and characterization of a spinal muscular atrophy-determining gene.</strong> Cell 80: 155-165, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7813012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7813012</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90460-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7813012">Lefebvre et al. (1995)</a> described an inverted duplication of a 500-kb element in normal chromosome 5q13, which contains the gene for spinal muscular atrophy. Within the telomeric region, they identified the SMN1 gene. A highly homologous gene, referred to as C-BCD541 and also known as SMNC or SMN2, was present in the duplicated centromeric element in 95% of controls. PCR amplification and sequence analysis revealed 5 nucleotide discrepancies between the centromeric and telomeric SMN genes, 2 of which occur in exons 7 and 8. The centromeric SMN gene undergoes alternative splicing of exon 7, resulting in a truncated mRNA transcript lacking exon 7 and a putative protein with a different C-terminal end. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7813012" 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>Using a panel of anti-SMN antibodies, <a href="#8" class="mim-tip-reference" title="Coovert, D. D., Le, T. T., McAndrew, P. E., Strasswimmer, J., Crawford, T. O., Mendell, J. R., Coulson, S. E., Androphy, E. J., Prior, T. W., Burghes, A. H. M. <strong>The survival motor neuron protein in spinal muscular atrophy.</strong> Hum. Molec. Genet. 6: 1205-1214, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9259265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9259265</a>] [<a href="https://doi.org/10.1093/hmg/6.8.1205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9259265">Coovert et al. (1997)</a> demonstrated that the SMN protein is expressed from both the SMN1 and SMN2 genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9259265" 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="#5" class="mim-tip-reference" title="Burglen, L., Lefebvre, S., Clermont, O., Burlet, P., Viollet, L., Cruaud, C., Munnich, A., Melki, J. <strong>Structure and organization of the human survival motor neurone (SMN) gene.</strong> Genomics 32: 479-482, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8838816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8838816</a>] [<a href="https://doi.org/10.1006/geno.1996.0147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8838816">Burglen et al. (1996)</a> determined that the SMN gene has 9 exons and spans approximately 20 kb. <a href="#5" class="mim-tip-reference" title="Burglen, L., Lefebvre, S., Clermont, O., Burlet, P., Viollet, L., Cruaud, C., Munnich, A., Melki, J. <strong>Structure and organization of the human survival motor neurone (SMN) gene.</strong> Genomics 32: 479-482, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8838816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8838816</a>] [<a href="https://doi.org/10.1006/geno.1996.0147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8838816">Burglen et al. (1996)</a> referred to exon 2 as exons 2a and 2b. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8838816" 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="Boda, B., Mas, C., Giudicelli, C., Nepote, V., Guimiot, F., Levacher, B., Zvara, A., Santha, M., LeGall, I., Simonneau, M. <strong>Survival motor neuron SMN1 and SMN2 gene promoters: identical sequences and differential expression in neurons and non-neuronal cells.</strong> Europ. J. Hum. Genet. 12: 729-737, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15162126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15162126</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15162126">Boda et al. (2004)</a> determined that the first 4.6 kb of the SMN1 and SMN2 promoters are identical. The promoters contain 12 SP1 (<a href="/entry/189906">189906</a>), 8 AP1 (see <a href="/entry/165160">165160</a>), 3 AP2 (<a href="/entry/107580">107580</a>), 6 HNF3 (see <a href="/entry/602294">602294</a>), 24 Zeste (see <a href="/entry/601674">601674</a>), and 4 RXR-beta (<a href="/entry/180246">180246</a>) sites. There are no RE1 elements. <a href="#3" class="mim-tip-reference" title="Boda, B., Mas, C., Giudicelli, C., Nepote, V., Guimiot, F., Levacher, B., Zvara, A., Santha, M., LeGall, I., Simonneau, M. <strong>Survival motor neuron SMN1 and SMN2 gene promoters: identical sequences and differential expression in neurons and non-neuronal cells.</strong> Europ. J. Hum. Genet. 12: 729-737, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15162126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15162126</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15162126">Boda et al. (2004)</a> transfected primary cultures of mouse embryonic spinal cord and fibroblasts with constructs containing 1.8, 3.2, or 4.6 kb of the promoter region fused to a reporter gene. Expression of the 1.8- and 3.2-kb constructs was stronger in spinal cord than in fibroblast cultures; the 4.6-kb construct gave 5-fold higher expression in neurons than in fibroblasts, with expression in fibroblasts lower than that achieved with the 3.2-kb construct. <a href="#3" class="mim-tip-reference" title="Boda, B., Mas, C., Giudicelli, C., Nepote, V., Guimiot, F., Levacher, B., Zvara, A., Santha, M., LeGall, I., Simonneau, M. <strong>Survival motor neuron SMN1 and SMN2 gene promoters: identical sequences and differential expression in neurons and non-neuronal cells.</strong> Europ. J. Hum. Genet. 12: 729-737, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15162126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15162126</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15162126">Boda et al. (2004)</a> concluded that these results suggest the presence of an enhancer element between 1.8 and 3.2 kb upstream from the transcriptional start site of the SMN genes that functions in both culture types, and a silencer between 3.2 and 4.6 kb that is active only in fibroblast cultures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15162126" 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><a href="#28" class="mim-tip-reference" title="Lefebvre, S., Burglen, L., Reboullet, S., Clermont, O., Burlet, P., Viollet, L., Benichou, B., Cruaud, C., Millasseau, P., Zeviani, M., Le Paslier, D., Frezal, J., Cohen, D., Weissenbach, J., Munnich, A., Melki, J. <strong>Identification and characterization of a spinal muscular atrophy-determining gene.</strong> Cell 80: 155-165, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7813012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7813012</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90460-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7813012">Lefebvre et al. (1995)</a> determined that the SMN2 gene lies within the centromeric half of a large inverted duplication on chromosome 5q13. The SMN1 gene lies in the telomeric half of the duplication. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7813012" 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="#30" class="mim-tip-reference" title="Monani, U. R., Lorson, C. L., Parsons, D. W., Prior, T. W., Androphy, E. J., Burghes, A. H. M., McPherson, J. D. <strong>A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2.</strong> Hum. Molec. Genet. 8: 1177-1183, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10369862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10369862</a>] [<a href="https://doi.org/10.1093/hmg/8.7.1177" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10369862">Monani et al. (1999)</a> sequenced 3 genomic clones over 32 kb in length, which spanned both the SMN1 and SMN2 genes. Of 35 sequence differences noted between SMN1 and SMN2, only 3 were located in either exon 7 or intron 7. Of note was a translationally silent 840C-T transition at position +6 in exon 7, which affects splicing. Using minigene constructs, the authors found that the presence of cytosine at position +6 in exon 7 produced a normal splicing pattern retaining exon 7, whereas thymine in this position resulted in the absence of exon 7 in the majority of the transcripts. Since the majority of human SMN2 transcripts lack exon 7, the authors hypothesized that the 5-prime portion of exon 7 in SMN1 contains an exonic splice enhancer (ESE), and that low levels of full-length SMN transcript are responsible for the SMA phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10369862" 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="#1" class="mim-tip-reference" title="Andreassi, C., Jarecki, J., Zhou, J., Coovert, D. D., Monani, U. R., Chen, X., Whitney, M., Pollok, B., Zhang, M., Androphy, E., Burghes, A. H. M. <strong>Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients.</strong> Hum. Molec. Genet. 10: 2841-2849, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11734549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11734549</a>] [<a href="https://doi.org/10.1093/hmg/10.24.2841" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11734549">Andreassi et al. (2001)</a> screened a library of compounds and found that aclarubicin increased the retention of exon 7 into the SMN2 transcript from the endogenous gene in type I SMA fibroblasts, as well as from an SMN2 minigene in a motor neuron cell line. In type I fibroblasts, treatment resulted in an increase in SMN protein and gems to normal levels. The authors demonstrated the utility of high-throughput screens in detecting compounds that affect the splicing pattern of a gene, and suggested that alteration of splicing patterns may represent a feasible approach to modification of gene expression in disease treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11734549" 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>Using in vivo splicing assays, <a href="#21" class="mim-tip-reference" title="Hofmann, Y., Wirth, B. <strong>hnRNP-G promotes exon 7 inclusion of survival motor neuron (SMN) via direct interaction with Htra2-beta1.</strong> Hum. Molec. Genet. 11: 2037-2049, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12165565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12165565</a>] [<a href="https://doi.org/10.1093/hmg/11.17.2037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12165565">Hofmann and Wirth (2002)</a> identified the protein hnRNPG (<a href="/entry/300199">300199</a>) and its paralog RBM (<a href="/entry/400006">400006</a>) as 2 novel splicing factors that promote the inclusion of SMN2 exon 7. Both hnRNPG and RBM nonspecifically bind RNA, but directly and specifically bind Htra2-beta1, an SR-like splicing factor which stimulates inclusion of exon 7 through a direct interaction with SMN2 exon 7 pre-mRNA. Using deletion mutants of hnRNPG, the authors demonstrated a specific protein-protein interaction of hnRNPG with Htra2-beta1 which mediates the inclusion of SMN2 exon 7 rather than the nonspecific interaction of hnRNPG with SMN pre-mRNA. These trans-acting splicing factors were also effective on endogenous SMN2 transcripts and increased the endogenous SMN protein level. The authors presented a model of how exon 7 mRNA processing may be regulated by these splicing factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12165565" 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="Kashima, T., Manley, J. L. <strong>A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy.</strong> Nature Genet. 34: 460-463, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12833158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12833158</a>] [<a href="https://doi.org/10.1038/ng1207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12833158">Kashima and Manley (2003)</a> showed that the exonic splicing silencer in SMN2 functions as a binding site for a known repressor protein, HNRNPA1 (<a href="/entry/164017">164017</a>), which binds to SMN2 but not SMN1 exon 7 RNA. By using small interfering RNAs (siRNAs) to reduce HNRNPA1 protein levels in living cells, <a href="#23" class="mim-tip-reference" title="Kashima, T., Manley, J. L. <strong>A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy.</strong> Nature Genet. 34: 460-463, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12833158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12833158</a>] [<a href="https://doi.org/10.1038/ng1207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12833158">Kashima and Manley (2003)</a> demonstrated efficient SMN2 exon 7 splicing. The findings not only defined a new mechanism underlying the inefficient splicing of SMN2 exon 7 but also illustrated more generally the remarkable sensitivity and precision that characterizes control of mRNA splicing. The work also made it possible to consider therapeutic approaches to spinal muscular atrophy that involved decreasing HNRNPA1 RNA binding to or function on SMN2 exon 7. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12833158" 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="#20" class="mim-tip-reference" title="Helmken, C., Hofmann, Y., Schoenen, F., Oprea, G., Raschke, H., Rudnik-Schoneborn, S., Zerres, K., Wirth, B. <strong>Evidence for a modifying pathway in SMA discordant families: reduced SMN level decreases the amount of its interacting partners and Htra2-beta1.</strong> Hum. Genet. 114: 11-21, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14520560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14520560</a>] [<a href="https://doi.org/10.1007/s00439-003-1025-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14520560">Helmken et al. (2003)</a> stated that sibs with identical 5q13 homologs and homozygous absence of SMN1 can have variable phenotypes, suggesting that the spinal muscular atrophy phenotype is modified by other factors, which function either on the transcriptional level, to produce more full-length SMN (FL-SMN) transcripts, or on the translational level, to increase the amount of SMN2 protein. By analyzing 9 SMA discordant families, <a href="#20" class="mim-tip-reference" title="Helmken, C., Hofmann, Y., Schoenen, F., Oprea, G., Raschke, H., Rudnik-Schoneborn, S., Zerres, K., Wirth, B. <strong>Evidence for a modifying pathway in SMA discordant families: reduced SMN level decreases the amount of its interacting partners and Htra2-beta1.</strong> Hum. Genet. 114: 11-21, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14520560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14520560</a>] [<a href="https://doi.org/10.1007/s00439-003-1025-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14520560">Helmken et al. (2003)</a> demonstrated that in all families unaffected sibs produced significantly higher amounts of SMN, SMN-interacting protein-1 (SIP1; <a href="/entry/602595">602595</a>), GEMIN3 (<a href="/entry/606168">606168</a>), ZPR1 (<a href="/entry/603901">603901</a>), and hnRNPQ protein in lymphoblastoid cell lines, but not in primary fibroblasts, compared with their affected sibs. The results suggested that the modifying factor or factors act on the SMN gene to influence SMN protein levels, thus modifying the SMA phenotype, and not through an independent pathway. In addition, the observed coregulations appeared to be tissue-specific. SMN significantly coregulated its interacting partners, including its own splicing factor, HTRA2-beta-1 (see <a href="/entry/606441">606441</a>), due to an indirect feedback mechanism. Thus, <a href="#20" class="mim-tip-reference" title="Helmken, C., Hofmann, Y., Schoenen, F., Oprea, G., Raschke, H., Rudnik-Schoneborn, S., Zerres, K., Wirth, B. <strong>Evidence for a modifying pathway in SMA discordant families: reduced SMN level decreases the amount of its interacting partners and Htra2-beta1.</strong> Hum. Genet. 114: 11-21, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14520560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14520560</a>] [<a href="https://doi.org/10.1007/s00439-003-1025-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14520560">Helmken et al. (2003)</a> showed that reduction of the SMN protein has a significant impact on the expression level of a splicing factor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14520560" 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="#4" class="mim-tip-reference" title="Brichta, L., Hofmann, Y., Hahnen, E., Siebzehnrubl, F. A., Raschke, H., Blumcke, I., Eyupoglu, I. Y., Wirth, B. <strong>Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy.</strong> Hum. Molec. Genet. 12: 2481-2489, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915451</a>] [<a href="https://doi.org/10.1093/hmg/ddg256" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12915451">Brichta et al. (2003)</a> showed that in fibroblast cultures derived from SMA patients treated with therapeutic doses of valproic acid, the level of full-length SMN2 mRNA/protein increased 2- to 4-fold. This upregulation of SMN was most likely attributable to increased levels of HTRA2-beta-1 as well as to SMN gene transcription activation. Valproic acid also increased SMN protein levels through transcription activation in organotypic hippocampal rat brain slices. Additionally, valproic acid increased the expression of other serine-arginine family proteins, which may have important implications for other disorders affected by alternative splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12915451" 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="#17" class="mim-tip-reference" title="Grzeschik, S. M., Ganta, M., Prior, T. W., Heavlin, W. D., Wang, C. H. <strong>Hydroxyurea enhances SMN2 gene expression in spinal muscular atrophy cells.</strong> Ann. Neurol. 58: 194-202, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16049920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16049920</a>] [<a href="https://doi.org/10.1002/ana.20548" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16049920">Grzeschik et al. (2005)</a> reported that cultured lymphocytes from patients with SMA showed increased production of the full-length SMN mRNA and protein in response to treatment with hydroxyurea. The findings suggested that hydroxyurea promoted inclusion of exon 7 during SMN2 transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16049920" 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="#26" class="mim-tip-reference" title="Kernochan, L. E., Russo, M. L., Woodling, N. S., Huynh, T. N., Avila, A. M., Fischbeck, K. H., Sumner, C. J. <strong>The role of histone acetylation in SMN gene expression.</strong> Hum. Molec. Genet. 14: 1171-1182, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15772088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15772088</a>] [<a href="https://doi.org/10.1093/hmg/ddi130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15772088">Kernochan et al. (2005)</a> investigated the levels of acetylated H3 and H4 histones and histone deacetylases (HDACs) associated with different regions of the human and mouse SMN genes in both cultured cells and tissues. The SMN gene had a reproducible pattern of histone acetylation that was largely conserved among different tissues and species. A limited region of the promoter surrounding the transcriptional start site had relatively high levels of histone acetylation. After HDAC inhibitor treatment, acetylated histone levels increased, particularly at upstream regions, correlating with a 2-fold increase in promoter activity. During development in mouse tissues, histone acetylation levels decreased and associated HDAC2 (<a href="/entry/605164">605164</a>) levels increased at the region closest to the transcriptional start site, correlating with a 40 to 60% decrease in SMN transcript and protein levels. <a href="#26" class="mim-tip-reference" title="Kernochan, L. E., Russo, M. L., Woodling, N. S., Huynh, T. N., Avila, A. M., Fischbeck, K. H., Sumner, C. J. <strong>The role of histone acetylation in SMN gene expression.</strong> Hum. Molec. Genet. 14: 1171-1182, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15772088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15772088</a>] [<a href="https://doi.org/10.1093/hmg/ddi130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15772088">Kernochan et al. (2005)</a> suggested that histone acetylation may modulate SMN gene expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15772088" 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>Skipping of SMN2 exon 7 had been attributed to either the loss of an SF2/ASF-dependent exonic splicing enhancer or the creation of an hnRNP A/B-dependent exonic splicing silencer, as a result of the C-to-T transition. <a href="#6" class="mim-tip-reference" title="Cartegni, L., Hastings, M. L., Calarco, J. A., de Stanchina, E., Krainer, A. R. <strong>Determinants of exon 7 splicing in the spinal muscular atrophy genes, SMN1 and SMN2.</strong> Am. J. Hum. Genet. 78: 63-77, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16385450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16385450</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16385450[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/10.1086/498853" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16385450">Cartegni et al. (2006)</a> reported the extensive testing of the enhancer-loss and silencer-gain models by mutagenesis, RNA interference, overexpression, RNA splicing, and RNA-protein interaction experiments. The results supported the enhancer-loss model but also demonstrated that hnRNP A/B proteins antagonize SF2/ASF-dependent ESE activity and promote exon 7 skipping by a mechanism that is independent of the C-to-T transition and is, therefore, common to both SMN1 and SMN2. The findings explained the basis of defective SMN2 splicing, illustrated the fine balance between positive and negative determinants of exon identity and alternative splicing, and underscored the importance of antagonistic splicing factors and exonic elements in a disease context. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16385450" 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="Kashima, T., Rao, N., David, C. J., Manley, J. L. <strong>hnRNP A1 functions with specificity in repression of SMN2 exon 7 splicing.</strong> Hum. Molec. Genet. 16: 3149-3159, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17884807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17884807</a>] [<a href="https://doi.org/10.1093/hmg/ddm276" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17884807">Kashima et al. (2007)</a> showed that the 840C-T transition in SMN2 created a high-affinity HNRNPA1-binding site. Depletion of HNRNPA1 in HeLa cells restored exon 7 inclusion, indicating that splicing of exon 7 in SMN2 is repressed by an HNRNPA1-dependent exonic splicing silencer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17884807" 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="Kashima, T., Rao, N., Manley, J. L. <strong>An intronic element contributes to splicing repression in spinal muscular atrophy.</strong> Proc. Nat. Acad. Sci. 104: 3426-3431, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17307868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17307868</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17307868[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.0700343104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17307868">Kashima et al. (2007)</a> identified a novel single nucleotide difference between SMN1 and SMN2, an A-to-G change at position +100 within intron 7 of SMN2, which creates a second high-affinity HNRNPA1-binding site specific to SMN2. Base substitutions that disrupted this site in SMN2 restored exon 7 inclusion in vivo and prevented HNRNPA1 binding in vitro. <a href="#25" class="mim-tip-reference" title="Kashima, T., Rao, N., Manley, J. L. <strong>An intronic element contributes to splicing repression in spinal muscular atrophy.</strong> Proc. Nat. Acad. Sci. 104: 3426-3431, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17307868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17307868</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17307868[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.0700343104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17307868">Kashima et al. (2007)</a> proposed that interactions between HNRNPA1 molecules bound to the exonic and intronic sites cooperate to exclude exon 7 in SMN2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17307868" 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="#2" class="mim-tip-reference" title="Angelozzi, C., Borgo, F., Tiziano, F. D., Martella, A., Neri, G., Brahe, C. <strong>Salbutamol increases SMN mRNA and protein levels in spinal muscular atrophy cells.</strong> J. Med. Genet. 45: 29-31, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17932121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17932121</a>] [<a href="https://doi.org/10.1136/jmg.2007.051177" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17932121">Angelozzi et al. (2008)</a> found that salbutamol increased full-length SMN2 mRNA transcript levels in fibroblasts derived from patients with SMA. The maximum increase (over 200%) was observed after 30 to 60 minutes. This rapid rise correlated with decreased levels of SMN2 mRNA with deletion of exon 7. Salbutamol treatment also resulted in increased SMN protein levels and nuclear gems. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17932121" 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>Using SMN minigenes, <a href="#16" class="mim-tip-reference" title="Gladman, J. T., Chandler, D. S. <strong>Intron 7 conserved sequence elements regulate the splicing of the SMN gene.</strong> Hum. Genet. 126: 833-841, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19701774/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19701774</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19701774[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/10.1007/s00439-009-0733-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19701774">Gladman and Chandler (2009)</a> identified 2 elements within intron 7 of the SMN genes that influenced exon 7 splicing in a cell type-independent manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19701774" 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>Using in vitro splicing assays, minigenes, and knockdown and overexpression studies with human constructs and cells, <a href="#22" class="mim-tip-reference" title="Jodelka, F. M., Ebert, A. D., Duelli, D. M., Hastings, M. L. <strong>A feedback loop regulates splicing of the spinal muscular atrophy-modifying gene, SMN2.</strong> Hum. Molec. Genet. 19: 4906-4917, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20884664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20884664</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20884664[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/10.1093/hmg/ddq425" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20884664">Jodelka et al. (2010)</a> showed that total SMN protein content and the relative abundance of individual snRNPs determined inclusion or skipping of SMN2 exon 7. Exon 7 was not included in SMN2 mRNAs in the absence of SMN protein. Exon 7 inclusion was highly sensitive to the level of U1 snRNP. <a href="#22" class="mim-tip-reference" title="Jodelka, F. M., Ebert, A. D., Duelli, D. M., Hastings, M. L. <strong>A feedback loop regulates splicing of the spinal muscular atrophy-modifying gene, SMN2.</strong> Hum. Molec. Genet. 19: 4906-4917, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20884664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20884664</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20884664[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/10.1093/hmg/ddq425" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20884664">Jodelka et al. (2010)</a> noted that U1 snRNP recognizes the 5-prime splice site of pre-mRNAs through direct basepairing, and they found that the 5-prime splice site of SMN2 exon 7 was a critical determinant of exon inclusion. <a href="#22" class="mim-tip-reference" title="Jodelka, F. M., Ebert, A. D., Duelli, D. M., Hastings, M. L. <strong>A feedback loop regulates splicing of the spinal muscular atrophy-modifying gene, SMN2.</strong> Hum. Molec. Genet. 19: 4906-4917, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20884664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20884664</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20884664[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/10.1093/hmg/ddq425" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20884664">Jodelka et al. (2010)</a> concluded that SMN protein controls its own expression via positive-feedback regulation of alternative SMN2 pre-mRNA splicing and that reduced SMN protein content in SMA has a deleterious effect on expression of the full-length protein via SMN2 mRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20884664" 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>Spinal Muscular Atrophy</em></strong></p><p>
|
|
<a href="#18" class="mim-tip-reference" title="Hahnen, E., Schonling, J., Rudnik-Schoneborn, S., Zerres, K., Wirth, B. <strong>Hybrid survival motor neuron genes in patients with autosomal recessive spinal muscular atrophy: new insights into molecular mechanisms responsible for the disease.</strong> Am. J. Hum. Genet. 59: 1057-1065, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8900234/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8900234</a>]" pmid="8900234">Hahnen et al. (1996)</a> reported molecular analysis of 42 SMA patients who carried homozygous deletions of exon 7 but not of exon 8 in the telomeric copy of the SMN gene (SMN1). Additional homozygous deletions of exon 8 in the centromeric copy of SMN (SMN2) were found in 2 of the patients. By a simple PCR test, they demonstrated the existence of hybrid SMN genes, i.e., genes composed of both the centromeric SMN2 and the telomeric SMN1. They reported a high frequency of hybrid SMN genes in SMA patients with Czech or Polish background. <a href="#18" class="mim-tip-reference" title="Hahnen, E., Schonling, J., Rudnik-Schoneborn, S., Zerres, K., Wirth, B. <strong>Hybrid survival motor neuron genes in patients with autosomal recessive spinal muscular atrophy: new insights into molecular mechanisms responsible for the disease.</strong> Am. J. Hum. Genet. 59: 1057-1065, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8900234/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8900234</a>]" pmid="8900234">Hahnen et al. (1996)</a> identified a single haplotype for half of the hybrid genes analyzed, suggesting that in these cases the SMA chromosomes shared a common origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8900234" 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="#36" class="mim-tip-reference" title="Schwartz, M., Sorensen, N., Hansen, F. J., Hertz, J. M., Norby, S., Tranebjaerg, L., Skovby, F. <strong>Quantification, by solid-phase minisequencing, of the telomeric and centromeric copies of the survival motor neuron gene in families with spinal muscular atrophy.</strong> Hum. Molec. Genet. 6: 99-104, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9002676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9002676</a>] [<a href="https://doi.org/10.1093/hmg/6.1.99" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9002676">Schwartz et al. (1997)</a> used solid-phase minisequencing to determine the ratio between the number of telomeric and centromeric copies of the SMN gene in affected and unaffected members of 30 SMA families. Six predominant haplotypes were identified, 3 for normal chromosomes and 3 for SMA chromosomes, characterized by having 0, 1, or 2 copies, respectively, of SMN2. They found patients homozygous for a deletion of SMN1 and with only one copy of SMN2, but found none deleted for all copies of SMN2. Several asymptomatic carriers of SMA with only a single copy of SMN1 and no copy of SMN2 were identified. <a href="#36" class="mim-tip-reference" title="Schwartz, M., Sorensen, N., Hansen, F. J., Hertz, J. M., Norby, S., Tranebjaerg, L., Skovby, F. <strong>Quantification, by solid-phase minisequencing, of the telomeric and centromeric copies of the survival motor neuron gene in families with spinal muscular atrophy.</strong> Hum. Molec. Genet. 6: 99-104, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9002676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9002676</a>] [<a href="https://doi.org/10.1093/hmg/6.1.99" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9002676">Schwartz et al. (1997)</a> could not confirm the hypothesis that the presence of more copies of SMN2 is correlated with a less severe course of the disease. The frequencies of haplotypes characterized by having 0, 1, or 2 copies, respectively, of SMN2 were found to differ significantly between normal and SMA chromosomes. This distribution could be explained by an underrepresentation of the haplotype completely lacking SMN genes, which is expected to cause early embryonic death in homozygotes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9002676" 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="Srivastava, S., Mukherjee, M., Panigrahi, I., Pandey, G. S., Pradhan, S., Mittal, B. <strong>SMN2-deletion in childhood-onset spinal muscular atrophy.</strong> Am. J. Med. Genet. 101: 198-202, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11424133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11424133</a>] [<a href="https://doi.org/10.1002/ajmg.1386" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11424133">Srivastava et al. (2001)</a> reported a 5-year-old boy with childhood-onset SMA who had a homozygous deletion of SMN2. He had wasting, weakness, and hyporeflexia, predominantly in the distal muscles. The affected muscles showed chronic neurogenic changes on electromyography. There was no sensory involvement. A nerve conduction study showed near-normal conduction velocity with reduction in the amplitude of the compound muscle action potential. The SMN2 deletion was demonstrated by studies of exons 7 and 8 of the SMN genes. Base sequencing and densitometric analysis of the critical exon 7 region did not show any microdeletion or duplication of SMN1, but confirmed the deletion of SMN2. <a href="#38" class="mim-tip-reference" title="Srivastava, S., Mukherjee, M., Panigrahi, I., Pandey, G. S., Pradhan, S., Mittal, B. <strong>SMN2-deletion in childhood-onset spinal muscular atrophy.</strong> Am. J. Med. Genet. 101: 198-202, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11424133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11424133</a>] [<a href="https://doi.org/10.1002/ajmg.1386" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11424133">Srivastava et al. (2001)</a> concluded that deletion of SMN2 can also result in the SMA phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11424133" 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="#13" class="mim-tip-reference" title="Feldkotter, M., Schwarzer, V., Wirth, R., Wienker, T. F., Wirth, B. <strong>Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy.</strong> Am. J. Hum. Genet. 70: 358-368, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11791208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11791208</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11791208[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/10.1086/338627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11791208">Feldkotter et al. (2002)</a> developed a quantitative test for either SMN1 or SMN2 to analyze SMA patients for their SMN2 copy number and to correlate the SMN2 copy number with type of SMA and duration of survival. The quantitative analysis of SMN2 copies in 375 patients with type I, type II, or type III SMA showed a significant correlation between SMN2 copy number and type of SMA as well as duration of survival. Thus, 80% of patients with type I SMA carried 1 or 2 SMN2 copies and 82% of patients with type II SMA carried 3 SMN2 copies, whereas 96% of patients with type III SMA carried 3 or 4 SMN2 copies. Among 113 patients with type I SMA, 9 with 1 SMN2 copy lived less than 11 months, 88 of 94 with 2 SMN2 copies lived less than 21 months, and 8 of 10 with 3 SMN2 copies lived 33 to 66 months. On the basis of SMN2 copy number, Feldkotter et al. (2002) calculated the posterior probability that a child with homozygous absence of SMN1 will develop type I, type II, or type III SMA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11791208" 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="#33" class="mim-tip-reference" title="Ogino, S., Wilson, R. B., Gold, B. <strong>New insights on the evolution of the SMN1 and SMN2 region: simulation and meta-analysis for allele and haplotype frequency calculations.</strong> Europ. J. Hum. Genet. 12: 1015-1023, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15470363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15470363</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201288" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15470363">Ogino et al. (2004)</a> analyzed all 'available and reliable' data to calculate allele/haplotype frequencies and new mutation rates in the SMN region. The authors stated that their data provided the basis for the most accurate genetic risk calculations as well as evidence that nucleotide position 840 constitutes a mutation hotspot. <a href="#33" class="mim-tip-reference" title="Ogino, S., Wilson, R. B., Gold, B. <strong>New insights on the evolution of the SMN1 and SMN2 region: simulation and meta-analysis for allele and haplotype frequency calculations.</strong> Europ. J. Hum. Genet. 12: 1015-1023, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15470363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15470363</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201288" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15470363">Ogino et al. (2004)</a> suggested that there is selection of the single-copy SMN1-SMN2 haplotype and that rare chromosomes with 3 copies of SMN1 exist. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15470363" 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="#40" class="mim-tip-reference" title="Wirth, B., Brichta, L., Schrank, B., Lochmuller, H., Blick, S., Baasner, A., Heller, R. <strong>Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number.</strong> Hum. Genet. 119: 422-428, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16508748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16508748</a>] [<a href="https://doi.org/10.1007/s00439-006-0156-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16508748">Wirth et al. (2006)</a> analyzed SMN2 copy number in 115 patients with SMA3 (<a href="/entry/253400">253400</a>) or SMA4 (<a href="/entry/271150">271150</a>) who had confirmed homozygous absence of SMN1 and found that 62% of SMA3 patients with age of onset less than 3 years had 2 or 3 SMN2 copies, whereas 65% of SMA3 patients with age of onset greater than 3 years had 4 to 5 SMN2 copies. Of the 4 adult-onset (SMA4) patients, 3 had 4 SMN2 copies and 1 had 6 copies. <a href="#40" class="mim-tip-reference" title="Wirth, B., Brichta, L., Schrank, B., Lochmuller, H., Blick, S., Baasner, A., Heller, R. <strong>Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number.</strong> Hum. Genet. 119: 422-428, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16508748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16508748</a>] [<a href="https://doi.org/10.1007/s00439-006-0156-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16508748">Wirth et al. (2006)</a> concluded that SMN2 may have a disease-modifying role in SMA, with a greater SMN2 copy number associated with later onset and better prognosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16508748" 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="#19" class="mim-tip-reference" title="Hauke, J., Riessland, M., Lunke, S., Eyupoglu, I. Y., Blumcke, I., El-Osta, A., Wirth, B., Hahnen, E. <strong>Survival motor neuron gene 2 silencing by DNA methylation correlates with spinal muscular atrophy disease severity and can be bypassed by histone deacetylase inhibition.</strong> Hum. Molec. Genet. 18: 304-317, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18971205/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18971205</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18971205[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/10.1093/hmg/ddn357" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18971205">Hauke et al. (2009)</a> demonstrated that SMN2 is subject to gene silencing by DNA methylation. SMN2 contains 4 CpG islands which present highly conserved methylation patterns and little interindividual variation in SMN1-deleted SMA patients. The comprehensive analysis of SMN2 methylation in patients suffering from severe versus mild SMA carrying identical SMN2 copy numbers revealed a correlation of CpG methylation at the positions -290 and -296 with disease severity and the activity of the first transcriptional start site of SMN2 at position -296. The methyl-CpG-binding protein-2 (MECP2; <a href="/entry/300005">300005</a>), a transcriptional repressor, bound to the critical SMN2 promoter region in a methylation-dependent manner. The authors identified histone deacetylase (HDAC) inhibitors (including vorinostat and romidepsin) that were able to bypass SMN2 gene silencing by DNA methylation, while others (such as valproic acid and phenylbutyrate) did not, due to HDAC isoenzyme specificities. The authors concluded that DNA methylation is functionally important regarding SMA disease progression, and pharmacologic SMN2 gene activation might have implications for future SMA therapy regimens. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18971205" 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>Amyotrophic Lateral Sclerosis</em></strong></p><p>
|
|
<a href="#31" class="mim-tip-reference" title="Moulard, B., Salachas, F., Chassande, B., Briolotti, V., Meininger, V., Malafosse, A., Camu, W. <strong>Association between centromeric deletions of the SMN gene and sporadic adult-onset lower motor neuron disease.</strong> Ann. Neurol. 43: 640-644, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9585359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9585359</a>] [<a href="https://doi.org/10.1002/ana.410430513" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9585359">Moulard et al. (1998)</a> found homozygous deletions of SMN2 in 36% of individuals with sporadic adult-onset lower motor neuron disease (LMND), but in only 6.2% of individuals with sporadic amyotrophic lateral sclerosis (ALS; <a href="/entry/105400">105400</a>) and 1.5% of individuals with familial ALS. The authors argued that SMN2, but not SMN1, deletions are a susceptibility factor for LMND, a disorder distinguishable from ALS by the absence of upper motor neuron signs. LMND patients with SMN2 deletions differed from those patients without such deletions by earlier age of onset (40 vs 56 years), more rapid disease progression (25 vs 36 months to death), and a lower preponderance of males (M:F ratio of 1.5 vs 2.5). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9585359" 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>Among 124 ALS patients, <a href="#14" class="mim-tip-reference" title="Gamez, J., Barcelo, M. J., Munoz, X., Carmona, F., Cusco, I., Baiget, M., Cervera, C., Tizzano, E. F. <strong>Survival and respiratory decline are not related to homozygous SMN2 deletions in ALS patients.</strong> Neurology 59: 1456-1460, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12427907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12427907</a>] [<a href="https://doi.org/10.1212/01.wnl.0000032496.64510.4e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12427907">Gamez et al. (2002)</a> found no association between homozygous deletion of SMN2 and disease onset, respiratory decline, or survival. A homozygous SMN2 deletion was identified in 11 (8.8%) patients and 20 (10%) of 200 control individuals. <a href="#10" class="mim-tip-reference" title="Corcia, P., Mayeux-Portas, V., Khoris, J., de Toffol, B., Autret, A., Muh, J.-P., Camu, W., Andres, C., the French ALS Research Group. <strong>Abnormal SMN1 gene copy number is a susceptibility factor for amyotrophic lateral sclerosis.</strong> Ann. Neurol. 51: 243-246, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11835381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11835381</a>] [<a href="https://doi.org/10.1002/ana.10104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11835381">Corcia et al. (2002)</a> found no difference in SMN2 gene copies among 167 ALS patients and 167 controls. Homozygous deletion of the SMN2 gene was found in 9 and 10% of patients and controls, respectively. Among 600 patients with sporadic ALS, <a href="#9" class="mim-tip-reference" title="Corcia, P., Camu, W., Halimi, J.-M., Vourc'h, P., Antar, C., Vedrine, S., Giraudeau, B., de Toffol, B., Andres, C. R., the French ALS Research Group. <strong>SMN1 gene, but not SMN2, is a risk factor for sporadic ALS.</strong> Neurology 67: 1147-1150, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16931506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16931506</a>] [<a href="https://doi.org/10.1212/01.wnl.0000233830.85206.1e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16931506">Corcia et al. (2006)</a> found no disease association with SMN2 copy number. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12427907+11835381+16931506" 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="Crawford, T. O., Skolasky, R. L., Jr. <strong>The relationship of SMN to amyotrophic lateral sclerosis. (Letter)</strong> Ann. Neurol. 52: 857-858, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12447945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12447945</a>] [<a href="https://doi.org/10.1002/ana.10378" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12447945">Crawford and Skolasky (2002)</a> briefly reviewed several reported associations of SMN to ALS and concluded that the findings likely represented nonsignificant or borderline significant fluctuations. <a href="#11" class="mim-tip-reference" title="Corcia, P., Moulard, B., Andres, C., Camu, W., the French ALS Research Group. <strong>Reply to Crawford and Skolasky. (Letter)</strong> Ann. Neurol. 52: 858-860, 2002."None>Corcia et al. (2002)</a> responded that although they still supported a role for the SMN2 gene in LMND (<a href="#31" class="mim-tip-reference" title="Moulard, B., Salachas, F., Chassande, B., Briolotti, V., Meininger, V., Malafosse, A., Camu, W. <strong>Association between centromeric deletions of the SMN gene and sporadic adult-onset lower motor neuron disease.</strong> Ann. Neurol. 43: 640-644, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9585359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9585359</a>] [<a href="https://doi.org/10.1002/ana.410430513" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9585359">Moulard et al., 1998</a>), the evidence of an association between homozygous SMN2 deletion and ALS was less convincing. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12447945+9585359" 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="evolution" class="mim-anchor"></a>
|
|
<h4 href="#mimEvolutionFold" id="mimEvolutionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimEvolutionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Evolution</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimEvolutionFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><a href="#35" class="mim-tip-reference" title="Rochette, C. F., Gilbert, N., Simard, L. R. <strong>SMN gene duplication and the emergence of the SMN2 gene occurred in distinct hominids: SMN2 is unique to Homo sapiens.</strong> Hum. Genet. 108: 255-266, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11354640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11354640</a>] [<a href="https://doi.org/10.1007/s004390100473" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11354640">Rochette et al. (2001)</a> used a number of approaches to probe the evolutionary history of the SMN1 and SMN2 genes and showed that SMN gene duplication and the appearance of SMN2 occurred at very distinct evolutionary times. Molecular fossil and molecular clock data suggested that this duplication may have occurred as recently as 3 million years ago in that the position and repetitive elements are identical for both human SMN genes and overall sequence divergence ranges from 0.15 to 0.34%. However, these approaches ignored the possibility of sequence homogenization by means of gene conversion. Consequently, <a href="#35" class="mim-tip-reference" title="Rochette, C. F., Gilbert, N., Simard, L. R. <strong>SMN gene duplication and the emergence of the SMN2 gene occurred in distinct hominids: SMN2 is unique to Homo sapiens.</strong> Hum. Genet. 108: 255-266, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11354640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11354640</a>] [<a href="https://doi.org/10.1007/s004390100473" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11354640">Rochette et al. (2001)</a> used quantitative polymerase chain reaction and analysis of allelic variants to provide physical evidence for or against SMN gene duplication in the chimpanzee, mankind's closest relative. These studies revealed that chimpanzees have 2 to 7 copies of the SMN gene per diploid genome; however, the 2 nucleotides diagnostic for exons 7-8 and the SMNdel7 mRNA product of the SMN2 gene are absent in nonhuman primates. In contrast, the SMN2 gene has been detected in all extant human populations studied to date, including representatives from Europe, the Central African Republic, and the Congo. These data provided conclusive evidence that SMN gene duplication occurred more than 5 million years ago, before the separation of human and chimpanzee lineages, but that SMN2 appeared for the first time in Homo sapiens. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11354640" 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="#27" class="mim-tip-reference" title="Le, T. T., Pham, L. T., Butchbach, M. E. R., Zhang, H. L., Monani, U. R., Coovert, D. D., Gavrilina, T. O., Xing, L., Bassell, G. J., Burghes, A. H. M. <strong>SMN-delta-7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN.</strong> Hum. Molec. Genet. 14: 845-857, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15703193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15703193</a>] [<a href="https://doi.org/10.1093/hmg/ddi078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15703193">Le et al. (2005)</a> created transgenic mice expressing SMN2 lacking exon 7 (SMN-delta-7) and crossed them onto a severe SMA background. Expression of SMN-delta-7 appeared to extend survival of SMA mice from 5 to 13 days. Unlike mice with selective deletion of SMN exon 7 in muscle, mice with a small amount of full-length SMN (FL-SMN) did not show a dystrophic phenotype. The authors suggested that low levels of FL-SMN (as found in SMA patients) and absence of FL-SMN in muscle tissue may have different effects, and raised the question of the importance of high SMN levels in muscle in the presentation of SMA. SMN and SMN-delta-7 can associate with each other; <a href="#27" class="mim-tip-reference" title="Le, T. T., Pham, L. T., Butchbach, M. E. R., Zhang, H. L., Monani, U. R., Coovert, D. D., Gavrilina, T. O., Xing, L., Bassell, G. J., Burghes, A. H. M. <strong>SMN-delta-7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN.</strong> Hum. Molec. Genet. 14: 845-857, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15703193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15703193</a>] [<a href="https://doi.org/10.1093/hmg/ddi078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15703193">Le et al. (2005)</a> suggested that this association may stabilize SMN-delta-7 protein turnover and ameliorate the SMA phenotype by increasing the amount of oligomeric SMN. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15703193" 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 SMA-like mouse embryonic fibroblasts and human SMN2-transfected motor neuron cells, <a href="#39" class="mim-tip-reference" title="Ting, C.-H., Lin, C.-W., Wen, S.-L., Hsieh-Li, H.-M., Li, H. <strong>Stat5 constitutive activation rescues defects in spinal muscular atrophy.</strong> Hum. Molec. Genet. 16: 499-514, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17220171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17220171</a>] [<a href="https://doi.org/10.1093/hmg/ddl482" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17220171">Ting et al. (2007)</a> found that sodium vanadate, trichostatin A, and aclarubicin effectively enhanced SMN2 expression by inducing Stat5 (<a href="/entry/601511">601511</a>) activation. This resulted in enhanced SMN2 promoter activity with an increase in both full-length and deletion exon 7 SMN transcripts in human cells with SMN2. Knockdown of Stat5 expression disrupted the effects of sodium vanadate on SMN2 activation, but did not influence SMN2 splicing, suggesting that Stat5 signaling is involved in SMN2 transcriptional regulation. Constitutive expression of the activated Stat5 mutant Stat5A1*6 profoundly increased the number of nuclear gems in SMA patient lymphocytes and reduced SMA-like motor neuron axon outgrowth defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17220171" 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="#41" class="mim-tip-reference" title="Workman, E., Saieva, L., Carrel, T. L., Crawford, T. O., Liu, D., Lutz, C., Beattie, C. E., Pellizzoni, L., Burghes, A. H. M. <strong>A SMN missense mutation complements SMN2 restoring snRNPs and rescuing SMA mice.</strong> Hum. Molec. Genet. 18: 2215-2229, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19329542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19329542</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19329542[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/10.1093/hmg/ddp157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19329542">Workman et al. (2009)</a> showed that SMN(A111G), an allele capable of snRNP assembly (A111G; <a href="/entry/600354#0015">600354.0015</a>), can rescue mice that lacked Smn and contained either 1 or 2 copies of SMN2 (SMA mice). The correction of SMA in these animals was directly correlated with snRNP assembly activity in spinal cord, as was correction of snRNA levels. These data support snRNP assembly as being the critical function affected in SMA and suggests that the levels of snRNPs are critical to motor neurons. Furthermore, SMN(A111G) could not rescue Smn-null mice without SMN2, suggesting that both SMN(A111G) and SMN from SMN2 may undergo intragenic complementation in vivo to function in heteromeric complexes that have greater function than either allele alone. The oligomer composed of limiting full-length SMN and SMN(A111G) had substantial snRNP assembly activity. The SMN(A2G) (A2G; <a href="/entry/600354#0002">600354.0002</a>) and SMN(A111G) alleles in vivo did not complement each other, leading to the possibility that these mutations could affect the same function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19329542" 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 human SMN1 and SMN2 both encode the SMN protein, the SMN2 gene is unable to compensate for the loss of SMN1 protein in SMA patients. A translationally silent T at nucleotide +6 of SMN2 exon 7 instead of SMN1's C causes the final RNA product to be improperly regulated, with the majority of SMN2 pre-mRNA transcripts lacking exon 7. While humans have both SMN1 and SMN2 genes, mice and other mammals have only a single Smn gene. Using mouse and human SMN minigenes and homologous recombination, <a href="#15" class="mim-tip-reference" title="Gladman, J. T., Bebee, T. W., Edwards, C., Wang, X., Sahenk, Z., Rich, M. M., Chandler, D. S. <strong>A humanized Smn gene containing the SMN2 nucleotide alteration in exon 7 mimics SMN2 splicing and the SMA disease phenotype.</strong> Hum. Molec. Genet. 19: 4239-4252, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20705738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20705738</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20705738[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/10.1093/hmg/ddq343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20705738">Gladman et al. (2010)</a> created a mouse model of SMA by inserting the SMN2 C-to-T nucleotide alteration into the endogenous mouse Smn gene. The C-to-T mutation was sufficient to induce exon 7 skipping in the mouse minigene as in the human SMN2. When the mouse Smn gene was humanized to carry the C-to-T mutation, keeping it under the control of the endogenous promoter, and in the natural genomic context, the resulting mice exhibited exon 7 skipping and mild adult-onset SMA characterized by muscle weakness, decreased activity, and an alteration of muscle fiber size. <a href="#15" class="mim-tip-reference" title="Gladman, J. T., Bebee, T. W., Edwards, C., Wang, X., Sahenk, Z., Rich, M. M., Chandler, D. S. <strong>A humanized Smn gene containing the SMN2 nucleotide alteration in exon 7 mimics SMN2 splicing and the SMA disease phenotype.</strong> Hum. Molec. Genet. 19: 4239-4252, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20705738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20705738</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20705738[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/10.1093/hmg/ddq343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20705738">Gladman et al. (2010)</a> proposed that the Smn C-to-T mouse is a model for the adult-onset form of SMA (type III/IV; see <a href="/entry/253400">253400</a>) known as Kugelberg-Welander disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20705738" 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>Through chemical screening and optimization, <a href="#32" class="mim-tip-reference" title="Naryshkin, N. A., Weetall, M., Dakka, A., Narasimhan, J., Zhao, X., Feng, Z., Ling, K. K. Y., Karp, G. M., Qi, H., Woll, M. G., Chen, G., Zhang, N., and 36 others. <strong>SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy.</strong> Science 345: 688-693, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25104390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25104390</a>] [<a href="https://doi.org/10.1126/science.1250127" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25104390">Naryshkin et al. (2014)</a> identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 mRNA with high selectivity. Administration of these compounds to delta-7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25104390" 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>1 Selected Example</a>):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div id="mimAllelicVariantsFold" class="collapse in mimTextToggleFold">
|
|
<div>
|
|
<a href="/allelicVariants/601627" class="btn btn-default" role="button"> Table View </a>
|
|
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=601627[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 SPINAL MUSCULAR ATROPHY, MODIFIER OF</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
SMN2, GLY287ARG
|
|
</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> rs121909192 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909192;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/rs121909192?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=rs121909192" 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=rs121909192" 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=RCV000008426 OR RCV000487481 OR RCV001824116 OR RCV004525848" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008426, RCV000487481, RCV001824116, RCV004525848" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008426...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 42-year-old woman with a mild form of SMA type III (<a href="/entry/253400">253400</a>), despite a homozygous absence of SMN1 exon 7 (<a href="/entry/600354">600354</a>), <a href="#34" class="mim-tip-reference" title="Prior, T. W., Krainer, A. R., Hua, Y., Swoboda, K. J., Snyder, P. C., Bridgeman, S. J., Burghes, A. H. M., Kissel, J. T. <strong>A positive modifier of spinal muscular atrophy in the SMN2 gene.</strong> Am. J. Hum. Genet. 85: 408-413, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19716110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19716110</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19716110[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/10.1016/j.ajhg.2009.08.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19716110">Prior et al. (2009)</a> identified a homozygous 859G-C transversion in exon 7 of the SMN2 gene, resulting in a gly287-to-arg (G287R) substitution. In vitro functional expression studies showed that the change resulted in the creation of an exonic splicing enhancer element and increased the amount of full-length SMN2 transcripts compared to wildtype. The SMN1 genotype (0 SMN1, 0 SNM2) predicted a more severe disorder (SMA1; <a href="/entry/253300">253300</a>), but the SMN2 variant increased SMN2 transcripts, resulting in a less severe phenotype. The same 859G-C transversion was identified in heterozygosity in 2 additional unrelated patients with mild forms of SMA, who were predicted to have a more severe form of the disorder from their genotypes (0 SMN1/1 SMN2 and 0 SMN1, 2 SMN2). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19716110" 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="seeAlso" class="mim-anchor"></a>
|
|
<h4 href="#mimSeeAlsoFold" id="mimSeeAlsoToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span class="mim-font">
|
|
<span id="mimSeeAlsoToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<div id="mimSeeAlsoFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<a href="#Cartegni2002" class="mim-tip-reference" title="Cartegni, L., Krainer, A. R. <strong>Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1.</strong> Nature Genet. 30: 377-384, 2002.">Cartegni and Krainer (2002)</a>; <a href="#Matthijs1996" class="mim-tip-reference" title="Matthijs, G., Schollen, E., Legius, E., Devriendt, K., Goemans, N., Kayserili, H., Apak, M. Y., Cassiman, J.-J. <strong>Unusual molecular findings in autosomal recessive spinal muscular atrophy.</strong> J. Med. Genet. 33: 469-474, 1996.">Matthijs et al. (1996)</a>; <a href="#Skordis2003" class="mim-tip-reference" title="Skordis, L. A., Dunckley, M. G., Yue, B., Eperon, I. C., Muntoni, F. <strong>Bifunctional antisense oligonucleotides provide a trans-acting splicing enhancer that stimulates SMN2 gene expression in patient fibroblasts.</strong> Proc. Nat. Acad. Sci. 100: 4114-4119, 2003.">Skordis et al.
|
|
(2003)</a>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</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="Andreassi2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Andreassi, C., Jarecki, J., Zhou, J., Coovert, D. D., Monani, U. R., Chen, X., Whitney, M., Pollok, B., Zhang, M., Androphy, E., Burghes, A. H. M.
|
|
<strong>Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients.</strong>
|
|
Hum. Molec. Genet. 10: 2841-2849, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11734549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11734549</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11734549" 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/hmg/10.24.2841" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="2" class="mim-anchor"></a>
|
|
<a id="Angelozzi2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Angelozzi, C., Borgo, F., Tiziano, F. D., Martella, A., Neri, G., Brahe, C.
|
|
<strong>Salbutamol increases SMN mRNA and protein levels in spinal muscular atrophy cells.</strong>
|
|
J. Med. Genet. 45: 29-31, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17932121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17932121</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17932121" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1136/jmg.2007.051177" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="3" class="mim-anchor"></a>
|
|
<a id="Boda2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Boda, B., Mas, C., Giudicelli, C., Nepote, V., Guimiot, F., Levacher, B., Zvara, A., Santha, M., LeGall, I., Simonneau, M.
|
|
<strong>Survival motor neuron SMN1 and SMN2 gene promoters: identical sequences and differential expression in neurons and non-neuronal cells.</strong>
|
|
Europ. J. Hum. Genet. 12: 729-737, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15162126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15162126</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15162126" 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/sj.ejhg.5201217" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="4" class="mim-anchor"></a>
|
|
<a id="Brichta2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Brichta, L., Hofmann, Y., Hahnen, E., Siebzehnrubl, F. A., Raschke, H., Blumcke, I., Eyupoglu, I. Y., Wirth, B.
|
|
<strong>Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy.</strong>
|
|
Hum. Molec. Genet. 12: 2481-2489, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915451</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12915451" 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/hmg/ddg256" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="5" class="mim-anchor"></a>
|
|
<a id="Burglen1996" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Burglen, L., Lefebvre, S., Clermont, O., Burlet, P., Viollet, L., Cruaud, C., Munnich, A., Melki, J.
|
|
<strong>Structure and organization of the human survival motor neurone (SMN) gene.</strong>
|
|
Genomics 32: 479-482, 1996.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8838816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8838816</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8838816" 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.1996.0147" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="6" class="mim-anchor"></a>
|
|
<a id="Cartegni2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Cartegni, L., Hastings, M. L., Calarco, J. A., de Stanchina, E., Krainer, A. R.
|
|
<strong>Determinants of exon 7 splicing in the spinal muscular atrophy genes, SMN1 and SMN2.</strong>
|
|
Am. J. Hum. Genet. 78: 63-77, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16385450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16385450</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16385450[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=16385450" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1086/498853" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="7" class="mim-anchor"></a>
|
|
<a id="Cartegni2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Cartegni, L., Krainer, A. R.
|
|
<strong>Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1.</strong>
|
|
Nature Genet. 30: 377-384, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11925564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11925564</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11925564" 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/ng854" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="8" class="mim-anchor"></a>
|
|
<a id="Coovert1997" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Coovert, D. D., Le, T. T., McAndrew, P. E., Strasswimmer, J., Crawford, T. O., Mendell, J. R., Coulson, S. E., Androphy, E. J., Prior, T. W., Burghes, A. H. M.
|
|
<strong>The survival motor neuron protein in spinal muscular atrophy.</strong>
|
|
Hum. Molec. Genet. 6: 1205-1214, 1997.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9259265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9259265</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9259265" 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/hmg/6.8.1205" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="9" class="mim-anchor"></a>
|
|
<a id="Corcia2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Corcia, P., Camu, W., Halimi, J.-M., Vourc'h, P., Antar, C., Vedrine, S., Giraudeau, B., de Toffol, B., Andres, C. R., the French ALS Research Group.
|
|
<strong>SMN1 gene, but not SMN2, is a risk factor for sporadic ALS.</strong>
|
|
Neurology 67: 1147-1150, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16931506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16931506</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16931506" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1212/01.wnl.0000233830.85206.1e" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="10" class="mim-anchor"></a>
|
|
<a id="Corcia2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Corcia, P., Mayeux-Portas, V., Khoris, J., de Toffol, B., Autret, A., Muh, J.-P., Camu, W., Andres, C., the French ALS Research Group.
|
|
<strong>Abnormal SMN1 gene copy number is a susceptibility factor for amyotrophic lateral sclerosis.</strong>
|
|
Ann. Neurol. 51: 243-246, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11835381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11835381</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11835381" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/ana.10104" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="11" class="mim-anchor"></a>
|
|
<a id="Corcia2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Corcia, P., Moulard, B., Andres, C., Camu, W., the French ALS Research Group.
|
|
<strong>Reply to Crawford and Skolasky. (Letter)</strong>
|
|
Ann. Neurol. 52: 858-860, 2002.
|
|
|
|
|
|
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="12" class="mim-anchor"></a>
|
|
<a id="Crawford2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Crawford, T. O., Skolasky, R. L., Jr.
|
|
<strong>The relationship of SMN to amyotrophic lateral sclerosis. (Letter)</strong>
|
|
Ann. Neurol. 52: 857-858, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12447945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12447945</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12447945" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/ana.10378" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="13" class="mim-anchor"></a>
|
|
<a id="Feldkotter2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Feldkotter, M., Schwarzer, V., Wirth, R., Wienker, T. F., Wirth, B.
|
|
<strong>Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy.</strong>
|
|
Am. J. Hum. Genet. 70: 358-368, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11791208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11791208</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11791208[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=11791208" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1086/338627" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="14" class="mim-anchor"></a>
|
|
<a id="Gamez2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Gamez, J., Barcelo, M. J., Munoz, X., Carmona, F., Cusco, I., Baiget, M., Cervera, C., Tizzano, E. F.
|
|
<strong>Survival and respiratory decline are not related to homozygous SMN2 deletions in ALS patients.</strong>
|
|
Neurology 59: 1456-1460, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12427907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12427907</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12427907" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1212/01.wnl.0000032496.64510.4e" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="15" class="mim-anchor"></a>
|
|
<a id="Gladman2010" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Gladman, J. T., Bebee, T. W., Edwards, C., Wang, X., Sahenk, Z., Rich, M. M., Chandler, D. S.
|
|
<strong>A humanized Smn gene containing the SMN2 nucleotide alteration in exon 7 mimics SMN2 splicing and the SMA disease phenotype.</strong>
|
|
Hum. Molec. Genet. 19: 4239-4252, 2010.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20705738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20705738</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20705738[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=20705738" 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/hmg/ddq343" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="16" class="mim-anchor"></a>
|
|
<a id="Gladman2009" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Gladman, J. T., Chandler, D. S.
|
|
<strong>Intron 7 conserved sequence elements regulate the splicing of the SMN gene.</strong>
|
|
Hum. Genet. 126: 833-841, 2009.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19701774/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19701774</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19701774[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=19701774" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1007/s00439-009-0733-7" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="17" class="mim-anchor"></a>
|
|
<a id="Grzeschik2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Grzeschik, S. M., Ganta, M., Prior, T. W., Heavlin, W. D., Wang, C. H.
|
|
<strong>Hydroxyurea enhances SMN2 gene expression in spinal muscular atrophy cells.</strong>
|
|
Ann. Neurol. 58: 194-202, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16049920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16049920</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16049920" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/ana.20548" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="18" class="mim-anchor"></a>
|
|
<a id="Hahnen1996" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Hahnen, E., Schonling, J., Rudnik-Schoneborn, S., Zerres, K., Wirth, B.
|
|
<strong>Hybrid survival motor neuron genes in patients with autosomal recessive spinal muscular atrophy: new insights into molecular mechanisms responsible for the disease.</strong>
|
|
Am. J. Hum. Genet. 59: 1057-1065, 1996.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8900234/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8900234</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8900234" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="19" class="mim-anchor"></a>
|
|
<a id="Hauke2009" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Hauke, J., Riessland, M., Lunke, S., Eyupoglu, I. Y., Blumcke, I., El-Osta, A., Wirth, B., Hahnen, E.
|
|
<strong>Survival motor neuron gene 2 silencing by DNA methylation correlates with spinal muscular atrophy disease severity and can be bypassed by histone deacetylase inhibition.</strong>
|
|
Hum. Molec. Genet. 18: 304-317, 2009.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18971205/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18971205</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18971205[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=18971205" 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/hmg/ddn357" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="20" class="mim-anchor"></a>
|
|
<a id="Helmken2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Helmken, C., Hofmann, Y., Schoenen, F., Oprea, G., Raschke, H., Rudnik-Schoneborn, S., Zerres, K., Wirth, B.
|
|
<strong>Evidence for a modifying pathway in SMA discordant families: reduced SMN level decreases the amount of its interacting partners and Htra2-beta1.</strong>
|
|
Hum. Genet. 114: 11-21, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14520560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14520560</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14520560" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1007/s00439-003-1025-2" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="21" class="mim-anchor"></a>
|
|
<a id="Hofmann2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Hofmann, Y., Wirth, B.
|
|
<strong>hnRNP-G promotes exon 7 inclusion of survival motor neuron (SMN) via direct interaction with Htra2-beta1.</strong>
|
|
Hum. Molec. Genet. 11: 2037-2049, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12165565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12165565</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12165565" 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/hmg/11.17.2037" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="22" class="mim-anchor"></a>
|
|
<a id="Jodelka2010" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Jodelka, F. M., Ebert, A. D., Duelli, D. M., Hastings, M. L.
