3477 lines
360 KiB
Text
3477 lines
360 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
|
|
|
|
- *606009 - DOUBLE HOMEOBOX PROTEIN 4; DUX4
|
|
|
|
|
|
- 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=606009"><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">*606009</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="#text"><strong>Text</strong></a>
|
|
</li>
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#description">Description</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#cloning">Cloning and Expression</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#geneStructure">Gene Structure</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#mapping">Mapping</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#geneFunction">Gene Function</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#molecularGenetics">Molecular Genetics</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#cytogenetics">Cytogenetics</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#evolution">Evolution</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#animalModel">Animal Model</a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#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=ENSG00000260596;t=ENST00000565211" 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=100288687" 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=606009" 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=ENSG00000260596;t=ENST00000565211" 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_001293798,NM_001306068,NM_001363820,NR_137167" 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_001306068" 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=606009" 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=16189&isoform_id=16189_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/DUX4" 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/74720085,224746063,227437548,227437549,300509459,300509461,300509465,300509467,300509469,300509471,300509483,300509485,300509487,300509489,300509491,300509493,300509495,300509497,300509499,300509501,300509503,300509505,300509507,300509509,300509511,300509513,300509515,300509517,300509529,300509531,300885349,300885484,300885486,300885488,300885490,300885492,300885494,300885500,300885502,300885504,307604608,307604610,307604612,658132464,807045795,1293359507,1293360217,1293361215,1293361216,1293361218,1293361219,1293362091,1293362092,1293370447,1293370449,1293370451,1293370453,1293370455,1293370457,1293371340,1293371341,1293374041,1293374043,1293374662,1293374664,1293374666,1293374668,1393494688" 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/Q9UBX2" 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=100288687" 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=ENSG00000260596;t=ENST00000565211" 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=DUX4" 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=DUX4" 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+100288687" 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/DUX4" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/gene/100288687" 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=chr4&hgg_gene=ENST00000565211.1&hgg_start=190173774&hgg_end=190185911&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
|
|
|
<div style="display: table-cell;">Clinical Resources</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://medlineplus.gov/genetics/gene/dux4" 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=606009[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=606009[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000260596" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.gwascentral.org/search?q=DUX4" 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="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=DUX4&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/PA27538" 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:50800" 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="http://v1.marrvel.org/search/gene/DUX4#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="https://www.ncbi.nlm.nih.gov/gene/100288687/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=100288687" 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>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
|
|
|
<div style="display: table-cell;">Cellular Pathways</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://reactome.org/content/query?q=DUX4&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
|
|
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
<span>
|
|
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
|
|
|
|
</span>
|
|
</span>
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
|
|
|
|
<div>
|
|
|
|
<a id="title" class="mim-anchor"></a>
|
|
|
|
<div>
|
|
<a id="number" class="mim-anchor"></a>
|
|
<div class="text-right">
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
<div>
|
|
<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
606009
|
|
</span>
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
<div>
|
|
<a id="preferredTitle" class="mim-anchor"></a>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
DOUBLE HOMEOBOX PROTEIN 4; DUX4
|
|
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="includedTitles" class="mim-anchor"></a>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
D4Z4 MACROSATELLITE REPEAT, INCLUDED
|
|
</span>
|
|
</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=DUX4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">DUX4</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/4/737?start=-3&limit=10&highlight=737">4q35.2</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr4:190173774-190185911&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'})">4:190,173,774-190,185,911</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</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><strong><em>DUX4 Gene</em></strong></p><p>
|
|
DUX4 encodes a putative transcription factor that contains 2 homeobox domains. A copy of DUX4 is found within each of up to 100 copies of the D4Z4 macrosatellite repeat in the subtelomeric region of chromosome 4q. Only the last repeat appears to encode a functional DUX4 transcript with a polyadenylation site that lies telomeric and outside the D4Z4 repeat region (summary by <a href="#28" class="mim-tip-reference" title="Snider, L., Geng, L. N., Lemmers, R. J. L. F., Kyba, M., Ware, C. B., Nelson, A. M., Tawil, R., Filippova, G. N., van der Maarel, S. M., Tapscott, S. J., Miller, D. G. <strong>Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene.</strong> PLoS Genet. 6: e1001181, 2010. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21060811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21060811</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21060811[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/10.1371/journal.pgen.1001181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21060811">Snider et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21060811" 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>D4Z4 Microsatellite Repeat</em></strong></p><p>
|
|
Multiple copies of a 3.3-kb repeat, designated D4Z4, exist in the proximal subtelomeric region of 4q35. Each repeat contains a copy of DUX4. The polymorphic D4Z4 repeat array is composed of 11 to 150 repeats in normal individuals. Most patients with facioscapulohumeral muscular dystrophy (FSHD; <a href="/entry/158900">158900</a>) carry a D4Z4 repeat array of less than 11 repeats. A similar subtelomeric repeat array configuration occurs on chromosome 10qter (summary by <a href="#33" class="mim-tip-reference" title="van Overveld, P. G. M., Enthoven, L., Ricci, E., Rossi, M., Felicetti, L., Jeanpierre, M., Winokur, S. T., Frants, R. R., Padberg, G. W., van der Maarel, S. M. <strong>Variable hypomethylation of D4Z4 in facioscapulohumeral muscular dystrophy.</strong> Ann. Neurol. 58: 569-576, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16178028/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16178028</a>] [<a href="https://doi.org/10.1002/ana.20625" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16178028">van Overveld et al., 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16178028" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="cloning" class="mim-anchor"></a>
|
|
<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimCloningFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p>While sequencing the 3.3-kb repeat elements remaining in an FSHD patient, <a href="#10" class="mim-tip-reference" title="Gabriels, J., Beckers, M.-C., Ding, H., De Vriese, A., Plaisance, S., van der Maarel, S. M., Padberg, G. W., Frants, R. R., Hewitt, J. E., Collen, D., Belayew, A. <strong>Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element.</strong> Gene 236: 25-32, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10433963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10433963</a>] [<a href="https://doi.org/10.1016/s0378-1119(99)00267-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10433963">Gabriels et al. (1999)</a> identified a putative promoter for an ORF encompassing the 2 homeoboxes reported by <a href="#12" class="mim-tip-reference" title="Hewitt, J. E., Lyle, R., Clark, L. N., Valleley, E. M., Wright, T. J., Wijmenga, C., van Deutekom, J. C. T., Francis, F., Sharpe, P. T., Hofker, M., Frants, R. R., Williamson, R. <strong>Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy.</strong> Hum. Molec. Genet. 3: 1287-1295, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7987304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7987304</a>] [<a href="https://doi.org/10.1093/hmg/3.8.1287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7987304">Hewitt et al. (1994)</a> and named the putative gene DUX4. DUX4 encodes a deduced 391-amino acid protein containing 2 homeodomains. <a href="#10" class="mim-tip-reference" title="Gabriels, J., Beckers, M.-C., Ding, H., De Vriese, A., Plaisance, S., van der Maarel, S. M., Padberg, G. W., