3606 lines
292 KiB
Text
3606 lines
292 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
|
|
|
|
- *600221 - TEK TYROSINE KINASE, ENDOTHELIAL; TEK
|
|
|
|
|
|
- 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=600221"><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">*600221</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="#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="#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/600221">Table View</a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#references"><strong>References</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#contributors"><strong>Contributors</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#creationDate"><strong>Creation Date</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#editHistory"><strong>Edit History</strong></a>
|
|
</li>
|
|
|
|
</ul>
|
|
|
|
</nav>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimFloatingLinksMenu">
|
|
|
|
<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
|
|
<h4 class="panel-title">
|
|
<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
|
|
<div style="display: table-row">
|
|
<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
|
|
|
|
<div style="display: table-cell;">External Links</div>
|
|
</div>
|
|
</a>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
|
|
<div id="mimExternalLinksFold" class="collapse in">
|
|
|
|
<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000120156;t=ENST00000380036" 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=7010" 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=600221" 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=ENSG00000120156;t=ENST00000380036" 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_000459,NM_001290077,NM_001290078,NM_001375475,NM_001375476" 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_000459" 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=600221" 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=02571&isoform_id=02571_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/TEK" 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/292824,27348226,62087172,112180440,119578975,119578976,158256982,194318478,194318480,194378462,194379086,218511853,300498143,300498145,300498147,300498149,300498151,1770499959,1770499961,1798088738,2633575832,2633575848" 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/Q02763" 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=7010" 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=ENSG00000120156;t=ENST00000380036" 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=TEK" 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=TEK" 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+7010" 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/TEK" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
|
|
|
|
|
|
|
|
<dd><a href="https://monarchinitiative.org/NCBIGene:7010" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/gene/7010" 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=chr9&hgg_gene=ENST00000380036.10&hgg_start=27109225&hgg_end=27230174&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
|
|
|
<div style="display: table-cell;">Clinical Resources</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
|
|
|
|
<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:11724" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://medlineplus.gov/genetics/gene/tek" 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=600221[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=600221[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.deciphergenomics.org/gene/TEK/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000120156" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.ebi.ac.uk/gwas/search?query=TEK" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.gwascentral.org/search?q=TEK" 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=TEK" 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=TEK&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/PA36441" 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:11724" 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/FBgn0003733.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:98664" 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/TEK#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:98664" 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/7010/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=7010" 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=WBGene00012270;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><a href="https://zfin.org/ZDB-GENE-990415-56" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
|
|
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
|
|
|
<div style="display: table-cell;">Cellular Pathways</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:7010" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://reactome.org/content/query?q=TEK&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">
|
|
|
|
|
|
|
|
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
|
|
|
|
<strong>SNOMEDCT:</strong> 699301008<br />
|
|
|
|
|
|
|
|
|
|
|
|
|
|
">ICD+</a>
|
|
|
|
</div>
|
|
<div>
|
|
<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
600221
|
|
</span>
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
<div>
|
|
<a id="preferredTitle" class="mim-anchor"></a>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
TEK TYROSINE KINASE, ENDOTHELIAL; TEK
|
|
|
|
</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">
|
|
PROTEIN RECEPTOR TYROSINE KINASE, EPITHELIAL-SPECIFIC, TIE-2; TIE2
|
|
</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=TEK" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TEK</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/9/113?start=-3&limit=10&highlight=113">9p21.2</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr9:27109225-27230174&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'})">9:27,109,225-27,230,174</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=617272,600195" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/9/113?start=-3&limit=10&highlight=113">
|
|
9p21.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Glaucoma 3, primary congenital, E
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/617272"> 617272 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Venous malformations, multiple cutaneous and mucosal
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/600195"> 600195 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/600221" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/600221" 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 TEK receptor tyrosine kinase is expressed almost exclusively in endothelial cells in mice, rats, and humans. This receptor possesses a unique extracellular domain containing 2 immunoglobulin-like loops separated by 3 epidermal growth factor-like repeats that are connected to 3 fibronectin type III-like repeats. The complex extracellular domain and the fact that the expression of this receptor tyrosine kinase is restricted to the endothelial cell lineage suggest that TEK plays a unique role within this cell lineage. In fact, disruption of the TEK gene by homologous recombination in ES cells results in embryonic lethality in homozygous mutant mouse embryos due to deficiency of the endothelium. The ligand for the receptor is angiopoietin-1 (ANG1; <a href="/entry/601667">601667</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>The tek gene and its closely related subfamily member, tie, have both been mapped to mouse chromosome 4 (<a href="#5" class="mim-tip-reference" title="Dumont, D. J., Yamaguchi, T. P., Conlon, R. A., Rossant, J., Breitman, M. L. <strong>tek, a novel tyrosine kinase gene located on mouse chromosome 4, is expressed in endothelial cells and their presumptive precursors.</strong> Oncogene 7: 1471-1480, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1630810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1630810</a>]" pmid="1630810">Dumont et al., 1992</a>; <a href="#14" class="mim-tip-reference" title="Sato, T. N., Qin, Y., Kozak, C. A., Audus, K. L. <strong>tie-1 and tie-2 define another class of putative receptor tyrosine kinase genes expressed in early embryonic vascular system.</strong> Proc. Nat. Acad. Sci. 90: 9355-9358, 1993. Note: Erratum: Proc. Nat. Acad. Sci. 90: 12056 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8415706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8415706</a>] [<a href="https://doi.org/10.1073/pnas.90.20.9355" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8415706">Sato et al., 1993</a>), and the human TIE gene has been localized to human 1p34-p33 by <a href="#11" class="mim-tip-reference" title="Partanen, J., Armstrong, E., Makela, T. P., Korhonen, J., Sandberg, M., Renkonen, R., Knuutila, S., Huebner, K., Alitalo, K. <strong>A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains.</strong> Molec. Cell. Biol. 12: 1698-1707, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1312667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1312667</a>] [<a href="https://doi.org/10.1128/mcb.12.4.1698-1707.1992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1312667">Partanen et al. (1992)</a>. By isotopic in situ hybridization, <a href="#4" class="mim-tip-reference" title="Dumont, D. J., Anderson, L., Breitman, M. L., Duncan, A. M. V. <strong>Assignment of the endothelial-specific protein receptor tyrosine kinase gene (TEK) to human chromosome 9p21.</strong> Genomics 23: 512-513, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7835909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7835909</a>] [<a href="https://doi.org/10.1006/geno.1994.1536" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7835909">Dumont et al. (1994)</a> assigned the human TEK gene to 9p21. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1312667+1630810+7835909+8415706" 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>See TIE1 (<a href="/entry/600222">600222</a>) for discussion of the relationship between TEK (TIE2) and the TIE1 receptor tyrosine kinase in vascular development.</p><p>Angiogenesis is coordinated with follicular cell growth in goitrogenesis. The angiopoietins ANG1 and ANG2 (<a href="/entry/601922">601922</a>) are angiogenic growth factors acting through TIE2. <a href="#12" class="mim-tip-reference" title="Ramsden, J. D., Cocks, H. C., Shams, M., Nijjar, S., Watkinson, J. C., Sheppard, M. C., Ahmed, A., Eggo, M. C. <strong>Tie-2 is expressed on thyroid follicular cells, is increased in goiter, and is regulated by thyrotropin through cyclic adenosine 3-prime,5-prime-monophosphate.</strong> J. Clin. Endocr. Metab. 86: 2709-2716, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11397875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11397875</a>] [<a href="https://doi.org/10.1210/jcem.86.6.7552" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11397875">Ramsden et al. (2001)</a> examined the expression and regulation of the angiopoietins and TIE2 in human and rat thyroids. In human goiters there was increased TIE2 immunostaining, compared with that in normal thyroids, on both follicular and endothelial cells. In an induced goiter in rats, in situ hybridization showed increased expression of mRNAs for Tie2 and Ang1 in follicular cells. Since TIE2 expression is believed to be restricted to cells of endothelial lineage in adults, they examined its expression further in isolated follicular cells. TIE2 and ANG1 mRNA expression in human thyrocytes was confirmed by ribonuclease protection assay. In both human follicular cell cultures and rat thyroid cells, immunoblotting showed that TIE2 expression was increased by thyroid-stimulating hormone (TSH; <a href="/entry/188540">188540</a>) and agents that increased intracellular cAMP. The authors concluded that TIE2 and ANG1 are expressed in thyroid epithelial and endothelial cells, and that TIE2 is regulated by TSH and cAMP in follicular cells. They also concluded that TIE2 expression is increased in goiter in both humans and rats, consistent with a role in goitrogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11397875" 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>Interaction of hematopoietic stem cells (HSCs) with their particular microenvironments, known as stem cell niches, is critical for adult hematopoiesis in bone marrow. <a href="#1" class="mim-tip-reference" title="Arai, F., Hirao, A., Ohmura, M., Sato, H., Matsuoka, S., Takubo, K., Ito, K., Koh, G. Y., Suda, T. <strong>Tie2/Angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche.</strong> Cell 118: 149-161, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15260986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15260986</a>] [<a href="https://doi.org/10.1016/j.cell.2004.07.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15260986">Arai et al. (2004)</a> demonstrated that HSCs expressing the receptor tyrosine kinase TIE2 are quiescent and antiapoptotic and comprise a side population of HSCs that adhere to osteoblasts in the bone marrow niche. The interaction of TIE2 with its ligand, ANG1, induced cobblestone formation of HSCs in vitro and maintained in vivo long-term repopulating activity of HSCs. Furthermore, ANG1 enhanced the ability of HSCs to become quiescent and induced adhesion to bone, resulting in protection of the HSC compartment from myelosuppressive stress. These data suggested that the TIE2/ANG1 signaling pathway plays a critical role in the maintenance of HSCs in a quiescent state in the bone marrow niche. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15260986" 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>Independently, <a href="#6" class="mim-tip-reference" title="Fukuhara, S., Sako, K., Minami, T., Noda, K., Kim, H. Z., Kodama, T., Shibuya, M., Takakura, N., Koh, G. Y., Mochizuki, N. <strong>Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1.</strong> Nature Cell Biol. 10: 513-526, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18425120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18425120</a>] [<a href="https://doi.org/10.1038/ncb1714" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18425120">Fukuhara et al. (2008)</a> and <a href="#13" class="mim-tip-reference" title="Saharinen, P., Eklund, L., Miettinen, J., Wirkkala, R., Anisimov, A., Winderlich, M., Nottebaum, A., Vestweber, D., Deutsch, U., Koh, G. Y., Olsen, B. R., Alitalo, K. <strong>Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts.</strong> Nature Cell Biol. 10: 527-537, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18425119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18425119</a>] [<a href="https://doi.org/10.1038/ncb1715" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18425119">Saharinen et al. (2008)</a> showed that ANG1 bridged TIE2 molecules on the surface of adjacent endothelial cells at cell-cell contacts. In contrast, extracellular matrix-bound ANG1 located TIE2 at cell-substratum contacts in isolated cells. <a href="#6" class="mim-tip-reference" title="Fukuhara, S., Sako, K., Minami, T., Noda, K., Kim, H. Z., Kodama, T., Shibuya, M., Takakura, N., Koh, G. Y., Mochizuki, N. <strong>Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1.</strong> Nature Cell Biol. 10: 513-526, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18425120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18425120</a>] [<a href="https://doi.org/10.1038/ncb1714" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18425120">Fukuhara et al. (2008)</a> reported that TIE2 preferentially activated AKT (see <a href="/entry/164730">164730</a>) signaling at cell-cell contacts and ERK (see MAPK1; <a href="/entry/176948">176948</a>) signaling at cell-substratum contacts. <a href="#13" class="mim-tip-reference" title="Saharinen, P., Eklund, L., Miettinen, J., Wirkkala, R., Anisimov, A., Winderlich, M., Nottebaum, A., Vestweber, D., Deutsch, U., Koh, G. Y., Olsen, B. R., Alitalo, K. <strong>Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts.</strong> Nature Cell Biol. 10: 527-537, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18425119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18425119</a>] [<a href="https://doi.org/10.1038/ncb1715" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18425119">Saharinen et al. (2008)</a> found that ANG1 induced phosphorylation of TIE2-associated eNOS (NOS3; <a href="/entry/163729">163729</a>), a downstream substrate of AKT, in intercellular contacts of confluent cells. The authors concluded that the cellular microenvironment determines TIE2 signaling between activated angiogenic endothelial cells and quiescent endothelium. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18425120+18425119" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Kim, C., Lee, H. S., Lee, D., Lee, S. D., Cho, E.-G., Yang, S. J., Kim, S. B., Park, D., Kim, M. G. <strong>Epithin/PRSS14 proteolytically regulates angiopoietin receptor Tie2 during transendothelial migration.</strong> Blood 117: 1415-1424, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21097670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21097670</a>] [<a href="https://doi.org/10.1182/blood-2010-03-275289" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21097670">Kim et al. (2011)</a> found that the mouse cell surface serine protease epithin (ST14; <a href="/entry/606797">606797</a>) cleaved Tie2. Immunoprecipitation analysis revealed that interaction of epithin and Tie2 required phorbol ester-mediated cell activation. Tie2 was predominantly expressed in endothelial cells, while epithin was often expressed on the surface of surrounding cells, including epithelial cells. Coculture experiments revealed that epithin expressed on mouse thymic epithelial cells could cleave Tie2 expressed on endothelial cells. Soluble epithin released to the culture medium did not cleave Tie2. Epithin-mediated Tie2 cleavage induced phosphorylation and activation of the truncated Tie2 protein independent of Ang1, resulting in downstream Tie2 signaling via the p85 subunit of PI3 kinase (PIK3R1; <a href="/entry/171833">171833</a>). Knockdown of epithin reduced the ability of mouse epithelial cells to migrate through a confluent endothelial cell monolayer and reduced metastasis of mouse mammary tumor cells in vivo. <a href="#8" class="mim-tip-reference" title="Kim, C., Lee, H. S., Lee, D., Lee, S. D., Cho, E.-G., Yang, S. J., Kim, S. B., Park, D., Kim, M. G. <strong>Epithin/PRSS14 proteolytically regulates angiopoietin receptor Tie2 during transendothelial migration.</strong> Blood 117: 1415-1424, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21097670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21097670</a>] [<a href="https://doi.org/10.1182/blood-2010-03-275289" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21097670">Kim et al. (2011)</a> concluded that epithin expressed on tumor cell surfaces can generate a pathway for metastasis directly by breaking down endothelial cell junctions via TIE2 cleavage and indirectly via activation of truncated TIE2, leading to downstream remodeling of the endothelial cell cytoskeleton and cell retraction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21097670" 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>Multiple Cutaneous and Mucosal Venous Malformations</em></strong></p><p>
|
|
Venous malformations, the most common errors of vascular morphogenesis in humans, are composed of dilated, serpiginous channels. The walls of the channels have a variable thickness of smooth muscle; some mural regions lack smooth muscle altogether. In affected members of 2 unrelated families with multiple cutaneous and mucosal venous malformations (VMCM; <a href="/entry/600195">600195</a>), <a href="#16" class="mim-tip-reference" title="Vikkula, M., Boon, L. M., Carraway, K. L., III, Calvert, J. T., Diamonti, A. J., Goumnerov, B., Pasyk, K. A., Marchuk, D. A., Warman, M. L., Cantley, L. C., Mulliken, J. B., Olsen, B. R. <strong>Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2.</strong> Cell 87: 1181-1190, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8980225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8980225</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81814-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8980225">Vikkula et al. (1996)</a> identified a missense arg849-to-trp mutation (R849W; <a href="#0001">600221.0001</a>) in the kinase domain of TIE2. Using proteins expressed in insect cells, they demonstrated that the mutation resulted in increased activity of TIE2. They concluded that activating mutation in TIE2 caused inherited venous malformations in the 2 families and that the TIE2 signaling pathway is critical for endothelial cell-smooth muscle cell communication in venous morphogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8980225" 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="Calvert, J. T., Riney, T. J., Kontos, C. D., Cha, E. H., Prieto, V. G., Shea, C. R., Berg, J. N., Nevin, N. C., Simpson, S. A., Pasyk, K. A., Speer, M. C., Peters, K. G., Marchuk, D. A. <strong>Allelic and locus heterogeneity in inherited venous malformations.</strong> Hum. Molec. Genet. 8: 1279-1289, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10369874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10369874</a>] [<a href="https://doi.org/10.1093/hmg/8.7.1279" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10369874">Calvert et al. (1999)</a> studied 4 kindreds with inherited venous malformations and identified heterozygosity for the R849W mutation in 1 family. In another family the disease phenotype cosegregated with a different missense mutation (Y897S; <a href="#0002">600221.0002</a>), also located in the first kinase domain. Transfection experiments in COS-1 cells using constructs containing either the R849W or the Y897S mutation demonstrated that the receptors containing either mutation showed ligand-independent hyperphosphorylation, suggesting a gain-of-function mechanism for development of venous malformations in these families. Of the 2 remaining families, 1 excluded linkage to the TIE2 locus, providing evidence for the existence of at least 1 additional locus for dominantly inherited venous malformations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10369874" 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="#9" class="mim-tip-reference" title="Limaye, N., Wouters, V., Uebelhoer, M., Tuominen, M., Wirkkala, R., Mulliken, J. B., Eklund, L., Boon, L. M., Vikkula, M. <strong>Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations.</strong> Nature Genet. 41: 118-124, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19079259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19079259</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19079259[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/10.1038/ng.272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19079259">Limaye et al. (2009)</a> assessed whether localized tissue-specific events have a role in the etiology of sporadic venous malformations, which are far more common than mucocutaneous venous malformations (<a href="/entry/600195">600195</a>). <a href="#9" class="mim-tip-reference" title="Limaye, N., Wouters, V., Uebelhoer, M., Tuominen, M., Wirkkala, R., Mulliken, J. B., Eklund, L., Boon, L. M., Vikkula, M. <strong>Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations.</strong> Nature Genet. 41: 118-124, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19079259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19079259</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19079259[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/10.1038/ng.272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19079259">Limaye et al. (2009)</a> identified 8 somatic TEK mutations in lesions from 28 of 57 individuals (49.1%) with sporadic venous malformations. The somatic mutations included one causing a frequent L914F substitution (leu914 to phe) and several double mutations in cis, all of which resulted in ligand-independent TEK hyperphosphorylation in vitro. When overexpressed in human umbilical vein endothelial cells, the L914F mutant was abnormally localized and responded to ligand, in contrast to wildtype TEK and the common, inherited R849W (<a href="#0001">600221.0001</a>) mutant, suggesting that the mutations have distinct effects. The presence of the same mutations in multifocal sporadic venous malformations in 2 individuals suggested a common origin for the abnormal endothelial cells at the distant sites. <a href="#9" class="mim-tip-reference" title="Limaye, N., Wouters, V., Uebelhoer, M., Tuominen, M., Wirkkala, R., Mulliken, J. B., Eklund, L., Boon, L. M., Vikkula, M. <strong>Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations.</strong> Nature Genet. 41: 118-124, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19079259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19079259</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19079259[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/10.1038/ng.272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19079259">Limaye et al. (2009)</a> concluded that their data showed that a sporadic disease may be explained by somatic changes in a gene causing rare, inherited forms and pinpointed TEK pathways as potential therapeutic targets for venous malformations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19079259" 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="Wouters, V., Limaye, N., Uebelhoer, M., Irrthum, A., Boon, L. M., Mulliken, J. B., Enjolras, O., Baselga, E., Berg, J., Dompmartin, A., Ivarsson, S. A., Kangesu, L., Lacassie, Y., Murphy, J., Teebi, A. S., Penington, A., Rieu, P., Vikkula, M. <strong>Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects.</strong> Europ. J. Hum. Genet. 18: 414-420, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19888299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19888299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19888299[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/10.1038/ejhg.2009.193" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19888299">Wouters et al. (2010)</a> analyzed the TEK gene in 26 affected individuals from 12 unrelated families with cutaneomucosal venous malformations and identified a heterozygous R849W mutation in 14 patients from 6 of the families. In the remaining families, 6 different heterozygous missense mutations were identified, respectively (see, e.g., <a href="#0003">600221.0003</a> and <a href="#0004">600221.0004</a>). All mutations were located in the intracellular portion of TEK, 3 in the first tyrosine kinase domain, 3 in the kinase insert domain, and 1 in the C-terminal tail. Although the level of ligand-independent hyperphosphorylation of TEK demonstrated with these VMCM-associated substitutions was highly variable, <a href="#17" class="mim-tip-reference" title="Wouters, V., Limaye, N., Uebelhoer, M., Irrthum, A., Boon, L. M., Mulliken, J. B., Enjolras, O., Baselga, E., Berg, J., Dompmartin, A., Ivarsson, S. A., Kangesu, L., Lacassie, Y., Murphy, J., Teebi, A. S., Penington, A., Rieu, P., Vikkula, M. <strong>Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects.</strong> Europ. J. Hum. Genet. 18: 414-420, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19888299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19888299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19888299[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/10.1038/ejhg.2009.193" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19888299">Wouters et al. (2010)</a> observed no genotype-phenotype correlation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19888299" 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 endothelial cell cultures, mouse models, and ultrastructural examination of patient tissue biopsies, <a href="#10" class="mim-tip-reference" title="Natynki, M., Kangas, J., Miinalainen, I., Sormunen, R., Pietila, R., Soblet, J., Boon, L. M., Vikkula, M., Limaye, N., Eklund, L. <strong>Common and specific effects of TIE2 mutations causing venous malformations.</strong> Hum. Molec. Genet. 24: 6374-6389, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26319232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26319232</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26319232[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/ddv349" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26319232">Natynki et al. (2015)</a> analyzed 22 TEK mutations previously identified in patients with venous malformations. The data suggested that the development of TEK-associated venous malformations results from several molecular mechanisms that occur in tandem: AKT activation, which reduces the major endothelial cell-secreted smooth muscle cell-attractant PDGFB (<a href="/entry/190040">190040</a>); loss of plasma membrane TEK, which results in lower responsiveness to angiopoietin (see <a href="/entry/601667">601667</a>) ligand-mediated regulation; and ERK1 (<a href="/entry/601795">601795</a>)/ERK2 (<a href="/entry/176948">176948</a>) activation, which negatively impacts endothelial cell morphology and extracellular matrix fibronectin (<a href="/entry/135600">135600</a>) and dysregulates the plasminogen (<a href="/entry/173350">173350</a>)/plasmin coagulation cascade. The authors noted that the venous malformation phenotypes these pathways mediate in patients were recapitulated in a spheroid-transplantation mouse model. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26319232" 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>Primary Congenital Glaucoma 3E</em></strong></p><p>
|
|
By exome sequencing in a multiethnic cohort of 189 unrelated families with primary congenital glaucoma (see GLC3E, <a href="/entry/617272">617272</a>), <a href="#15" class="mim-tip-reference" title="Souma, T., Tompson, S. W., Thomson, B. R., Siggs, O. M., Kizhatil, K., Yamaguchi, S., Feng, L., Limviphuvadh, V., Whisenhunt, K. N., Maurer-Stroh, S., Yanovitch, T. L., Kalaydjieva, L., and 23 others. <strong>Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity.</strong> J. Clin. Invest. 126: 2575-2587, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27270174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27270174</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27270174[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI85830" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27270174">Souma et al. (2016)</a> identified 10 heterozygous loss-of-function mutations in the TEK gene (see, e.g., <a href="#0005">600221.0005</a> and <a href="#0006">600221.0006</a>) in 10 of the families. Copy-number variant analysis revealed no evidence for additional exon-spanning duplications or deletions. <a href="#15" class="mim-tip-reference" title="Souma, T., Tompson, S. W., Thomson, B. R., Siggs, O. M., Kizhatil, K., Yamaguchi, S., Feng, L., Limviphuvadh, V., Whisenhunt, K. N., Maurer-Stroh, S., Yanovitch, T. L., Kalaydjieva, L., and 23 others. <strong>Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity.</strong> J. Clin. Invest. 126: 2575-2587, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27270174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27270174</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27270174[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI85830" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27270174">Souma et al. (2016)</a> concluded that gain-of-function mutations in TEK result in venous malformations in nonocular tissues, whereas loss-of-function mutations affect anterior chamber vascular development and result in primary congenital glaucoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27270174" 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="#15" class="mim-tip-reference" title="Souma, T., Tompson, S. W., Thomson, B. R., Siggs, O. M., Kizhatil, K., Yamaguchi, S., Feng, L., Limviphuvadh, V., Whisenhunt, K. N., Maurer-Stroh, S., Yanovitch, T. L., Kalaydjieva, L., and 23 others. <strong>Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity.</strong> J. Clin. Invest. 126: 2575-2587, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27270174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27270174</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27270174[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI85830" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27270174">Souma et al. (2016)</a> generated Tek hemizygous and conditional knockout mice and analyzed their aqueous humor outflow pathways. Confocal microscopy revealed that Tek-haploinsufficient mice developed a severely hypomorphic canal with convolutions and focal narrowing, whereas the Schlemm canal was completely absent in Tek-knockout mice, consistent with a requirement for TEK as well as gene-dosage sensitivity during Schlemm canal development. Serial histologic sections of the iridocorneal region in Tek-haploinsufficient mice showed a hypoplastic Schlemm canal and trabecular meshwork, and analysis of intraocular pressures by rebound tonometry showed a 25% elevation compared to control mice. <a href="#15" class="mim-tip-reference" title="Souma, T., Tompson, S. W., Thomson, B. R., Siggs, O. M., Kizhatil, K., Yamaguchi, S., Feng, L., Limviphuvadh, V., Whisenhunt, K. N., Maurer-Stroh, S., Yanovitch, T. L., Kalaydjieva, L., and 23 others. <strong>Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity.</strong> J. Clin. Invest. 126: 2575-2587, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27270174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27270174</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27270174[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI85830" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27270174">Souma et al. (2016)</a> concluded that reduced TEK signaling causes developmental defects of aqueous humor outflow structures and correlates with elevated intraocular pressure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27270174" 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>6 Selected Examples</a>):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div id="mimAllelicVariantsFold" class="collapse in mimTextToggleFold">
|
|
<div>
|
|
<a href="/allelicVariants/600221" class="btn btn-default" role="button"> Table View </a>
|
|
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=600221[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 VENOUS MALFORMATIONS, MULTIPLE CUTANEOUS AND MUCOSAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
TEK, ARG849TRP
|
|
</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> rs80338908 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338908;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/rs80338908?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=rs80338908" 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=rs80338908" 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=RCV000009876 OR RCV001327969 OR RCV001705587 OR RCV001810841 OR RCV004754251" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009876, RCV001327969, RCV001705587, RCV001810841, RCV004754251" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009876...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 2 unrelated families with multiple venous malformations of the skin and mucous membranes (VMCM; <a href="/entry/600195">600195</a>), previously studied by <a href="#2" class="mim-tip-reference" title="Boon, L. M., Mulliken, J. B., Vikkula, M., Watkins, H., Seidman, J., Olsen, B. R., Warman, M. L. <strong>Assignment of a locus for dominantly inherited venous malformations to chromosome 9p.</strong> Hum. Molec. Genet. 3: 1583-1587, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7833915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7833915</a>] [<a href="https://doi.org/10.1093/hmg/3.9.1583" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7833915">Boon et al. (1994)</a> and <a href="#7" class="mim-tip-reference" title="Gallione, C. J., Pasyk, K. A., Boon, L. M., Lennon, F., Johnson, D. W., Helmbold, E. A., Markel, D. S., Vikkula, M., Mulliken, J. B., Warman, M. L., Pericak-Vance, M. A., Marchuk, D. A. <strong>A gene for familial venous malformations maps to chromosome 9p in a second large kindred.</strong> J. Med. Genet. 32: 197-199, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7783168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7783168</a>] [<a href="https://doi.org/10.1136/jmg.32.3.197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7783168">Gallione et al. (1995)</a>, respectively, <a href="#16" class="mim-tip-reference" title="Vikkula, M., Boon, L. M., Carraway, K. L., III, Calvert, J. T., Diamonti, A. J., Goumnerov, B., Pasyk, K. A., Marchuk, D. A., Warman, M. L., Cantley, L. C., Mulliken, J. B., Olsen, B. R. <strong>Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2.</strong> Cell 87: 1181-1190, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8980225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8980225</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81814-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8980225">Vikkula et al. (1996)</a> identified heterozygosity for a 2545C-T transition in the TEK gene, resulting in an arg849-to-trp (R849W) substitution in the kinase domain of the receptor. The mutation was not found in 138 controls. Using proteins expressed in insect cells, they demonstrated that the mutation results in increased phosphorylation activity of TEK and therefore represents an activating mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7833915+7783168+8980225" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a family with VMCM, <a href="#3" class="mim-tip-reference" title="Calvert, J. T., Riney, T. J., Kontos, C. D., Cha, E. H., Prieto, V. G., Shea, C. R., Berg, J. N., Nevin, N. C., Simpson, S. A., Pasyk, K. A., Speer, M. C., Peters, K. G., Marchuk, D. A. <strong>Allelic and locus heterogeneity in inherited venous malformations.</strong> Hum. Molec. Genet. 8: 1279-1289, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10369874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10369874</a>] [<a href="https://doi.org/10.1093/hmg/8.7.1279" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10369874">Calvert et al. (1999)</a> identified heterozygosity for the R849W mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10369874" 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 14 affected individuals from 6 unrelated families with VMCM, <a href="#17" class="mim-tip-reference" title="Wouters, V., Limaye, N., Uebelhoer, M., Irrthum, A., Boon, L. M., Mulliken, J. B., Enjolras, O., Baselga, E., Berg, J., Dompmartin, A., Ivarsson, S. A., Kangesu, L., Lacassie, Y., Murphy, J., Teebi, A. S., Penington, A., Rieu, P., Vikkula, M. <strong>Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects.</strong> Europ. J. Hum. Genet. 18: 414-420, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19888299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19888299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19888299[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/10.1038/ejhg.2009.193" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19888299">Wouters et al. (2010)</a> identified heterozygosity for the R849W mutation in exon 15 of the TEK gene. In addition to mucocutaneous lesions, venous malformations were also present in the lung in 2 patients and in the brain in 1 patient. Haplotype analysis did not support the hypothesis that the R849W change is due to a single common ancestral allele, and <a href="#17" class="mim-tip-reference" title="Wouters, V., Limaye, N., Uebelhoer, M., Irrthum, A., Boon, L. M., Mulliken, J. B., Enjolras, O., Baselga, E., Berg, J., Dompmartin, A., Ivarsson, S. A., Kangesu, L., Lacassie, Y., Murphy, J., Teebi, A. S., Penington, A., Rieu, P., Vikkula, M. <strong>Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects.</strong> Europ. J. Hum. Genet. 18: 414-420, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19888299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19888299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19888299[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/10.1038/ejhg.2009.193" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19888299">Wouters et al. (2010)</a> concluded that 2545C is probably a hotspot region for mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19888299" 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 an analysis of 22 TEK mutations previously identified in patients with venous malformations, <a href="#10" class="mim-tip-reference" title="Natynki, M., Kangas, J., Miinalainen, I., Sormunen, R., Pietila, R., Soblet, J., Boon, L. M., Vikkula, M., Limaye, N., Eklund, L. <strong>Common and specific effects of TIE2 mutations causing venous malformations.</strong> Hum. Molec. Genet. 24: 6374-6389, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26319232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26319232</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26319232[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/ddv349" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26319232">Natynki et al. (2015)</a> stated that inherited R849W mutations clustered with Y897 (see <a href="#0002">600221.0002</a>) single mutations, supporting the status of R849W as a 'predisposing' mutation that requires an additional (somatic) change to cause disease. They noted that this was further strengthened by the venous-malformation (VM) mouse model, in which both the Y897F variant and R849W showed low VM-formation capacity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26319232" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0002" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 VENOUS MALFORMATIONS, MULTIPLE CUTANEOUS AND MUCOSAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
TEK, TYR897SER
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80338909 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338909;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80338909" 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=rs80338909" 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=RCV000009877 OR RCV002254262" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009877, RCV002254262" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009877...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 3-generation family with multiple venous malformations of the skin and mucous membranes (VMCM; <a href="/entry/600195">600195</a>), <a href="#3" class="mim-tip-reference" title="Calvert, J. T., Riney, T. J., Kontos, C. D., Cha, E. H., Prieto, V. G., Shea, C. R., Berg, J. N., Nevin, N. C., Simpson, S. A., Pasyk, K. A., Speer, M. C., Peters, K. G., Marchuk, D. A. <strong>Allelic and locus heterogeneity in inherited venous malformations.</strong> Hum. Molec. Genet. 8: 1279-1289, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10369874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10369874</a>] [<a href="https://doi.org/10.1093/hmg/8.7.1279" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10369874">Calvert et al. (1999)</a> identified an A-to-C transversion at nucleotide 2690 of the TEK gene, resulting in a tyr897-to-ser (Y897S) missense mutation within the first kinase domain. The A2690C substitution created a novel NlaIV restriction site. The mutation fully cosegregated with disease status within the family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10369874" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0003" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 VENOUS MALFORMATIONS, MULTIPLE CUTANEOUS AND MUCOSAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
TEK, TYR897CYS
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80338909 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338909;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80338909" 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=rs80338909" 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=RCV000022955 OR RCV000756767 OR RCV001327971" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022955, RCV000756767, RCV001327971" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022955...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a father and 2 sons with 15 to 30 localized cutaneous and mucosal venous malformations (VMCM; <a href="/entry/600195">600195</a>), <a href="#17" class="mim-tip-reference" title="Wouters, V., Limaye, N., Uebelhoer, M., Irrthum, A., Boon, L. M., Mulliken, J. B., Enjolras, O., Baselga, E., Berg, J., Dompmartin, A., Ivarsson, S. A., Kangesu, L., Lacassie, Y., Murphy, J., Teebi, A. S., Penington, A., Rieu, P., Vikkula, M. <strong>Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects.</strong> Europ. J. Hum. Genet. 18: 414-420, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19888299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19888299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19888299[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/10.1038/ejhg.2009.193" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19888299">Wouters et al. (2010)</a> identified heterozygosity for a 2690A-G transition in exon 17 of the TEK gene, resulting in a tyr897-to-cys (Y897C) substitution in the intracellular first tyrosine kinase domain. Studies in COS-7 cells demonstrated that the Y897C mutation induced an approximately 13-fold increase in ligand-independent receptor phosphorylation compared to wildtype. In addition to mucocutaneous lesions, the father and 2 sons had venous malformations of the internal organs, including the intestines, kidney, thorax, and brain. D-dimer levels were elevated in all 3 patients. The paternal grandmother was also affected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19888299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0004" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 VENOUS MALFORMATIONS, MULTIPLE CUTANEOUS AND MUCOSAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
TEK, ARG915HIS
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906745 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906745;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906745" 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=rs387906745" 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=RCV000022956 OR RCV002254270" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022956, RCV002254270" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022956...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a mother and 2 daughters with 1 to 4 cutaneomucosal venous malformations (VMCM; <a href="/entry/600195">600195</a>), <a href="#17" class="mim-tip-reference" title="Wouters, V., Limaye, N., Uebelhoer, M., Irrthum, A., Boon, L. M., Mulliken, J. B., Enjolras, O., Baselga, E., Berg, J., Dompmartin, A., Ivarsson, S. A., Kangesu, L., Lacassie, Y., Murphy, J., Teebi, A. S., Penington, A., Rieu, P., Vikkula, M. <strong>Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects.</strong> Europ. J. Hum. Genet. 18: 414-420, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19888299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19888299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19888299[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/10.1038/ejhg.2009.193" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19888299">Wouters et al. (2010)</a> identified heterozygosity for a 2744G-A transition in exon 17 of the TEK gene, resulting in an arg915-to-his (R915H) substitution in the intracellular first tyrosine kinase domain. Studies in COS-7 cells demonstrated that the R915H mutation induced a 29-fold increase in ligand-independent receptor phosphorylation compared to wildtype. In addition to VMCMs, all 3 patients had a restrictive perimembranous ventricular septal defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19888299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0005" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 GLAUCOMA 3, PRIMARY CONGENITAL, E</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
TEK, TYR307TER
|
|
</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> rs541217363 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs541217363;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/rs541217363?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=rs541217363" 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=rs541217363" 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=RCV000415569" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000415569" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000415569</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a mother and son from a Latino family (family 1) with primary congenital glaucoma (GLC3E; <a href="/entry/617272">617272</a>), <a href="#15" class="mim-tip-reference" title="Souma, T., Tompson, S. W., Thomson, B. R., Siggs, O. M., Kizhatil, K., Yamaguchi, S., Feng, L., Limviphuvadh, V., Whisenhunt, K. N., Maurer-Stroh, S., Yanovitch, T. L., Kalaydjieva, L., and 23 others. <strong>Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity.</strong> J. Clin. Invest. 126: 2575-2587, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27270174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27270174</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27270174[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI85830" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27270174">Souma et al. (2016)</a> identified heterozygosity for a c.921C-A transversion (c.921C-A, NM_000459.4) in exon 7 of the TEK gene, resulting in a tyr307-to-ter (Y307X) substitution within the third EGF domain that was predicted to generate a protein lacking the entire intracellular protein kinase domain. The mutation was not found in 203 in-house control exomes or in the Exome Variant Server or ExAC databases. Analysis in HEK293 cells confirmed that the Y307X mutation does not produce a full-length intact protein. Onset of disease occurred in infancy in the mother and at age 4 months in the son, and glaucoma was unilateral in both. The unaffected maternal grandmother did not carry the mutation, and DNA was unavailable from the unaffected maternal grandfather. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27270174" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0006" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 GLAUCOMA 3, PRIMARY CONGENITAL, E</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
TEK, GLU150TER
|
|
</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> rs753021890 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs753021890;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/rs753021890?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=rs753021890" 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=rs753021890" 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=RCV000415600" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000415600" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000415600</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a mother and son from a European American family (family 10) with primary congenital glaucoma (GLC3E; <a href="/entry/617272">617272</a>), <a href="#15" class="mim-tip-reference" title="Souma, T., Tompson, S. W., Thomson, B. R., Siggs, O. M., Kizhatil, K., Yamaguchi, S., Feng, L., Limviphuvadh, V., Whisenhunt, K. N., Maurer-Stroh, S., Yanovitch, T. L., Kalaydjieva, L., and 23 others. <strong>Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity.</strong> J. Clin. Invest. 126: 2575-2587, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27270174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27270174</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27270174[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI85830" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27270174">Souma et al. (2016)</a> identified heterozygosity for a c.448G-T transversion (c.448G-T, NM_000459.4) in exon 3 of the TEK gene, resulting in a glu150-to-ter (E150X) substitution. The mutation was not found in 203 in-house control exomes or in the Exome Variant Server or ExAC databases. Onset of disease occurred at age 2 months in the mother and at birth in the son, and glaucoma was bilateral in both. Variable expressivity was demonstrated in this family, with late-onset disease occurring in the boy's maternal aunt, who carried the E150X mutation, and no apparent disease in his 25-year-old sister, who carried the mutation. In addition, the maternal grandmother, for whom DNA was unavailable, had late-onset disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27270174" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="references"class="mim-anchor"></a>
|
|
<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span class="mim-font">
|
|
<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div id="mimReferencesFold" class="collapse in mimTextToggleFold">
|
|
<ol>
|
|
|
|
<li>
|
|
<a id="1" class="mim-anchor"></a>
|
|
<a id="Arai2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Arai, F., Hirao, A., Ohmura, M., Sato, H., Matsuoka, S., Takubo, K., Ito, K., Koh, G. Y., Suda, T.