|
|
<strong>A feedback loop regulates splicing of the spinal muscular atrophy-modifying gene, SMN2.</strong>
|
|
Hum. Molec. Genet. 19: 4906-4917, 2010.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20884664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20884664</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20884664[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=20884664" 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/hmg/ddq425" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="23" class="mim-anchor"></a>
|
|
<a id="Kashima2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Kashima, T., Manley, J. L.
|
|
<strong>A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy.</strong>
|
|
Nature Genet. 34: 460-463, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12833158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12833158</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12833158" 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/ng1207" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="24" class="mim-anchor"></a>
|
|
<a id="Kashima2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Kashima, T., Rao, N., David, C. J., Manley, J. L.
|
|
<strong>hnRNP A1 functions with specificity in repression of SMN2 exon 7 splicing.</strong>
|
|
Hum. Molec. Genet. 16: 3149-3159, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17884807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17884807</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17884807" 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/hmg/ddm276" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="25" class="mim-anchor"></a>
|
|
<a id="Kashima2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Kashima, T., Rao, N., Manley, J. L.
|
|
<strong>An intronic element contributes to splicing repression in spinal muscular atrophy.</strong>
|
|
Proc. Nat. Acad. Sci. 104: 3426-3431, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17307868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17307868</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17307868[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=17307868" 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.0700343104" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="26" class="mim-anchor"></a>
|
|
<a id="Kernochan2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Kernochan, L. E., Russo, M. L., Woodling, N. S., Huynh, T. N., Avila, A. M., Fischbeck, K. H., Sumner, C. J.
|
|
<strong>The role of histone acetylation in SMN gene expression.</strong>
|
|
Hum. Molec. Genet. 14: 1171-1182, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15772088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15772088</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15772088" 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/hmg/ddi130" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="27" class="mim-anchor"></a>
|
|
<a id="Le2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Le, T. T., Pham, L. T., Butchbach, M. E. R., Zhang, H. L., Monani, U. R., Coovert, D. D., Gavrilina, T. O., Xing, L., Bassell, G. J., Burghes, A. H. M.
|
|
<strong>SMN-delta-7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN.</strong>
|
|
Hum. Molec. Genet. 14: 845-857, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15703193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15703193</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15703193" 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/hmg/ddi078" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="28" class="mim-anchor"></a>
|
|
<a id="Lefebvre1995" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Lefebvre, S., Burglen, L., Reboullet, S., Clermont, O., Burlet, P., Viollet, L., Benichou, B., Cruaud, C., Millasseau, P., Zeviani, M., Le Paslier, D., Frezal, J., Cohen, D., Weissenbach, J., Munnich, A., Melki, J.
|
|
<strong>Identification and characterization of a spinal muscular atrophy-determining gene.</strong>
|
|
Cell 80: 155-165, 1995.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7813012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7813012</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7813012" 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(95)90460-3" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="29" class="mim-anchor"></a>
|
|
<a id="Matthijs1996" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Matthijs, G., Schollen, E., Legius, E., Devriendt, K., Goemans, N., Kayserili, H., Apak, M. Y., Cassiman, J.-J.
|
|
<strong>Unusual molecular findings in autosomal recessive spinal muscular atrophy.</strong>
|
|
J. Med. Genet. 33: 469-474, 1996.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782046</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782046" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1136/jmg.33.6.469" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="30" class="mim-anchor"></a>
|
|
<a id="Monani1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Monani, U. R., Lorson, C. L., Parsons, D. W., Prior, T. W., Androphy, E. J., Burghes, A. H. M., McPherson, J. D.
|
|
<strong>A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2.</strong>
|
|
Hum. Molec. Genet. 8: 1177-1183, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10369862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10369862</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10369862" 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/hmg/8.7.1177" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="31" class="mim-anchor"></a>
|
|
<a id="Moulard1998" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Moulard, B., Salachas, F., Chassande, B., Briolotti, V., Meininger, V., Malafosse, A., Camu, W.
|
|
<strong>Association between centromeric deletions of the SMN gene and sporadic adult-onset lower motor neuron disease.</strong>
|
|
Ann. Neurol. 43: 640-644, 1998.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9585359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9585359</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9585359" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/ana.410430513" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="32" class="mim-anchor"></a>
|
|
<a id="Naryshkin2014" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Naryshkin, N. A., Weetall, M., Dakka, A., Narasimhan, J., Zhao, X., Feng, Z., Ling, K. K. Y., Karp, G. M., Qi, H., Woll, M. G., Chen, G., Zhang, N., and 36 others.
|
|
<strong>SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy.</strong>
|
|
Science 345: 688-693, 2014.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25104390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25104390</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25104390" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.1250127" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="33" class="mim-anchor"></a>
|
|
<a id="Ogino2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Ogino, S., Wilson, R. B., Gold, B.
|
|
<strong>New insights on the evolution of the SMN1 and SMN2 region: simulation and meta-analysis for allele and haplotype frequency calculations.</strong>
|
|
Europ. J. Hum. Genet. 12: 1015-1023, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15470363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15470363</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15470363" 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/sj.ejhg.5201288" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="34" class="mim-anchor"></a>
|
|
<a id="Prior2009" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Prior, T. W., Krainer, A. R., Hua, Y., Swoboda, K. J., Snyder, P. C., Bridgeman, S. J., Burghes, A. H. M., Kissel, J. T.
|
|
<strong>A positive modifier of spinal muscular atrophy in the SMN2 gene.</strong>
|
|
Am. J. Hum. Genet. 85: 408-413, 2009.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19716110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19716110</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19716110[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=19716110" 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.ajhg.2009.08.002" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="35" class="mim-anchor"></a>
|
|
<a id="Rochette2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Rochette, C. F., Gilbert, N., Simard, L. R.
|
|
<strong>SMN gene duplication and the emergence of the SMN2 gene occurred in distinct hominids: SMN2 is unique to Homo sapiens.</strong>
|
|
Hum. Genet. 108: 255-266, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11354640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11354640</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11354640" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1007/s004390100473" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="36" class="mim-anchor"></a>
|
|
<a id="Schwartz1997" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Schwartz, M., Sorensen, N., Hansen, F. J., Hertz, J. M., Norby, S., Tranebjaerg, L., Skovby, F.
|
|
<strong>Quantification, by solid-phase minisequencing, of the telomeric and centromeric copies of the survival motor neuron gene in families with spinal muscular atrophy.</strong>
|
|
Hum. Molec. Genet. 6: 99-104, 1997.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9002676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9002676</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9002676" 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/hmg/6.1.99" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="37" class="mim-anchor"></a>
|
|
<a id="Skordis2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Skordis, L. A., Dunckley, M. G., Yue, B., Eperon, I. C., Muntoni, F.
|
|
<strong>Bifunctional antisense oligonucleotides provide a trans-acting splicing enhancer that stimulates SMN2 gene expression in patient fibroblasts.</strong>
|
|
Proc. Nat. Acad. Sci. 100: 4114-4119, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12642665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12642665</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12642665[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=12642665" 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.0633863100" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="38" class="mim-anchor"></a>
|
|
<a id="Srivastava2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Srivastava, S., Mukherjee, M., Panigrahi, I., Pandey, G. S., Pradhan, S., Mittal, B.
|
|
<strong>SMN2-deletion in childhood-onset spinal muscular atrophy.</strong>
|
|
Am. J. Med. Genet. 101: 198-202, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11424133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11424133</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11424133" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/ajmg.1386" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="39" class="mim-anchor"></a>
|
|
<a id="Ting2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Ting, C.-H., Lin, C.-W., Wen, S.-L., Hsieh-Li, H.-M., Li, H.
|
|
<strong>Stat5 constitutive activation rescues defects in spinal muscular atrophy.</strong>
|
|
Hum. Molec. Genet. 16: 499-514, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17220171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17220171</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17220171" 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/hmg/ddl482" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="40" class="mim-anchor"></a>
|
|
<a id="Wirth2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Wirth, B., Brichta, L., Schrank, B., Lochmuller, H., Blick, S., Baasner, A., Heller, R.
|
|
<strong>Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number.</strong>
|
|
Hum. Genet. 119: 422-428, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16508748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16508748</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16508748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1007/s00439-006-0156-7" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="41" class="mim-anchor"></a>
|
|
<a id="Workman2009" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Workman, E., Saieva, L., Carrel, T. L., Crawford, T. O., Liu, D., Lutz, C., Beattie, C. E., Pellizzoni, L., Burghes, A. H. M.
|
|
<strong>A SMN missense mutation complements SMN2 restoring snRNPs and rescuing SMA mice.</strong>
|
|
Hum. Molec. Genet. 18: 2215-2229, 2009.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19329542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19329542</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19329542[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=19329542" 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/hmg/ddp157" 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">
|
|
George E. Tiller - updated : 06/26/2017
|
|
</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">
|
|
Ada Hamosh - updated : 8/29/2014<br>Patricia A. Hartz - updated : 1/15/2014<br>Patricia A. Hartz - updated : 8/25/2010<br>Cassandra L. Kniffin - updated : 6/8/2010<br>George E. Tiller - updated : 3/3/2010<br>Matthew B. Gross - updated : 10/26/2009<br>Patricia A. Hartz - updated : 10/14/2009<br>Cassandra L. Kniffin - updated : 10/6/2009<br>George E. Tiller - updated : 4/17/2009<br>George E. Tiller - updated : 5/19/2008<br>George E. Tiller - updated : 5/8/2008<br>Cassandra L. Kniffin - updated : 3/6/2008<br>Cassandra L. Kniffin - updated : 9/17/2007<br>Patricia A. Hartz - updated : 4/13/2007<br>Marla J. F. O'Neill - updated : 8/11/2006<br>Victor A. McKusick - updated : 1/5/2006<br>Cassandra L. Kniffin - updated : 12/1/2005<br>Cassandra L. Kniffin - reorganized : 11/29/2005<br>Cassandra L. Kniffin - updated : 11/22/2005<br>George E. Tiller - updated : 9/12/2005<br>Marla J. F. O'Neill - updated : 1/6/2005<br>Patricia A. Hartz - updated : 10/18/2004<br>Victor A. McKusick - updated : 12/9/2003<br>George E. Tiller - updated : 7/11/2003<br>Victor A. McKusick - updated : 7/1/2003<br>Victor A. McKusick - updated : 5/30/2003<br>Ada Hamosh - updated : 3/5/2003<br>George E. Tiller - updated : 10/4/2002<br>George E. Tiller - updated : 6/12/2002<br>Victor A. McKusick - updated : 3/1/2002<br>Victor A. McKusick - updated : 2/21/2002<br>Victor A. McKusick - updated : 7/31/2001<br>Ada Hamosh - updated : 4/19/2001<br>Victor A. McKusick - updated : 4/6/2001<br>George E. Tiller - updated : 1/18/2000<br>Orest Hurko - updated : 9/25/1998<br>Victor A. McKusick - updated : 6/5/1997
|
|
</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">
|
|
Moyra Smith : 1/14/1997
|
|
</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 : 02/22/2022
|
|
</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 : 01/23/2018<br>alopez : 06/26/2017<br>carol : 01/06/2016<br>carol : 1/5/2016<br>alopez : 8/29/2014<br>mgross : 1/17/2014<br>mcolton : 1/15/2014<br>mgross : 8/31/2010<br>terry : 8/25/2010<br>wwang : 6/15/2010<br>ckniffin : 6/8/2010<br>wwang : 3/15/2010<br>terry : 3/3/2010<br>mgross : 10/26/2009<br>terry : 10/14/2009<br>wwang : 10/8/2009<br>ckniffin : 10/6/2009<br>alopez : 4/17/2009<br>alopez : 2/24/2009<br>terry : 2/18/2009<br>wwang : 5/22/2008<br>terry : 5/19/2008<br>wwang : 5/8/2008<br>wwang : 5/8/2008<br>ckniffin : 3/6/2008<br>ckniffin : 3/6/2008<br>carol : 11/13/2007<br>wwang : 9/24/2007<br>ckniffin : 9/17/2007<br>mgross : 4/18/2007<br>terry : 4/13/2007<br>ckniffin : 2/13/2007<br>wwang : 8/15/2006<br>terry : 8/11/2006<br>alopez : 1/11/2006<br>terry : 1/5/2006<br>wwang : 12/5/2005<br>ckniffin : 12/1/2005<br>carol : 11/29/2005<br>ckniffin : 11/22/2005<br>alopez : 10/20/2005<br>terry : 9/12/2005<br>carol : 1/10/2005<br>terry : 1/6/2005<br>alopez : 10/18/2004<br>tkritzer : 12/16/2003<br>terry : 12/9/2003<br>alopez : 9/2/2003<br>cwells : 7/11/2003<br>alopez : 7/2/2003<br>terry : 7/1/2003<br>tkritzer : 6/5/2003<br>terry : 5/30/2003<br>cwells : 3/5/2003<br>cwells : 10/4/2002<br>cwells : 6/12/2002<br>cwells : 6/12/2002<br>alopez : 4/12/2002<br>alopez : 3/1/2002<br>terry : 3/1/2002<br>carol : 2/27/2002<br>cwells : 2/27/2002<br>terry : 2/21/2002<br>cwells : 8/10/2001<br>cwells : 8/8/2001<br>cwells : 8/1/2001<br>terry : 7/31/2001<br>alopez : 4/20/2001<br>terry : 4/19/2001<br>mcapotos : 4/9/2001<br>terry : 4/6/2001<br>alopez : 1/18/2000<br>carol : 9/25/1998<br>carol : 7/21/1998<br>mark : 6/5/1997<br>terry : 2/26/1997<br>jamie : 1/16/1997<br>jamie : 1/15/1997<br>jamie : 1/15/1997<br>terry : 1/14/1997<br>mark : 1/14/1997