|
|
<strong>Tie2/Angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche.</strong>
|
|
Cell 118: 149-161, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15260986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15260986</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15260986" 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.cell.2004.07.004" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="2" class="mim-anchor"></a>
|
|
<a id="Boon1994" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Boon, L. M., Mulliken, J. B., Vikkula, M., Watkins, H., Seidman, J., Olsen, B. R., Warman, M. L.
|
|
<strong>Assignment of a locus for dominantly inherited venous malformations to chromosome 9p.</strong>
|
|
Hum. Molec. Genet. 3: 1583-1587, 1994.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7833915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7833915</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7833915" 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/3.9.1583" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="3" class="mim-anchor"></a>
|
|
<a id="Calvert1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Calvert, J. T., Riney, T. J., Kontos, C. D., Cha, E. H., Prieto, V. G., Shea, C. R., Berg, J. N., Nevin, N. C., Simpson, S. A., Pasyk, K. A., Speer, M. C., Peters, K. G., Marchuk, D. A.
|
|
<strong>Allelic and locus heterogeneity in inherited venous malformations.</strong>
|
|
Hum. Molec. Genet. 8: 1279-1289, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10369874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10369874</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10369874" 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/8.7.1279" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="4" class="mim-anchor"></a>
|
|
<a id="Dumont1994" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Dumont, D. J., Anderson, L., Breitman, M. L., Duncan, A. M. V.
|
|
<strong>Assignment of the endothelial-specific protein receptor tyrosine kinase gene (TEK) to human chromosome 9p21.</strong>
|
|
Genomics 23: 512-513, 1994.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7835909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7835909</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7835909" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1006/geno.1994.1536" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="5" class="mim-anchor"></a>
|
|
<a id="Dumont1992" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Dumont, D. J., Yamaguchi, T. P., Conlon, R. A., Rossant, J., Breitman, M. L.
|
|
<strong>tek, a novel tyrosine kinase gene located on mouse chromosome 4, is expressed in endothelial cells and their presumptive precursors.</strong>
|
|
Oncogene 7: 1471-1480, 1992.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1630810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1630810</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1630810" 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="6" class="mim-anchor"></a>
|
|
<a id="Fukuhara2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Fukuhara, S., Sako, K., Minami, T., Noda, K., Kim, H. Z., Kodama, T., Shibuya, M., Takakura, N., Koh, G. Y., Mochizuki, N.
|
|
<strong>Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1.</strong>
|
|
Nature Cell Biol. 10: 513-526, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18425120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18425120</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18425120" 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/ncb1714" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="7" class="mim-anchor"></a>
|
|
<a id="Gallione1995" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Gallione, C. J., Pasyk, K. A., Boon, L. M., Lennon, F., Johnson, D. W., Helmbold, E. A., Markel, D. S., Vikkula, M., Mulliken, J. B., Warman, M. L., Pericak-Vance, M. A., Marchuk, D. A.
|
|
<strong>A gene for familial venous malformations maps to chromosome 9p in a second large kindred.</strong>
|
|
J. Med. Genet. 32: 197-199, 1995.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7783168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7783168</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7783168" 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.32.3.197" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="8" class="mim-anchor"></a>
|
|
<a id="Kim2011" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Kim, C., Lee, H. S., Lee, D., Lee, S. D., Cho, E.-G., Yang, S. J., Kim, S. B., Park, D., Kim, M. G.
|
|
<strong>Epithin/PRSS14 proteolytically regulates angiopoietin receptor Tie2 during transendothelial migration.</strong>
|
|
Blood 117: 1415-1424, 2011.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21097670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21097670</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21097670" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1182/blood-2010-03-275289" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="9" class="mim-anchor"></a>
|
|
<a id="Limaye2009" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Limaye, N., Wouters, V., Uebelhoer, M., Tuominen, M., Wirkkala, R., Mulliken, J. B., Eklund, L., Boon, L. M., Vikkula, M.
|
|
<strong>Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations.</strong>
|
|
Nature Genet. 41: 118-124, 2009.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19079259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19079259</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19079259[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=19079259" 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/ng.272" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="10" class="mim-anchor"></a>
|
|
<a id="Natynki2015" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Natynki, M., Kangas, J., Miinalainen, I., Sormunen, R., Pietila, R., Soblet, J., Boon, L. M., Vikkula, M., Limaye, N., Eklund, L.
|
|
<strong>Common and specific effects of TIE2 mutations causing venous malformations.</strong>
|
|
Hum. Molec. Genet. 24: 6374-6389, 2015.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26319232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26319232</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26319232[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=26319232" 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/ddv349" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="11" class="mim-anchor"></a>
|
|
<a id="Partanen1992" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Partanen, J., Armstrong, E., Makela, T. P., Korhonen, J., Sandberg, M., Renkonen, R., Knuutila, S., Huebner, K., Alitalo, K.
|
|
<strong>A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains.</strong>
|
|
Molec. Cell. Biol. 12: 1698-1707, 1992.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1312667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1312667</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1312667" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1128/mcb.12.4.1698-1707.1992" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="12" class="mim-anchor"></a>
|
|
<a id="Ramsden2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Ramsden, J. D., Cocks, H. C., Shams, M., Nijjar, S., Watkinson, J. C., Sheppard, M. C., Ahmed, A., Eggo, M. C.
|
|
<strong>Tie-2 is expressed on thyroid follicular cells, is increased in goiter, and is regulated by thyrotropin through cyclic adenosine 3-prime,5-prime-monophosphate.</strong>
|
|
J. Clin. Endocr. Metab. 86: 2709-2716, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11397875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11397875</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11397875" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1210/jcem.86.6.7552" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="13" class="mim-anchor"></a>
|
|
<a id="Saharinen2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Saharinen, P., Eklund, L., Miettinen, J., Wirkkala, R., Anisimov, A., Winderlich, M., Nottebaum, A., Vestweber, D., Deutsch, U., Koh, G. Y., Olsen, B. R., Alitalo, K.
|
|
<strong>Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts.</strong>
|
|
Nature Cell Biol. 10: 527-537, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18425119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18425119</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18425119" 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/ncb1715" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="14" class="mim-anchor"></a>
|
|
<a id="Sato1993" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Sato, T. N., Qin, Y., Kozak, C. A., Audus, K. L.
|
|
<strong>tie-1 and tie-2 define another class of putative receptor tyrosine kinase genes expressed in early embryonic vascular system.</strong>
|
|
Proc. Nat. Acad. Sci. 90: 9355-9358, 1993. Note: Erratum: Proc. Nat. Acad. Sci. 90: 12056 only, 1993.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8415706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8415706</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8415706" 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.90.20.9355" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="15" class="mim-anchor"></a>
|
|
<a id="Souma2016" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Souma, T., Tompson, S. W., Thomson, B. R., Siggs, O. M., Kizhatil, K., Yamaguchi, S., Feng, L., Limviphuvadh, V., Whisenhunt, K. N., Maurer-Stroh, S., Yanovitch, T. L., Kalaydjieva, L., and 23 others.
|
|
<strong>Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity.</strong>
|
|
J. Clin. Invest. 126: 2575-2587, 2016.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27270174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27270174</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27270174[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=27270174" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1172/JCI85830" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="16" class="mim-anchor"></a>
|
|
<a id="Vikkula1996" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Vikkula, M., Boon, L. M., Carraway, K. L., III, Calvert, J. T., Diamonti, A. J., Goumnerov, B., Pasyk, K. A., Marchuk, D. A., Warman, M. L., Cantley, L. C., Mulliken, J. B., Olsen, B. R.
|
|
<strong>Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2.</strong>
|
|
Cell 87: 1181-1190, 1996.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8980225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8980225</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8980225" 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/s0092-8674(00)81814-0" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="17" class="mim-anchor"></a>
|
|
<a id="Wouters2010" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Wouters, V., Limaye, N., Uebelhoer, M., Irrthum, A., Boon, L. M., Mulliken, J. B., Enjolras, O., Baselga, E., Berg, J., Dompmartin, A., Ivarsson, S. A., Kangesu, L., Lacassie, Y., Murphy, J., Teebi, A. S., Penington, A., Rieu, P., Vikkula, M.
|
|
<strong>Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects.</strong>
|
|
Europ. J. Hum. Genet. 18: 414-420, 2010.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19888299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19888299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19888299[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=19888299" 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/ejhg.2009.193" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
</ol>
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="contributors" class="mim-anchor"></a>
|
|
|
|
<div class="row">
|
|
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
|
<span class="mim-text-font">
|
|
<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Marla J. F. O'Neill - updated : 12/22/2016
|
|
</span>
|
|
</div>
|
|
</div>
|
|
<div class="row collapse" id="mimCollapseContributors">
|
|
<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Marla J. F. O'Neill - updated : 02/23/2016<br>Marla J. F. O'Neill - updated : 11/30/2011<br>Patricia A. Hartz - updated : 8/19/2011<br>Ada Hamosh - updated : 1/15/2010<br>Patricia A. Hartz - updated : 7/16/2009<br>Stylianos E. Antonarakis - updated : 8/17/2004<br>John A. Phillips, III - updated : 8/16/2001<br>George E. Tiller - updated : 1/17/2000<br>Victor A. McKusick - updated : 2/6/1997
|
|
</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">
|
|
Victor A. McKusick : 12/2/1994
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="editHistory" class="mim-anchor"></a>
|
|
|
|
<div class="row">
|
|
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
|
<span class="text-nowrap mim-text-font">
|
|
<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
carol : 03/07/2018
|
|
</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 : 03/06/2018<br>carol : 12/22/2016<br>carol : 02/23/2016<br>terry : 6/6/2012<br>carol : 11/30/2011<br>mgross : 10/11/2011<br>mgross : 10/11/2011<br>terry : 8/19/2011<br>alopez : 1/27/2010<br>terry : 1/15/2010<br>mgross : 7/17/2009<br>terry : 7/16/2009<br>mgross : 8/17/2004<br>cwells : 8/22/2001<br>cwells : 8/16/2001<br>alopez : 1/17/2000<br>terry : 2/6/1997<br>terry : 2/6/1997<br>terry : 2/3/1997<br>mark : 7/5/1995<br>carol : 12/2/1994
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div class="container visible-print-block">
|
|
|
|
<div class="row">
|
|
|
|
|
|
|
|
<div class="col-md-8 col-md-offset-1">
|
|
|
|
<div>
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
<strong>*</strong> 600221
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
TEK TYROSINE KINASE, ENDOTHELIAL; TEK
|
|
|
|
</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">
|
|
PROTEIN RECEPTOR TYROSINE KINASE, EPITHELIAL-SPECIFIC, TIE-2; TIE2
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: TEK</em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
|
|
<strong>SNOMEDCT:</strong> 699301008;
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 9p21.2
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 9:27,109,225-27,230,174 </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="2">
|
|
<span class="mim-font">
|
|
9p21.2
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Glaucoma 3, primary congenital, E
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
617272
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Venous malformations, multiple cutaneous and mucosal
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
600195
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>The TEK receptor tyrosine kinase is expressed almost exclusively in endothelial cells in mice, rats, and humans. This receptor possesses a unique extracellular domain containing 2 immunoglobulin-like loops separated by 3 epidermal growth factor-like repeats that are connected to 3 fibronectin type III-like repeats. The complex extracellular domain and the fact that the expression of this receptor tyrosine kinase is restricted to the endothelial cell lineage suggest that TEK plays a unique role within this cell lineage. In fact, disruption of the TEK gene by homologous recombination in ES cells results in embryonic lethality in homozygous mutant mouse embryos due to deficiency of the endothelium. The ligand for the receptor is angiopoietin-1 (ANG1; 601667).</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>The tek gene and its closely related subfamily member, tie, have both been mapped to mouse chromosome 4 (Dumont et al., 1992; Sato et al., 1993), and the human TIE gene has been localized to human 1p34-p33 by Partanen et al. (1992). By isotopic in situ hybridization, Dumont et al. (1994) assigned the human TEK gene to 9p21. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>See TIE1 (600222) for discussion of the relationship between TEK (TIE2) and the TIE1 receptor tyrosine kinase in vascular development.</p><p>Angiogenesis is coordinated with follicular cell growth in goitrogenesis. The angiopoietins ANG1 and ANG2 (601922) are angiogenic growth factors acting through TIE2. Ramsden et al. (2001) examined the expression and regulation of the angiopoietins and TIE2 in human and rat thyroids. In human goiters there was increased TIE2 immunostaining, compared with that in normal thyroids, on both follicular and endothelial cells. In an induced goiter in rats, in situ hybridization showed increased expression of mRNAs for Tie2 and Ang1 in follicular cells. Since TIE2 expression is believed to be restricted to cells of endothelial lineage in adults, they examined its expression further in isolated follicular cells. TIE2 and ANG1 mRNA expression in human thyrocytes was confirmed by ribonuclease protection assay. In both human follicular cell cultures and rat thyroid cells, immunoblotting showed that TIE2 expression was increased by thyroid-stimulating hormone (TSH; 188540) and agents that increased intracellular cAMP. The authors concluded that TIE2 and ANG1 are expressed in thyroid epithelial and endothelial cells, and that TIE2 is regulated by TSH and cAMP in follicular cells. They also concluded that TIE2 expression is increased in goiter in both humans and rats, consistent with a role in goitrogenesis. </p><p>Interaction of hematopoietic stem cells (HSCs) with their particular microenvironments, known as stem cell niches, is critical for adult hematopoiesis in bone marrow. Arai et al. (2004) demonstrated that HSCs expressing the receptor tyrosine kinase TIE2 are quiescent and antiapoptotic and comprise a side population of HSCs that adhere to osteoblasts in the bone marrow niche. The interaction of TIE2 with its ligand, ANG1, induced cobblestone formation of HSCs in vitro and maintained in vivo long-term repopulating activity of HSCs. Furthermore, ANG1 enhanced the ability of HSCs to become quiescent and induced adhesion to bone, resulting in protection of the HSC compartment from myelosuppressive stress. These data suggested that the TIE2/ANG1 signaling pathway plays a critical role in the maintenance of HSCs in a quiescent state in the bone marrow niche. </p><p>Independently, Fukuhara et al. (2008) and Saharinen et al. (2008) showed that ANG1 bridged TIE2 molecules on the surface of adjacent endothelial cells at cell-cell contacts. In contrast, extracellular matrix-bound ANG1 located TIE2 at cell-substratum contacts in isolated cells. Fukuhara et al. (2008) reported that TIE2 preferentially activated AKT (see 164730) signaling at cell-cell contacts and ERK (see MAPK1; 176948) signaling at cell-substratum contacts. Saharinen et al. (2008) found that ANG1 induced phosphorylation of TIE2-associated eNOS (NOS3; 163729), a downstream substrate of AKT, in intercellular contacts of confluent cells. The authors concluded that the cellular microenvironment determines TIE2 signaling between activated angiogenic endothelial cells and quiescent endothelium. </p><p>Kim et al. (2011) found that the mouse cell surface serine protease epithin (ST14; 606797) cleaved Tie2. Immunoprecipitation analysis revealed that interaction of epithin and Tie2 required phorbol ester-mediated cell activation. Tie2 was predominantly expressed in endothelial cells, while epithin was often expressed on the surface of surrounding cells, including epithelial cells. Coculture experiments revealed that epithin expressed on mouse thymic epithelial cells could cleave Tie2 expressed on endothelial cells. Soluble epithin released to the culture medium did not cleave Tie2. Epithin-mediated Tie2 cleavage induced phosphorylation and activation of the truncated Tie2 protein independent of Ang1, resulting in downstream Tie2 signaling via the p85 subunit of PI3 kinase (PIK3R1; 171833). Knockdown of epithin reduced the ability of mouse epithelial cells to migrate through a confluent endothelial cell monolayer and reduced metastasis of mouse mammary tumor cells in vivo. Kim et al. (2011) concluded that epithin expressed on tumor cell surfaces can generate a pathway for metastasis directly by breaking down endothelial cell junctions via TIE2 cleavage and indirectly via activation of truncated TIE2, leading to downstream remodeling of the endothelial cell cytoskeleton and cell retraction. </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>Multiple Cutaneous and Mucosal Venous Malformations</em></strong></p><p>
|
|
Venous malformations, the most common errors of vascular morphogenesis in humans, are composed of dilated, serpiginous channels. The walls of the channels have a variable thickness of smooth muscle; some mural regions lack smooth muscle altogether. In affected members of 2 unrelated families with multiple cutaneous and mucosal venous malformations (VMCM; 600195), Vikkula et al. (1996) identified a missense arg849-to-trp mutation (R849W; 600221.0001) in the kinase domain of TIE2. Using proteins expressed in insect cells, they demonstrated that the mutation resulted in increased activity of TIE2. They concluded that activating mutation in TIE2 caused inherited venous malformations in the 2 families and that the TIE2 signaling pathway is critical for endothelial cell-smooth muscle cell communication in venous morphogenesis. </p><p>Calvert et al. (1999) studied 4 kindreds with inherited venous malformations and identified heterozygosity for the R849W mutation in 1 family. In another family the disease phenotype cosegregated with a different missense mutation (Y897S; 600221.0002), also located in the first kinase domain. Transfection experiments in COS-1 cells using constructs containing either the R849W or the Y897S mutation demonstrated that the receptors containing either mutation showed ligand-independent hyperphosphorylation, suggesting a gain-of-function mechanism for development of venous malformations in these families. Of the 2 remaining families, 1 excluded linkage to the TIE2 locus, providing evidence for the existence of at least 1 additional locus for dominantly inherited venous malformations. </p><p>Limaye et al. (2009) assessed whether localized tissue-specific events have a role in the etiology of sporadic venous malformations, which are far more common than mucocutaneous venous malformations (600195). Limaye et al. (2009) identified 8 somatic TEK mutations in lesions from 28 of 57 individuals (49.1%) with sporadic venous malformations. The somatic mutations included one causing a frequent L914F substitution (leu914 to phe) and several double mutations in cis, all of which resulted in ligand-independent TEK hyperphosphorylation in vitro. When overexpressed in human umbilical vein endothelial cells, the L914F mutant was abnormally localized and responded to ligand, in contrast to wildtype TEK and the common, inherited R849W (600221.0001) mutant, suggesting that the mutations have