|
|
</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> 601627
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
SURVIVAL OF MOTOR NEURON 2; SMN2
|
|
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div >
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
SURVIVAL OF MOTOR NEURON, CENTROMERIC COPY; SMNC<br />
|
|
C-BCD541
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: SMN2</em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 5q13.2
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 5:70,049,523-70,090,528 </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="1">
|
|
<span class="mim-font">
|
|
5q13.2
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Spinal muscular atrophy, type III, modifier of}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
253400
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</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 SMN1 (600354) and SMN2 genes lie within the telomeric and centromeric halves, respectively, of a large, inverted duplication on chromosome 5q13. These genes share more than 99% nucleotide identity, and both are capable of encoding a 294-amino acid RNA-binding protein, SMN, that is required for efficient assembly of small nuclear ribonucleoprotein (snRNP) complexes. Homozygous loss of the SMN1 gene causes spinal muscular atrophy (SMA; 253300). Absence of SMN1 is partially compensated for by SMN2, which produces enough SMN protein to allow for relatively normal development in cell types other than motor neurons. However, SMN2 cannot fully compensate for loss of SMN1 because, although SMN2 is transcribed at a level comparable to that of SMN1, a large majority of SMN2 transcripts lack exon 7, resulting in production of a truncated, less stable SMN protein (Lefebvre et al., 1995; Kashima et al., 2007). </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>Lefebvre et al. (1995) described an inverted duplication of a 500-kb element in normal chromosome 5q13, which contains the gene for spinal muscular atrophy. Within the telomeric region, they identified the SMN1 gene. A highly homologous gene, referred to as C-BCD541 and also known as SMNC or SMN2, was present in the duplicated centromeric element in 95% of controls. PCR amplification and sequence analysis revealed 5 nucleotide discrepancies between the centromeric and telomeric SMN genes, 2 of which occur in exons 7 and 8. The centromeric SMN gene undergoes alternative splicing of exon 7, resulting in a truncated mRNA transcript lacking exon 7 and a putative protein with a different C-terminal end. </p><p>Using a panel of anti-SMN antibodies, Coovert et al. (1997) demonstrated that the SMN protein is expressed from both the SMN1 and SMN2 genes. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Burglen et al. (1996) determined that the SMN gene has 9 exons and spans approximately 20 kb. Burglen et al. (1996) referred to exon 2 as exons 2a and 2b. </p><p>Boda et al. (2004) determined that the first 4.6 kb of the SMN1 and SMN2 promoters are identical. The promoters contain 12 SP1 (189906), 8 AP1 (see 165160), 3 AP2 (107580), 6 HNF3 (see 602294), 24 Zeste (see 601674), and 4 RXR-beta (180246) sites. There are no RE1 elements. Boda et al. (2004) transfected primary cultures of mouse embryonic spinal cord and fibroblasts with constructs containing 1.8, 3.2, or 4.6 kb of the promoter region fused to a reporter gene. Expression of the 1.8- and 3.2-kb constructs was stronger in spinal cord than in fibroblast cultures; the 4.6-kb construct gave 5-fold higher expression in neurons than in fibroblasts, with expression in fibroblasts lower than that achieved with the 3.2-kb construct. Boda et al. (2004) concluded that these results suggest the presence of an enhancer element between 1.8 and 3.2 kb upstream from the transcriptional start site of the SMN genes that functions in both culture types, and a silencer between 3.2 and 4.6 kb that is active only in fibroblast cultures. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Lefebvre et al. (1995) determined that the SMN2 gene lies within the centromeric half of a large inverted duplication on chromosome 5q13. The SMN1 gene lies in the telomeric half of the duplication. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Monani et al. (1999) sequenced 3 genomic clones over 32 kb in length, which spanned both the SMN1 and SMN2 genes. Of 35 sequence differences noted between SMN1 and SMN2, only 3 were located in either exon 7 or intron 7. Of note was a translationally silent 840C-T transition at position +6 in exon 7, which affects splicing. Using minigene constructs, the authors found that the presence of cytosine at position +6 in exon 7 produced a normal splicing pattern retaining exon 7, whereas thymine in this position resulted in the absence of exon 7 in the majority of the transcripts. Since the majority of human SMN2 transcripts lack exon 7, the authors hypothesized that the 5-prime portion of exon 7 in SMN1 contains an exonic splice enhancer (ESE), and that low levels of full-length SMN transcript are responsible for the SMA phenotype. </p><p>Andreassi et al. (2001) screened a library of compounds and found that aclarubicin increased the retention of exon 7 into the SMN2 transcript from the endogenous gene in type I SMA fibroblasts, as well as from an SMN2 minigene in a motor neuron cell line. In type I fibroblasts, treatment resulted in an increase in SMN protein and gems to normal levels. The authors demonstrated the utility of high-throughput screens in detecting compounds that affect the splicing pattern of a gene, and suggested that alteration of splicing patterns may represent a feasible approach to modification of gene expression in disease treatment. </p><p>Using in vivo splicing assays, Hofmann and Wirth (2002) identified the protein hnRNPG (300199) and its paralog RBM (400006) as 2 novel splicing factors that promote the inclusion of SMN2 exon 7. Both hnRNPG and RBM nonspecifically bind RNA, but directly and specifically bind Htra2-beta1, an SR-like splicing factor which stimulates inclusion of exon 7 through a direct interaction with SMN2 exon 7 pre-mRNA. Using deletion mutants of hnRNPG, the authors demonstrated a specific protein-protein interaction of hnRNPG with Htra2-beta1 which mediates the inclusion of SMN2 exon 7 rather than the nonspecific interaction of hnRNPG with SMN pre-mRNA. These trans-acting splicing factors were also effective on endogenous SMN2 transcripts and increased the endogenous SMN protein level. The authors presented a model of how exon 7 mRNA processing may be regulated by these splicing factors. </p><p>Kashima and Manley (2003) showed that the exonic splicing silencer in SMN2 functions as a binding site for a known repressor protein, HNRNPA1 (164017), which binds to SMN2 but not SMN1 exon 7 RNA. By using small interfering RNAs (siRNAs) to reduce HNRNPA1 protein levels in living cells, Kashima and Manley (2003) demonstrated efficient SMN2 exon 7 splicing. The findings not only defined a new mechanism underlying the inefficient splicing of SMN2 exon 7 but also illustrated more generally the remarkable sensitivity and precision that characterizes control of mRNA splicing. The work also made it possible to consider therapeutic approaches to spinal muscular atrophy that involved decreasing HNRNPA1 RNA binding to or function on SMN2 exon 7. </p><p>Helmken et al. (2003) stated that sibs with identical 5q13 homologs and homozygous absence of SMN1 can have variable phenotypes, suggesting that the spinal muscular atrophy phenotype is modified by other factors, which function either on the transcriptional level, to produce more full-length SMN (FL-SMN) transcripts, or on the translational level, to increase the amount of SMN2 protein. By analyzing 9 SMA discordant families, Helmken et al. (2003) demonstrated that in all families unaffected sibs produced significantly higher amounts of SMN, SMN-interacting protein-1 (SIP1; 602595), GEMIN3 (606168), ZPR1 (603901), and hnRNPQ protein in lymphoblastoid cell lines, but not in primary fibroblasts, compared with their affected sibs. The results suggested that the modifying factor or factors act on the SMN gene to influence SMN protein levels, thus modifying the SMA phenotype, and not through an independent pathway. In addition, the observed coregulations appeared to be tissue-specific. SMN significantly coregulated its interacting partners, including its own splicing factor, HTRA2-beta-1 (see 606441), due to an indirect feedback mechanism. Thus, Helmken et al. (2003) showed that reduction of the SMN protein has a significant impact on the expression level of a splicing factor. </p><p>Brichta et al. (2003) showed that in fibroblast cultures derived from SMA patients treated with therapeutic doses of valproic acid, the level of full-length SMN2 mRNA/protein increased 2- to 4-fold. This upregulation of SMN was most likely attributable to increased levels of HTRA2-beta-1 as well as to SMN gene transcription activation. Valproic acid also increased SMN protein levels through transcription activation in organotypic hippocampal rat brain slices. Additionally, valproic acid increased the expression of other serine-arginine family proteins, which may have important implications for other disorders affected by alternative splicing. </p><p>Grzeschik et al. (2005) reported that cultured lymphocytes from patients with SMA showed increased production of the full-length SMN mRNA and protein in response to treatment with hydroxyurea. The findings suggested that hydroxyurea promoted inclusion of exon 7 during SMN2 transcription. </p><p>Kernochan et al. (2005) investigated the levels of acetylated H3 and H4 histones and histone deacetylases (HDACs) associated with different regions of the human and mouse SMN genes in both cultured cells and tissues. The SMN gene had a reproducible pattern of histone acetylation that was largely conserved among different tissues and species. A limited region of the promoter surrounding the transcriptional start site had relatively high levels of histone acetylation. After HDAC inhibitor treatment, acetylated histone levels increased, particularly at upstream regions, correlating with a 2-fold increase in promoter activity. During development in mouse tissues, histone acetylation levels decreased and associated HDAC2 (605164) levels increased at the region closest to the transcriptional start site, correlating with a 40 to 60% decrease in SMN transcript and protein levels. Kernochan et al. (2005) suggested that histone acetylation may modulate SMN gene expression. </p><p>Skipping of SMN2 exon 7 had been attributed to either the loss of an SF2/ASF-dependent exonic splicing enhancer or the creation of an hnRNP A/B-dependent exonic splicing silencer, as a result of the C-to-T transition. Cartegni et al. (2006) reported the extensive testing of the enhancer-loss and silencer-gain models by mutagenesis, RNA interference, overexpression, RNA splicing, and RNA-protein interaction experiments. The results supported the enhancer-loss model but also demonstrated that hnRNP A/B proteins antagonize SF2/ASF-dependent ESE activity and promote exon 7 skipping by a mechanism that is independent of the C-to-T transition and is, therefore, common to both SMN1 and SMN2. The findings explained the basis of defective SMN2 splicing, illustrated the fine balance between positive and negative determinants of exon identity and alternative splicing, and underscored the importance of antagonistic splicing factors and exonic elements in a disease context. </p><p>Kashima et al. (2007) showed that the 840C-T transition in SMN2 created a high-affinity HNRNPA1-binding site. Depletion of HNRNPA1 in HeLa cells restored exon 7 inclusion, indicating that splicing of exon 7 in SMN2 is repressed by an HNRNPA1-dependent exonic splicing silencer. </p><p>Kashima et al. (2007) identified a novel single nucleotide difference between SMN1 and SMN2, an A-to-G change at position +100 within intron 7 of SMN2, which creates a second high-affinity HNRNPA1-binding site specific to SMN2. Base substitutions that disrupted this site in SMN2 restored exon 7 inclusion in vivo and prevented HNRNPA1 binding in vitro. Kashima et al. (2007) proposed that interactions between HNRNPA1 molecules bound to the exonic and intronic sites cooperate to exclude exon 7 in SMN2. </p><p>Angelozzi et al. (2008) found that salbutamol increased full-length SMN2 mRNA transcript levels in fibroblasts derived from patients with SMA. The maximum increase (over 200%) was observed after 30 to 60 minutes. This rapid rise correlated with decreased levels of SMN2 mRNA with deletion of exon 7. Salbutamol treatment also resulted in increased SMN protein levels and nuclear gems. </p><p>Using SMN minigenes, Gladman and Chandler (2009) identified 2 elements within intron 7 of the SMN genes that influenced exon 7 splicing in a cell type-independent manner. </p><p>Using in vitro splicing assays, minigenes, and knockdown and overexpression studies with human constructs and cells, Jodelka et al. (2010) showed that total SMN protein content and the relative abundance of individual snRNPs determined inclusion or skipping of SMN2 exon 7. Exon 7 was not included in SMN2 mRNAs in the absence of SMN protein. Exon 7 inclusion was highly sensitive to the level of U1 snRNP. Jodelka et al. (2010) noted that U1 snRNP recognizes the 5-prime splice site of pre-mRNAs through direct basepairing, and they found that the 5-prime splice site of SMN2 exon 7 was a critical determinant of exon inclusion. Jodelka et al. (2010) concluded that SMN protein controls its own expression via positive-feedback regulation of alternative SMN2 pre-mRNA splicing and that reduced SMN protein content in SMA has a deleterious effect on expression of the full-length protein via SMN2 mRNA. </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>Spinal Muscular Atrophy</em></strong></p><p>
|
|
Hahnen et al. (1996) reported molecular analysis of 42 SMA patients who carried homozygous deletions of exon 7 but not of exon 8 in the telomeric copy of the SMN gene (SMN1). Additional homozygous deletions of exon 8 in the centromeric copy of SMN (SMN2) were found in 2 of the patients. By a simple PCR test, they demonstrated the existence of hybrid SMN genes, i.e., genes composed of both the centromeric SMN2 and the telomeric SMN1. They reported a high frequency of hybrid SMN genes in SMA patients with Czech or Polish background. Hahnen et al. (1996) identified a single haplotype for half of the hybrid genes analyzed, suggesting that in these cases the SMA chromosomes shared a common origin. </p><p>Schwartz et al. (1997) used solid-phase minisequencing to determine the ratio between the number of telomeric and centromeric copies of the SMN gene in affected and unaffected members of 30 SMA families. Six predominant haplotypes were identified, 3 for normal chromosomes and 3 for SMA chromosomes, characterized by having 0, 1, or 2 copies, respectively, of SMN2. They found patients homozygous for a deletion of SMN1 and with only one copy of SMN2, but found none deleted for all copies of SMN2. Several asymptomatic carriers of SMA with only a single copy of SMN1 and no copy of SMN2 were identified. Schwartz et al. (1997) could not confirm the hypothesis that the presence of more copies of SMN2 is correlated with a less severe course of the disease. The frequencies of haplotypes characterized by having 0, 1, or 2 copies, respectively, of SMN2 were found to differ significantly between normal and SMA chromosomes. This distribution could be explained by an underrepresentation of the haplotype completely lacking SMN genes, which is expected to cause early embryonic death in homozygotes. </p><p>Srivastava et al. (2001) reported a 5-year-old boy with childhood-onset SMA who had a homozygous deletion of SMN2. He had wasting, weakness, and hyporeflexia, predominantly in the distal muscles. The affected muscles showed chronic neurogenic changes on electromyography. There was no sensory involvement. A nerve conduction study showed near-normal conduction velocity with reduction in the amplitude of the compound muscle action potential. The SMN2 deletion was demonstrated by studies of exons 7 and 8 of the SMN genes. Base sequencing and densitometric analysis of the critical exon 7 region did not show any microdeletion or duplication of SMN1, but confirmed the deletion of SMN2. Srivastava et al. (2001) concluded that deletion of SMN2 can also result in the SMA phenotype. </p><p>Feldkotter et al. (2002) developed a quantitative test for either SMN1 or SMN2 to analyze SMA patients for their SMN2 copy number and to correlate the SMN2 copy number with type of SMA and duration of survival. The quantitative analysis of SMN2 copies in 375 patients with type I, type II, or type III SMA showed a significant correlation between SMN2 copy number and type of SMA as well as duration of survival. Thus, 80% of patients with type I SMA carried 1 or 2 SMN2 copies and 82% of patients with type II SMA carried 3 SMN2 copies, whereas 96% of patients with type III SMA carried 3 or 4 SMN2 copies. Among 113 patients with type I SMA, 9 with 1 SMN2 copy lived less than 11 months, 88 of 94 with 2 SMN2 copies lived less than 21 months, and 8 of 10 with 3 SMN2 copies lived 33 to 66 months. On the basis of SMN2 copy number, Feldkotter et al. (2002) calculated the posterior probability that a child with homozygous absence of SMN1 will develop type I, type II, or type III SMA. </p><p>Ogino et al. (2004) analyzed all 'available and reliable' data to calculate allele/haplotype frequencies and new mutation rates in the SMN region. The authors stated that their data provided the basis for the most accurate genetic risk calculations as well as evidence that nucleotide position 840 constitutes a mutation hotspot. Ogino et al. (2004) suggested that there is selection of the single-copy SMN1-SMN2 haplotype and that rare chromosomes with 3 copies of SMN1 exist. </p><p>Wirth et al. (2006) analyzed SMN2 copy number in 115 patients with SMA3 (253400) or SMA4 (271150) who had confirmed homozygous absence of SMN1 and found that 62% of SMA3 patients with age of onset less than 3 years had 2 or 3 SMN2 copies, whereas 65% of SMA3 patients with age of onset greater than 3 years had 4 to 5 SMN2 copies. Of the 4 adult-onset (SMA4) patients, 3 had 4 SMN2 copies and 1 had 6 copies. Wirth et al. (2006) concluded that SMN2 may have a disease-modifying role in SMA, with a greater SMN2 copy number associated with later onset and better prognosis. </p><p>Hauke et al. (2009) demonstrated that SMN2 is subject to gene silencing by DNA methylation. SMN2 contains 4 CpG islands which present highly conserved methylation patterns and little interindividual variation in SMN1-deleted SMA patients. The comprehensive analysis of SMN2 methylation in patients suffering from severe versus mild SMA carrying identical SMN2 copy numbers revealed a correlation of CpG methylation at the positions -290 and -296 with disease severity and the activity of the first transcriptional start site of SMN2 at position -296. The methyl-CpG-binding protein-2 (MECP2; 300005), a transcriptional repressor, bound to the critical SMN2 promoter region in a methylation-dependent manner. The authors identified histone deacetylase (HDAC) inhibitors (including vorinostat and romidepsin) that were able to bypass SMN2 gene silencing by DNA methylation, while others (such as valproic acid and phenylbutyrate) did not, due to HDAC isoenzyme specificities. The authors concluded that DNA methylation is functionally important regarding SMA disease progression, and pharmacologic SMN2 gene activation might have implications for future SMA therapy regimens. </p><p><strong><em>Amyotrophic Lateral Sclerosis</em></strong></p><p>
|
|
Moulard et al. (1998) found homozygous deletions of SMN2 in 36% of individuals with sporadic adult-onset lower motor neuron disease (LMND), but in only 6.2% of individuals with sporadic amyotrophic lateral sclerosis (ALS; 105400) and 1.5% of individuals with familial ALS. The authors argued that SMN2, but not SMN1, deletions are a susceptibility factor for LMND, a disorder distinguishable from ALS by the absence of upper motor neuron signs. LMND patients with SMN2 deletions differed from those patients without such deletions by earlier age of onset (40 vs 56 years), more rapid disease progression (25 vs 36 months to death), and a lower preponderance of males (M:F ratio of 1.5 vs 2.5). </p><p>Among 124 ALS patients, Gamez et al. (2002) found no association between homozygous deletion of SMN2 and disease onset, respiratory decline, or survival. A homozygous SMN2 deletion was identified in 11 (8.8%) patients and 20 (10%) of 200 control individuals. Corcia et al. (2002) found no difference in SMN2 gene copies among 167 ALS patients and 167 controls. Homozygous deletion of the SMN2 gene was found in 9 and 10% of patients and controls, respectively. Among 600 patients with sporadic ALS, Corcia et al. (2006) found no disease association with SMN2 copy number. </p><p>Crawford and Skolasky (2002) briefly reviewed several reported associations of SMN to ALS and concluded that the findings likely represented nonsignificant or borderline significant fluctuations. Corcia et al. (2002) responded that although they still supported a role for the SMN2 gene in LMND (Moulard et al., 1998), the evidence of an association between homozygous SMN2 deletion and ALS was less convincing. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Evolution</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Rochette et al. (2001) used a number of approaches to probe the evolutionary history of the SMN1 and SMN2 genes and showed that SMN gene duplication and the appearance of SMN2 occurred at very distinct evolutionary times. Molecular fossil and molecular clock data suggested that this duplication may have occurred as recently as 3 million years ago in that the position and repetitive elements are identical for both human SMN genes and overall sequence divergence ranges from 0.15 to 0.34%. However, these approaches ignored the possibility of sequence homogenization by means of gene conversion. Consequently, Rochette et al. (2001) used quantitative polymerase chain reaction and analysis of allelic variants to provide physical evidence for or against SMN gene duplication in the chimpanzee, mankind's closest relative. These studies revealed that chimpanzees have 2 to 7 copies of the SMN gene per diploid genome; however, the 2 nucleotides diagnostic for exons 7-8 and the SMNdel7 mRNA product of the SMN2 gene are absent in nonhuman primates. In contrast, the SMN2 gene has been detected in all extant human populations studied to date, including representatives from Europe, the Central African Republic, and the Congo. These data provided conclusive evidence that SMN gene duplication occurred more than 5 million years ago, before the separation of human and chimpanzee lineages, but that SMN2 appeared for the first time in Homo sapiens. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Le et al. (2005) created transgenic mice expressing SMN2 lacking exon 7 (SMN-delta-7) and crossed them onto a severe SMA background. Expression of SMN-delta-7 appeared to extend survival of SMA mice from 5 to 13 days. Unlike mice with selective deletion of SMN exon 7 in muscle, mice with a small amount of full-length SMN (FL-SMN) did not show a dystrophic phenotype. The authors suggested that low levels of FL-SMN (as found in SMA patients) and absence of FL-SMN in muscle tissue may have different effects, and raised the question of the importance of high SMN levels in muscle in the presentation of SMA. SMN and SMN-delta-7 can associate with each other; Le et al. (2005) suggested that this association may stabilize SMN-delta-7 protein turnover and ameliorate the SMA phenotype by increasing the amount of oligomeric SMN. </p><p>In SMA-like mouse embryonic fibroblasts and human SMN2-transfected motor neuron cells, Ting et al. (2007) found that sodium vanadate, trichostatin A, and aclarubicin effectively enhanced SMN2 expression by inducing Stat5 (601511) activation. This resulted in enhanced SMN2 promoter activity with an increase in both full-length and deletion exon 7 SMN transcripts in human cells with SMN2. Knockdown of Stat5 expression disrupted the effects of sodium vanadate on SMN2 activation, but did not influence SMN2 splicing, suggesting that Stat5 signaling is involved in SMN2 transcriptional regulation. Constitutive expression of the activated Stat5 mutant Stat5A1*6 profoundly increased the number of nuclear gems in SMA patient lymphocytes and reduced SMA-like motor neuron axon outgrowth defects. </p><p>Workman et al. (2009) showed that SMN(A111G), an allele capable of snRNP assembly (A111G; 600354.0015), can rescue mice that lacked Smn and contained either 1 or 2 copies of SMN2 (SMA mice). The correction of SMA in these animals was directly correlated with snRNP assembly activity in spinal cord, as was correction of snRNA levels. These data support snRNP assembly as being the critical function affected in SMA and suggests that the levels of snRNPs are critical to motor neurons. Furthermore, SMN(A111G) could not rescue Smn-null mice without SMN2, suggesting that both SMN(A111G) and SMN from SMN2 may undergo intragenic complementation in vivo to function in heteromeric complexes that have greater function than either allele alone. The oligomer composed of limiting full-length SMN and SMN(A111G) had substantial snRNP assembly activity. The SMN(A2G) (A2G; 600354.0002) and SMN(A111G) alleles in vivo did not complement each other, leading to the possibility that these mutations could affect the same function. </p><p>Although human SMN1 and SMN2 both encode the SMN protein, the SMN2 gene is unable to compensate for the loss of SMN1 protein in SMA patients. A translationally silent T at nucleotide +6 of SMN2 exon 7 instead of SMN1's C causes the final RNA product to be improperly regulated, with the majority of SMN2 pre-mRNA transcripts lacking exon 7. While humans have both SMN1 and SMN2 genes, mice and other mammals have only a single Smn gene. Using mouse and human SMN minigenes and homologous recombination, Gladman et al. (2010) created a mouse model of SMA by inserting the SMN2 C-to-T nucleotide alteration into the endogenous mouse Smn gene. The C-to-T mutation was sufficient to induce exon 7 skipping in the mouse minigene as in the human SMN2. When the mouse Smn gene was humanized to carry the C-to-T mutation, keeping it under the control of the endogenous promoter, and in the natural genomic context, the resulting mice exhibited exon 7 skipping and mild adult-onset SMA characterized by muscle weakness, decreased activity, and an alteration of muscle fiber size. Gladman et al. (2010) proposed that the Smn C-to-T mouse is a model for the adult-onset form of SMA (type III/IV; see 253400) known as Kugelberg-Welander disease. </p><p>Through chemical screening and optimization, Naryshkin et al. (2014) identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 mRNA with high selectivity. Administration of these compounds to delta-7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>1 Selected Example):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 SPINAL MUSCULAR ATROPHY, MODIFIER OF</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMN2, GLY287ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909192,
|
|
|
|
|
|
gnomAD: rs121909192,
|
|
|
|
|
|
ClinVar: RCV000008426, RCV000487481, RCV001824116, RCV004525848
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 42-year-old woman with a mild form of SMA type III (253400), despite a homozygous absence of SMN1 exon 7 (600354), Prior et al. (2009) identified a homozygous 859G-C transversion in exon 7 of the SMN2 gene, resulting in a gly287-to-arg (G287R) substitution. In vitro functional expression studies showed that the change resulted in the creation of an exonic splicing enhancer element and increased the amount of full-length SMN2 transcripts compared to wildtype. The SMN1 genotype (0 SMN1, 0 SNM2) predicted a more severe disorder (SMA1; 253300), but the SMN2 variant increased SMN2 transcripts, resulting in a less severe phenotype. The same 859G-C transversion was identified in heterozygosity in 2 additional unrelated patients with mild forms of SMA, who were predicted to have a more severe form of the disorder from their genotypes (0 SMN1/1 SMN2 and 0 SMN1, 2 SMN2). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Cartegni and Krainer (2002); Matthijs et al. (1996); Skordis et al.
|
|
(2003)
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Andreassi, C., Jarecki, J., Zhou, J., Coovert, D. D., Monani, U. R., Chen, X., Whitney, M., Pollok, B., Zhang, M., Androphy, E., Burghes, A. H. M.
|
|
<strong>Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients.</strong>
|
|
Hum. Molec. Genet. 10: 2841-2849, 2001.
|
|
|
|
|
|
[PubMed: 11734549]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/10.24.2841]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Angelozzi, C., Borgo, F., Tiziano, F. D., Martella, A., Neri, G., Brahe, C.
|
|
<strong>Salbutamol increases SMN mRNA and protein levels in spinal muscular atrophy cells.</strong>
|
|
J. Med. Genet. 45: 29-31, 2008.
|
|
|
|
|
|
[PubMed: 17932121]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1136/jmg.2007.051177]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Boda, B., Mas, C., Giudicelli, C., Nepote, V., Guimiot, F., Levacher, B., Zvara, A., Santha, M., LeGall, I., Simonneau, M.
|
|
<strong>Survival motor neuron SMN1 and SMN2 gene promoters: identical sequences and differential expression in neurons and non-neuronal cells.</strong>
|
|
Europ. J. Hum. Genet. 12: 729-737, 2004.
|
|
|
|
|
|
[PubMed: 15162126]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/sj.ejhg.5201217]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Brichta, L., Hofmann, Y., Hahnen, E., Siebzehnrubl, F. A., Raschke, H., Blumcke, I., Eyupoglu, I. Y., Wirth, B.
|
|
<strong>Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy.</strong>
|
|
Hum. Molec. Genet. 12: 2481-2489, 2003.
|
|
|
|
|
|
[PubMed: 12915451]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddg256]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Burglen, L., Lefebvre, S., Clermont, O., Burlet, P., Viollet, L., Cruaud, C., Munnich, A., Melki, J.
|
|
<strong>Structure and organization of the human survival motor neurone (SMN) gene.</strong>
|
|
Genomics 32: 479-482, 1996.
|
|
|
|
|
|
[PubMed: 8838816]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1006/geno.1996.0147]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Cartegni, L., Hastings, M. L., Calarco, J. A., de Stanchina, E., Krainer, A. R.
|
|
<strong>Determinants of exon 7 splicing in the spinal muscular atrophy genes, SMN1 and SMN2.</strong>
|
|
Am. J. Hum. Genet. 78: 63-77, 2006.
|
|
|
|
|
|
[PubMed: 16385450]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1086/498853]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Cartegni, L., Krainer, A. R.
|
|
<strong>Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1.</strong>
|
|
Nature Genet. 30: 377-384, 2002.
|
|
|
|
|
|
[PubMed: 11925564]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng854]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Coovert, D. D., Le, T. T., McAndrew, P. E., Strasswimmer, J., Crawford, T. O., Mendell, J. R., Coulson, S. E., Androphy, E. J., Prior, T. W., Burghes, A. H. M.
|
|
<strong>The survival motor neuron protein in spinal muscular atrophy.</strong>
|
|
Hum. Molec. Genet. 6: 1205-1214, 1997.
|
|
|
|
|
|
[PubMed: 9259265]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/6.8.1205]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Corcia, P., Camu, W., Halimi, J.-M., Vourc'h, P., Antar, C., Vedrine, S., Giraudeau, B., de Toffol, B., Andres, C. R., the French ALS Research Group.
|
|
<strong>SMN1 gene, but not SMN2, is a risk factor for sporadic ALS.</strong>
|
|
Neurology 67: 1147-1150, 2006.
|
|
|
|
|
|
[PubMed: 16931506]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1212/01.wnl.0000233830.85206.1e]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Corcia, P., Mayeux-Portas, V., Khoris, J., de Toffol, B., Autret, A., Muh, J.-P., Camu, W., Andres, C., the French ALS Research Group.
|
|
<strong>Abnormal SMN1 gene copy number is a susceptibility factor for amyotrophic lateral sclerosis.</strong>
|
|
Ann. Neurol. 51: 243-246, 2002.
|
|
|
|
|
|
[PubMed: 11835381]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ana.10104]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Corcia, P., Moulard, B., Andres, C., Camu, W., the French ALS Research Group.
|
|
<strong>Reply to Crawford and Skolasky. (Letter)</strong>
|
|
Ann. Neurol. 52: 858-860, 2002.