distinct effects. The presence of the same mutations in multifocal sporadic venous malformations in 2 individuals suggested a common origin for the abnormal endothelial cells at the distant sites. Limaye et al. (2009) concluded that their data showed that a sporadic disease may be explained by somatic changes in a gene causing rare, inherited forms and pinpointed TEK pathways as potential therapeutic targets for venous malformations. </p><p>Wouters et al. (2010) analyzed the TEK gene in 26 affected individuals from 12 unrelated families with cutaneomucosal venous malformations and identified a heterozygous R849W mutation in 14 patients from 6 of the families. In the remaining families, 6 different heterozygous missense mutations were identified, respectively (see, e.g., 600221.0003 and 600221.0004). All mutations were located in the intracellular portion of TEK, 3 in the first tyrosine kinase domain, 3 in the kinase insert domain, and 1 in the C-terminal tail. Although the level of ligand-independent hyperphosphorylation of TEK demonstrated with these VMCM-associated substitutions was highly variable, Wouters et al. (2010) observed no genotype-phenotype correlation. </p><p>Using endothelial cell cultures, mouse models, and ultrastructural examination of patient tissue biopsies, Natynki et al. (2015) analyzed 22 TEK mutations previously identified in patients with venous malformations. The data suggested that the development of TEK-associated venous malformations results from several molecular mechanisms that occur in tandem: AKT activation, which reduces the major endothelial cell-secreted smooth muscle cell-attractant PDGFB (190040); loss of plasma membrane TEK, which results in lower responsiveness to angiopoietin (see 601667) ligand-mediated regulation; and ERK1 (601795)/ERK2 (176948) activation, which negatively impacts endothelial cell morphology and extracellular matrix fibronectin (135600) and dysregulates the plasminogen (173350)/plasmin coagulation cascade. The authors noted that the venous malformation phenotypes these pathways mediate in patients were recapitulated in a spheroid-transplantation mouse model. </p><p><strong><em>Primary Congenital Glaucoma 3E</em></strong></p><p>
|
|
By exome sequencing in a multiethnic cohort of 189 unrelated families with primary congenital glaucoma (see GLC3E, 617272), Souma et al. (2016) identified 10 heterozygous loss-of-function mutations in the TEK gene (see, e.g., 600221.0005 and 600221.0006) in 10 of the families. Copy-number variant analysis revealed no evidence for additional exon-spanning duplications or deletions. Souma et al. (2016) concluded that gain-of-function mutations in TEK result in venous malformations in nonocular tissues, whereas loss-of-function mutations affect anterior chamber vascular development and result in primary congenital glaucoma. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Souma et al. (2016) generated Tek hemizygous and conditional knockout mice and analyzed their aqueous humor outflow pathways. Confocal microscopy revealed that Tek-haploinsufficient mice developed a severely hypomorphic canal with convolutions and focal narrowing, whereas the Schlemm canal was completely absent in Tek-knockout mice, consistent with a requirement for TEK as well as gene-dosage sensitivity during Schlemm canal development. Serial histologic sections of the iridocorneal region in Tek-haploinsufficient mice showed a hypoplastic Schlemm canal and trabecular meshwork, and analysis of intraocular pressures by rebound tonometry showed a 25% elevation compared to control mice. Souma et al. (2016) concluded that reduced TEK signaling causes developmental defects of aqueous humor outflow structures and correlates with elevated intraocular pressure. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>6 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 VENOUS MALFORMATIONS, MULTIPLE CUTANEOUS AND MUCOSAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TEK, ARG849TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80338908,
|
|
|
|
|
|
gnomAD: rs80338908,
|
|
|
|
|
|
ClinVar: RCV000009876, RCV001327969, RCV001705587, RCV001810841, RCV004754251
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 2 unrelated families with multiple venous malformations of the skin and mucous membranes (VMCM; 600195), previously studied by Boon et al. (1994) and Gallione et al. (1995), respectively, Vikkula et al. (1996) identified heterozygosity for a 2545C-T transition in the TEK gene, resulting in an arg849-to-trp (R849W) substitution in the kinase domain of the receptor. The mutation was not found in 138 controls. Using proteins expressed in insect cells, they demonstrated that the mutation results in increased phosphorylation activity of TEK and therefore represents an activating mutation. </p><p>In affected members of a family with VMCM, Calvert et al. (1999) identified heterozygosity for the R849W mutation. </p><p>In 14 affected individuals from 6 unrelated families with VMCM, Wouters et al. (2010) identified heterozygosity for the R849W mutation in exon 15 of the TEK gene. In addition to mucocutaneous lesions, venous malformations were also present in the lung in 2 patients and in the brain in 1 patient. Haplotype analysis did not support the hypothesis that the R849W change is due to a single common ancestral allele, and Wouters et al. (2010) concluded that 2545C is probably a hotspot region for mutations. </p><p>In an analysis of 22 TEK mutations previously identified in patients with venous malformations, Natynki et al. (2015) stated that inherited R849W mutations clustered with Y897 (see 600221.0002) single mutations, supporting the status of R849W as a 'predisposing' mutation that requires an additional (somatic) change to cause disease. They noted that this was further strengthened by the venous-malformation (VM) mouse model, in which both the Y897F variant and R849W showed low VM-formation capacity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 VENOUS MALFORMATIONS, MULTIPLE CUTANEOUS AND MUCOSAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TEK, TYR897SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80338909,
|
|
|
|
|
|
|
|
ClinVar: RCV000009877, RCV002254262
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 3-generation family with multiple venous malformations of the skin and mucous membranes (VMCM; 600195), Calvert et al. (1999) identified an A-to-C transversion at nucleotide 2690 of the TEK gene, resulting in a tyr897-to-ser (Y897S) missense mutation within the first kinase domain. The A2690C substitution created a novel NlaIV restriction site. The mutation fully cosegregated with disease status within the family. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 VENOUS MALFORMATIONS, MULTIPLE CUTANEOUS AND MUCOSAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TEK, TYR897CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80338909,
|
|
|
|
|
|
|
|
ClinVar: RCV000022955, RCV000756767, RCV001327971
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a father and 2 sons with 15 to 30 localized cutaneous and mucosal venous malformations (VMCM; 600195), Wouters et al. (2010) identified heterozygosity for a 2690A-G transition in exon 17 of the TEK gene, resulting in a tyr897-to-cys (Y897C) substitution in the intracellular first tyrosine kinase domain. Studies in COS-7 cells demonstrated that the Y897C mutation induced an approximately 13-fold increase in ligand-independent receptor phosphorylation compared to wildtype. In addition to mucocutaneous lesions, the father and 2 sons had venous malformations of the internal organs, including the intestines, kidney, thorax, and brain. D-dimer levels were elevated in all 3 patients. The paternal grandmother was also affected. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 VENOUS MALFORMATIONS, MULTIPLE CUTANEOUS AND MUCOSAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TEK, ARG915HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906745,
|
|
|
|
|
|
|
|
ClinVar: RCV000022956, RCV002254270
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a mother and 2 daughters with 1 to 4 cutaneomucosal venous malformations (VMCM; 600195), Wouters et al. (2010) identified heterozygosity for a 2744G-A transition in exon 17 of the TEK gene, resulting in an arg915-to-his (R915H) substitution in the intracellular first tyrosine kinase domain. Studies in COS-7 cells demonstrated that the R915H mutation induced a 29-fold increase in ligand-independent receptor phosphorylation compared to wildtype. In addition to VMCMs, all 3 patients had a restrictive perimembranous ventricular septal defect. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 GLAUCOMA 3, PRIMARY CONGENITAL, E</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TEK, TYR307TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs541217363,
|
|
|
|
|
|
gnomAD: rs541217363,
|
|
|
|
|
|
ClinVar: RCV000415569
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a mother and son from a Latino family (family 1) with primary congenital glaucoma (GLC3E; 617272), Souma et al. (2016) identified heterozygosity for a c.921C-A transversion (c.921C-A, NM_000459.4) in exon 7 of the TEK gene, resulting in a tyr307-to-ter (Y307X) substitution within the third EGF domain that was predicted to generate a protein lacking the entire intracellular protein kinase domain. The mutation was not found in 203 in-house control exomes or in the Exome Variant Server or ExAC databases. Analysis in HEK293 cells confirmed that the Y307X mutation does not produce a full-length intact protein. Onset of disease occurred in infancy in the mother and at age 4 months in the son, and glaucoma was unilateral in both. The unaffected maternal grandmother did not carry the mutation, and DNA was unavailable from the unaffected maternal grandfather. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 GLAUCOMA 3, PRIMARY CONGENITAL, E</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TEK, GLU150TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs753021890,
|
|
|
|
|
|
gnomAD: rs753021890,
|
|
|
|
|
|
ClinVar: RCV000415600
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a mother and son from a European American family (family 10) with primary congenital glaucoma (GLC3E; 617272), Souma et al. (2016) identified heterozygosity for a c.448G-T transversion (c.448G-T, NM_000459.4) in exon 3 of the TEK gene, resulting in a glu150-to-ter (E150X) substitution. The mutation was not found in 203 in-house control exomes or in the Exome Variant Server or ExAC databases. Onset of disease occurred at age 2 months in the mother and at birth in the son, and glaucoma was bilateral in both. Variable expressivity was demonstrated in this family, with late-onset disease occurring in the boy's maternal aunt, who carried the E150X mutation, and no apparent disease in his 25-year-old sister, who carried the mutation. In addition, the maternal grandmother, for whom DNA was unavailable, had late-onset disease. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Arai, F., Hirao, A., Ohmura, M., Sato, H., Matsuoka, S., Takubo, K., Ito, K., Koh, G. Y., Suda, T.
|
|
<strong>Tie2/Angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche.</strong>
|
|
Cell 118: 149-161, 2004.
|
|
|
|
|
|
[PubMed: 15260986]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.cell.2004.07.004]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Boon, L. M., Mulliken, J. B., Vikkula, M., Watkins, H., Seidman, J., Olsen, B. R., Warman, M. L.
|
|
<strong>Assignment of a locus for dominantly inherited venous malformations to chromosome 9p.</strong>
|
|
Hum. Molec. Genet. 3: 1583-1587, 1994.