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Crawford, T. O., Skolasky, R. L., Jr.
|
|
<strong>The relationship of SMN to amyotrophic lateral sclerosis. (Letter)</strong>
|
|
Ann. Neurol. 52: 857-858, 2002.
|
|
|
|
|
|
[PubMed: 12447945]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ana.10378]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Feldkotter, M., Schwarzer, V., Wirth, R., Wienker, T. F., Wirth, B.
|
|
<strong>Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy.</strong>
|
|
Am. J. Hum. Genet. 70: 358-368, 2002.
|
|
|
|
|
|
[PubMed: 11791208]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1086/338627]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gamez, J., Barcelo, M. J., Munoz, X., Carmona, F., Cusco, I., Baiget, M., Cervera, C., Tizzano, E. F.
|
|
<strong>Survival and respiratory decline are not related to homozygous SMN2 deletions in ALS patients.</strong>
|
|
Neurology 59: 1456-1460, 2002.
|
|
|
|
|
|
[PubMed: 12427907]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1212/01.wnl.0000032496.64510.4e]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gladman, J. T., Bebee, T. W., Edwards, C., Wang, X., Sahenk, Z., Rich, M. M., Chandler, D. S.
|
|
<strong>A humanized Smn gene containing the SMN2 nucleotide alteration in exon 7 mimics SMN2 splicing and the SMA disease phenotype.</strong>
|
|
Hum. Molec. Genet. 19: 4239-4252, 2010.
|
|
|
|
|
|
[PubMed: 20705738]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddq343]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gladman, J. T., Chandler, D. S.
|
|
<strong>Intron 7 conserved sequence elements regulate the splicing of the SMN gene.</strong>
|
|
Hum. Genet. 126: 833-841, 2009.
|
|
|
|
|
|
[PubMed: 19701774]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s00439-009-0733-7]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Grzeschik, S. M., Ganta, M., Prior, T. W., Heavlin, W. D., Wang, C. H.
|
|
<strong>Hydroxyurea enhances SMN2 gene expression in spinal muscular atrophy cells.</strong>
|
|
Ann. Neurol. 58: 194-202, 2005.
|
|
|
|
|
|
[PubMed: 16049920]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ana.20548]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hahnen, E., Schonling, J., Rudnik-Schoneborn, S., Zerres, K., Wirth, B.
|
|
<strong>Hybrid survival motor neuron genes in patients with autosomal recessive spinal muscular atrophy: new insights into molecular mechanisms responsible for the disease.</strong>
|
|
Am. J. Hum. Genet. 59: 1057-1065, 1996.
|
|
|
|
|
|
[PubMed: 8900234]
|
|
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hauke, J., Riessland, M., Lunke, S., Eyupoglu, I. Y., Blumcke, I., El-Osta, A., Wirth, B., Hahnen, E.
|
|
<strong>Survival motor neuron gene 2 silencing by DNA methylation correlates with spinal muscular atrophy disease severity and can be bypassed by histone deacetylase inhibition.</strong>
|
|
Hum. Molec. Genet. 18: 304-317, 2009.
|
|
|
|
|
|
[PubMed: 18971205]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddn357]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Helmken, C., Hofmann, Y., Schoenen, F., Oprea, G., Raschke, H., Rudnik-Schoneborn, S., Zerres, K., Wirth, B.
|
|
<strong>Evidence for a modifying pathway in SMA discordant families: reduced SMN level decreases the amount of its interacting partners and Htra2-beta1.</strong>
|
|
Hum. Genet. 114: 11-21, 2003.
|
|
|
|
|
|
[PubMed: 14520560]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s00439-003-1025-2]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hofmann, Y., Wirth, B.
|
|
<strong>hnRNP-G promotes exon 7 inclusion of survival motor neuron (SMN) via direct interaction with Htra2-beta1.</strong>
|
|
Hum. Molec. Genet. 11: 2037-2049, 2002.
|
|
|
|
|
|
[PubMed: 12165565]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/11.17.2037]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Jodelka, F. M., Ebert, A. D., Duelli, D. M., Hastings, M. L.
|
|
<strong>A feedback loop regulates splicing of the spinal muscular atrophy-modifying gene, SMN2.</strong>
|
|
Hum. Molec. Genet. 19: 4906-4917, 2010.
|
|
|
|
|
|
[PubMed: 20884664]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddq425]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kashima, T., Manley, J. L.
|
|
<strong>A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy.</strong>
|
|
Nature Genet. 34: 460-463, 2003.
|
|
|
|
|
|
[PubMed: 12833158]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng1207]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kashima, T., Rao, N., David, C. J., Manley, J. L.
|
|
<strong>hnRNP A1 functions with specificity in repression of SMN2 exon 7 splicing.</strong>
|
|
Hum. Molec. Genet. 16: 3149-3159, 2007.
|
|
|
|
|
|
[PubMed: 17884807]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddm276]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kashima, T., Rao, N., Manley, J. L.
|
|
<strong>An intronic element contributes to splicing repression in spinal muscular atrophy.</strong>
|
|
Proc. Nat. Acad. Sci. 104: 3426-3431, 2007.
|
|
|
|
|
|
[PubMed: 17307868]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.0700343104]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kernochan, L. E., Russo, M. L., Woodling, N. S., Huynh, T. N., Avila, A. M., Fischbeck, K. H., Sumner, C. J.
|
|
<strong>The role of histone acetylation in SMN gene expression.</strong>
|
|
Hum. Molec. Genet. 14: 1171-1182, 2005.
|
|
|
|
|
|
[PubMed: 15772088]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddi130]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Le, T. T., Pham, L. T., Butchbach, M. E. R., Zhang, H. L., Monani, U. R., Coovert, D. D., Gavrilina, T. O., Xing, L., Bassell, G. J., Burghes, A. H. M.
|
|
<strong>SMN-delta-7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN.</strong>
|
|
Hum. Molec. Genet. 14: 845-857, 2005.
|
|
|
|
|
|
[PubMed: 15703193]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddi078]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lefebvre, S., Burglen, L., Reboullet, S., Clermont, O., Burlet, P., Viollet, L., Benichou, B., Cruaud, C., Millasseau, P., Zeviani, M., Le Paslier, D., Frezal, J., Cohen, D., Weissenbach, J., Munnich, A., Melki, J.
|
|
<strong>Identification and characterization of a spinal muscular atrophy-determining gene.</strong>
|
|
Cell 80: 155-165, 1995.
|
|
|
|
|
|
[PubMed: 7813012]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/0092-8674(95)90460-3]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Matthijs, G., Schollen, E., Legius, E., Devriendt, K., Goemans, N., Kayserili, H., Apak, M. Y., Cassiman, J.-J.
|
|
<strong>Unusual molecular findings in autosomal recessive spinal muscular atrophy.</strong>
|
|
J. Med. Genet. 33: 469-474, 1996.
|
|
|
|
|
|
[PubMed: 8782046]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1136/jmg.33.6.469]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Monani, U. R., Lorson, C. L., Parsons, D. W., Prior, T. W., Androphy, E. J., Burghes, A. H. M., McPherson, J. D.
|
|
<strong>A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2.</strong>
|
|
Hum. Molec. Genet. 8: 1177-1183, 1999.
|
|
|
|
|
|
[PubMed: 10369862]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/8.7.1177]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Moulard, B., Salachas, F., Chassande, B., Briolotti, V., Meininger, V., Malafosse, A., Camu, W.
|
|
<strong>Association between centromeric deletions of the SMN gene and sporadic adult-onset lower motor neuron disease.</strong>
|
|
Ann. Neurol. 43: 640-644, 1998.
|
|
|
|
|
|
[PubMed: 9585359]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ana.410430513]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Naryshkin, N. A., Weetall, M., Dakka, A., Narasimhan, J., Zhao, X., Feng, Z., Ling, K. K. Y., Karp, G. M., Qi, H., Woll, M. G., Chen, G., Zhang, N., and 36 others.
|
|
<strong>SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy.</strong>
|
|
Science 345: 688-693, 2014.
|
|
|
|
|
|
[PubMed: 25104390]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1250127]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ogino, S., Wilson, R. B., Gold, B.
|
|
<strong>New insights on the evolution of the SMN1 and SMN2 region: simulation and meta-analysis for allele and haplotype frequency calculations.</strong>
|
|
Europ. J. Hum. Genet. 12: 1015-1023, 2004.
|
|
|
|
|
|
[PubMed: 15470363]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/sj.ejhg.5201288]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Prior, T. W., Krainer, A. R., Hua, Y., Swoboda, K. J., Snyder, P. C., Bridgeman, S. J., Burghes, A. H. M., Kissel, J. T.
|
|
<strong>A positive modifier of spinal muscular atrophy in the SMN2 gene.</strong>
|
|
Am. J. Hum. Genet. 85: 408-413, 2009.
|
|
|
|
|
|
[PubMed: 19716110]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.ajhg.2009.08.002]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Rochette, C. F., Gilbert, N., Simard, L. R.
|
|
<strong>SMN gene duplication and the emergence of the SMN2 gene occurred in distinct hominids: SMN2 is unique to Homo sapiens.</strong>
|
|
Hum. Genet. 108: 255-266, 2001.
|
|
|
|
|
|
[PubMed: 11354640]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s004390100473]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Schwartz, M., Sorensen, N., Hansen, F. J., Hertz, J. M., Norby, S., Tranebjaerg, L., Skovby, F.
|
|
<strong>Quantification, by solid-phase minisequencing, of the telomeric and centromeric copies of the survival motor neuron gene in families with spinal muscular atrophy.</strong>
|
|
Hum. Molec. Genet. 6: 99-104, 1997.
|
|
|
|
|
|
[PubMed: 9002676]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/6.1.99]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Skordis, L. A., Dunckley, M. G., Yue, B., Eperon, I. C., Muntoni, F.
|
|
<strong>Bifunctional antisense oligonucleotides provide a trans-acting splicing enhancer that stimulates SMN2 gene expression in patient fibroblasts.</strong>
|
|
Proc. Nat. Acad. Sci. 100: 4114-4119, 2003.
|
|
|
|
|
|
[PubMed: 12642665]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.0633863100]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Srivastava, S., Mukherjee, M., Panigrahi, I., Pandey, G. S., Pradhan, S., Mittal, B.
|
|
<strong>SMN2-deletion in childhood-onset spinal muscular atrophy.</strong>
|
|
Am. J. Med. Genet. 101: 198-202, 2001.
|
|
|
|
|
|
[PubMed: 11424133]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.1386]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ting, C.-H., Lin, C.-W., Wen, S.-L., Hsieh-Li, H.-M., Li, H.
|
|
<strong>Stat5 constitutive activation rescues defects in spinal muscular atrophy.</strong>
|
|
Hum. Molec. Genet. 16: 499-514, 2007.
|
|
|
|
|
|
[PubMed: 17220171]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddl482]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Wirth, B., Brichta, L., Schrank, B., Lochmuller, H., Blick, S., Baasner, A., Heller, R.
|
|
<strong>Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number.</strong>
|
|
Hum. Genet. 119: 422-428, 2006.
|
|
|
|
|
|
[PubMed: 16508748]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s00439-006-0156-7]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Workman, E., Saieva, L., Carrel, T. L., Crawford, T. O., Liu, D., Lutz, C., Beattie, C. E., Pellizzoni, L., Burghes, A. H. M.
|
|
<strong>A SMN missense mutation complements SMN2 restoring snRNPs and rescuing SMA mice.</strong>
|
|
Hum. Molec. Genet. 18: 2215-2229, 2009.
|
|
|
|
|
|
[PubMed: 19329542]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddp157]
|
|
|
|
|
|
</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">
|
|
George E. Tiller - updated : 06/26/2017<br>Ada Hamosh - updated : 8/29/2014<br>Patricia A. Hartz - updated : 1/15/2014<br>Patricia A. Hartz - updated : 8/25/2010<br>Cassandra L. Kniffin - updated : 6/8/2010<br>George E. Tiller - updated : 3/3/2010<br>Matthew B. Gross - updated : 10/26/2009<br>Patricia A. Hartz - updated : 10/14/2009<br>Cassandra L. Kniffin - updated : 10/6/2009<br>George E. Tiller - updated : 4/17/2009<br>George E. Tiller - updated : 5/19/2008<br>George E. Tiller - updated : 5/8/2008<br>Cassandra L. Kniffin - updated : 3/6/2008<br>Cassandra L. Kniffin - updated : 9/17/2007<br>Patricia A. Hartz - updated : 4/13/2007<br>Marla J. F. O'Neill - updated : 8/11/2006<br>Victor A. McKusick - updated : 1/5/2006<br>Cassandra L. Kniffin - updated : 12/1/2005<br>Cassandra L. Kniffin - reorganized : 11/29/2005<br>Cassandra L. Kniffin - updated : 11/22/2005<br>George E. Tiller - updated : 9/12/2005<br>Marla J. F. O'Neill - updated : 1/6/2005<br>Patricia A. Hartz - updated : 10/18/2004<br>Victor A. McKusick - updated : 12/9/2003<br>George E. Tiller - updated : 7/11/2003<br>Victor A. McKusick - updated : 7/1/2003<br>Victor A. McKusick - updated : 5/30/2003<br>Ada Hamosh - updated : 3/5/2003<br>George E. Tiller - updated : 10/4/2002<br>George E. Tiller - updated : 6/12/2002<br>Victor A. McKusick - updated : 3/1/2002<br>Victor A. McKusick - updated : 2/21/2002<br>Victor A. McKusick - updated : 7/31/2001<br>Ada Hamosh - updated : 4/19/2001<br>Victor A. McKusick - updated : 4/6/2001<br>George E. Tiller - updated : 1/18/2000<br>Orest Hurko - updated : 9/25/1998<br>Victor A. McKusick - updated : 6/5/1997
|
|
</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">
|
|
Moyra Smith : 1/14/1997
|
|
</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 : 02/22/2022<br>carol : 01/23/2018<br>alopez : 06/26/2017<br>carol : 01/06/2016<br>carol : 1/5/2016<br>alopez : 8/29/2014<br>mgross : 1/17/2014<br>mcolton : 1/15/2014<br>mgross : 8/31/2010<br>terry : 8/25/2010<br>wwang : 6/15/2010<br>ckniffin : 6/8/2010<br>wwang : 3/15/2010<br>terry : 3/3/2010<br>mgross : 10/26/2009<br>terry : 10/14/2009<br>wwang : 10/8/2009<br>ckniffin : 10/6/2009<br>alopez : 4/17/2009<br>alopez : 2/24/2009<br>terry : 2/18/2009<br>wwang : 5/22/2008<br>terry : 5/19/2008<br>wwang : 5/8/2008<br>wwang : 5/8/2008<br>ckniffin : 3/6/2008<br>ckniffin : 3/6/2008<br>carol : 11/13/2007<br>wwang : 9/24/2007<br>ckniffin : 9/17/2007<br>mgross : 4/18/2007<br>terry : 4/13/2007<br>ckniffin : 2/13/2007<br>wwang : 8/15/2006<br>terry : 8/11/2006<br>alopez : 1/11/2006<br>terry : 1/5/2006<br>wwang : 12/5/2005<br>ckniffin : 12/1/2005<br>carol : 11/29/2005<br>ckniffin : 11/22/2005<br>alopez : 10/20/2005<br>terry : 9/12/2005<br>carol : 1/10/2005<br>terry : 1/6/2005<br>alopez : 10/18/2004<br>tkritzer : 12/16/2003<br>terry : 12/9/2003<br>alopez : 9/2/2003<br>cwells : 7/11/2003<br>alopez : 7/2/2003<br>terry : 7/1/2003<br>tkritzer : 6/5/2003<br>terry : 5/30/2003<br>cwells : 3/5/2003<br>cwells : 10/4/2002<br>cwells : 6/12/2002<br>cwells : 6/12/2002<br>alopez : 4/12/2002<br>alopez : 3/1/2002<br>terry : 3/1/2002<br>carol : 2/27/2002<br>cwells : 2/27/2002<br>terry : 2/21/2002<br>cwells : 8/10/2001<br>cwells : 8/8/2001<br>cwells : 8/1/2001<br>terry : 7/31/2001<br>alopez : 4/20/2001<br>terry : 4/19/2001<br>mcapotos : 4/9/2001<br>terry : 4/6/2001<br>alopez : 1/18/2000<br>carol : 9/25/1998<br>carol : 7/21/1998<br>mark : 6/5/1997<br>terry : 2/26/1997<br>jamie : 1/16/1997<br>jamie : 1/15/1997<br>jamie : 1/15/1997<br>terry : 1/14/1997<br>mark : 1/14/1997
|
|
</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 5, 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>
|
|
|
|
|