|
|
|
|
|
|
[PubMed: 7833915]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/3.9.1583]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Calvert, J. T., Riney, T. J., Kontos, C. D., Cha, E. H., Prieto, V. G., Shea, C. R., Berg, J. N., Nevin, N. C., Simpson, S. A., Pasyk, K. A., Speer, M. C., Peters, K. G., Marchuk, D. A.
|
|
<strong>Allelic and locus heterogeneity in inherited venous malformations.</strong>
|
|
Hum. Molec. Genet. 8: 1279-1289, 1999.
|
|
|
|
|
|
[PubMed: 10369874]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/8.7.1279]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Dumont, D. J., Anderson, L., Breitman, M. L., Duncan, A. M. V.
|
|
<strong>Assignment of the endothelial-specific protein receptor tyrosine kinase gene (TEK) to human chromosome 9p21.</strong>
|
|
Genomics 23: 512-513, 1994.
|
|
|
|
|
|
[PubMed: 7835909]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1006/geno.1994.1536]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Dumont, D. J., Yamaguchi, T. P., Conlon, R. A., Rossant, J., Breitman, M. L.
|
|
<strong>tek, a novel tyrosine kinase gene located on mouse chromosome 4, is expressed in endothelial cells and their presumptive precursors.</strong>
|
|
Oncogene 7: 1471-1480, 1992.
|
|
|
|
|
|
[PubMed: 1630810]
|
|
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Fukuhara, S., Sako, K., Minami, T., Noda, K., Kim, H. Z., Kodama, T., Shibuya, M., Takakura, N., Koh, G. Y., Mochizuki, N.
|
|
<strong>Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1.</strong>
|
|
Nature Cell Biol. 10: 513-526, 2008.
|
|
|
|
|
|
[PubMed: 18425120]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ncb1714]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gallione, C. J., Pasyk, K. A., Boon, L. M., Lennon, F., Johnson, D. W., Helmbold, E. A., Markel, D. S., Vikkula, M., Mulliken, J. B., Warman, M. L., Pericak-Vance, M. A., Marchuk, D. A.
|
|
<strong>A gene for familial venous malformations maps to chromosome 9p in a second large kindred.</strong>
|
|
J. Med. Genet. 32: 197-199, 1995.
|
|
|
|
|
|
[PubMed: 7783168]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1136/jmg.32.3.197]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kim, C., Lee, H. S., Lee, D., Lee, S. D., Cho, E.-G., Yang, S. J., Kim, S. B., Park, D., Kim, M. G.
|
|
<strong>Epithin/PRSS14 proteolytically regulates angiopoietin receptor Tie2 during transendothelial migration.</strong>
|
|
Blood 117: 1415-1424, 2011.
|
|
|
|
|
|
[PubMed: 21097670]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1182/blood-2010-03-275289]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Limaye, N., Wouters, V., Uebelhoer, M., Tuominen, M., Wirkkala, R., Mulliken, J. B., Eklund, L., Boon, L. M., Vikkula, M.
|
|
<strong>Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations.</strong>
|
|
Nature Genet. 41: 118-124, 2009.
|
|
|
|
|
|
[PubMed: 19079259]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng.272]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Natynki, M., Kangas, J., Miinalainen, I., Sormunen, R., Pietila, R., Soblet, J., Boon, L. M., Vikkula, M., Limaye, N., Eklund, L.
|
|
<strong>Common and specific effects of TIE2 mutations causing venous malformations.</strong>
|
|
Hum. Molec. Genet. 24: 6374-6389, 2015.
|
|
|
|
|
|
[PubMed: 26319232]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddv349]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Partanen, J., Armstrong, E., Makela, T. P., Korhonen, J., Sandberg, M., Renkonen, R., Knuutila, S., Huebner, K., Alitalo, K.
|
|
<strong>A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains.</strong>
|
|
Molec. Cell. Biol. 12: 1698-1707, 1992.
|
|
|
|
|
|
[PubMed: 1312667]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1128/mcb.12.4.1698-1707.1992]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ramsden, J. D., Cocks, H. C., Shams, M., Nijjar, S., Watkinson, J. C., Sheppard, M. C., Ahmed, A., Eggo, M. C.
|
|
<strong>Tie-2 is expressed on thyroid follicular cells, is increased in goiter, and is regulated by thyrotropin through cyclic adenosine 3-prime,5-prime-monophosphate.</strong>
|
|
J. Clin. Endocr. Metab. 86: 2709-2716, 2001.
|
|
|
|
|
|
[PubMed: 11397875]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1210/jcem.86.6.7552]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Saharinen, P., Eklund, L., Miettinen, J., Wirkkala, R., Anisimov, A., Winderlich, M., Nottebaum, A., Vestweber, D., Deutsch, U., Koh, G. Y., Olsen, B. R., Alitalo, K.
|
|
<strong>Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts.</strong>
|
|
Nature Cell Biol. 10: 527-537, 2008.
|
|
|
|
|
|
[PubMed: 18425119]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ncb1715]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Sato, T. N., Qin, Y., Kozak, C. A., Audus, K. L.
|
|
<strong>tie-1 and tie-2 define another class of putative receptor tyrosine kinase genes expressed in early embryonic vascular system.</strong>
|
|
Proc. Nat. Acad. Sci. 90: 9355-9358, 1993. Note: Erratum: Proc. Nat. Acad. Sci. 90: 12056 only, 1993.
|
|
|
|
|
|
[PubMed: 8415706]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.90.20.9355]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Souma, T., Tompson, S. W., Thomson, B. R., Siggs, O. M., Kizhatil, K., Yamaguchi, S., Feng, L., Limviphuvadh, V., Whisenhunt, K. N., Maurer-Stroh, S., Yanovitch, T. L., Kalaydjieva, L., and 23 others.
|
|
<strong>Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity.</strong>
|
|
J. Clin. Invest. 126: 2575-2587, 2016.
|
|
|
|
|
|
[PubMed: 27270174]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1172/JCI85830]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Vikkula, M., Boon, L. M., Carraway, K. L., III, Calvert, J. T., Diamonti, A. J., Goumnerov, B., Pasyk, K. A., Marchuk, D. A., Warman, M. L., Cantley, L. C., Mulliken, J. B., Olsen, B. R.
|
|
<strong>Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2.</strong>
|
|
Cell 87: 1181-1190, 1996.
|
|
|
|
|
|
[PubMed: 8980225]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0092-8674(00)81814-0]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Wouters, V., Limaye, N., Uebelhoer, M., Irrthum, A., Boon, L. M., Mulliken, J. B., Enjolras, O., Baselga, E., Berg, J., Dompmartin, A., Ivarsson, S. A., Kangesu, L., Lacassie, Y., Murphy, J., Teebi, A. S., Penington, A., Rieu, P., Vikkula, M.
|
|
<strong>Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects.</strong>
|
|
Europ. J. Hum. Genet. 18: 414-420, 2010.
|
|
|
|
|
|
[PubMed: 19888299]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ejhg.2009.193]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
</ol>
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div class="row">
|
|
<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
|
<span class="text-nowrap mim-text-font">
|
|
Contributors:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Marla J. F. O'Neill - updated : 12/22/2016<br>Marla J. F. O'Neill - updated : 02/23/2016<br>Marla J. F. O'Neill - updated : 11/30/2011<br>Patricia A. Hartz - updated : 8/19/2011<br>Ada Hamosh - updated : 1/15/2010<br>Patricia A. Hartz - updated : 7/16/2009<br>Stylianos E. Antonarakis - updated : 8/17/2004<br>John A. Phillips, III - updated : 8/16/2001<br>George E. Tiller - updated : 1/17/2000<br>Victor A. McKusick - updated : 2/6/1997
|
|
</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">
|
|
Victor A. McKusick : 12/2/1994
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div class="row">
|
|
<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
|
<span class="text-nowrap mim-text-font">
|
|
Edit History:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
carol : 03/07/2018<br>carol : 03/06/2018<br>carol : 12/22/2016<br>carol : 02/23/2016<br>terry : 6/6/2012<br>carol : 11/30/2011<br>mgross : 10/11/2011<br>mgross : 10/11/2011<br>terry : 8/19/2011<br>alopez : 1/27/2010<br>terry : 1/15/2010<br>mgross : 7/17/2009<br>terry : 7/16/2009<br>mgross : 8/17/2004<br>cwells : 8/22/2001<br>cwells : 8/16/2001<br>alopez : 1/17/2000<br>terry : 2/6/1997<br>terry : 2/6/1997<br>terry : 2/3/1997<br>mark : 7/5/1995<br>carol : 12/2/1994
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div id="mimFooter">
|
|
|
|
|
|
<div class="container ">
|
|
<div class="row">
|
|
<br />
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div class="hidden-print mim-footer">
|
|
<div class="container">
|
|
<div class="row">
|
|
<p />
|
|
</div>
|
|
<div class="row text-center small">
|
|
NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers,
|
|
and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal
|
|
medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
|
|
<br />
|
|
OMIM<sup>®</sup> and Online Mendelian Inheritance in Man<sup>®</sup> are registered trademarks of the Johns Hopkins University.
|
|
<br />
|
|
Copyright<sup>®</sup> 1966-2025 Johns Hopkins University.
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div class="visible-print-block mim-footer" style="position: relative;">
|
|
<div class="container">
|
|
<div class="row">
|
|
<p />
|
|
</div>
|
|
<div class="row text-center small">
|
|
NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers,
|
|
and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal
|
|
medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
|
|
<br />
|
|
OMIM<sup>®</sup> and Online Mendelian Inheritance in Man<sup>®</sup> are registered trademarks of the Johns Hopkins University.
|
|
<br />
|
|
Copyright<sup>®</sup> 1966-2025 Johns Hopkins University.
|
|
<br />
|
|
Printed: March 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>
|
|
|
|
|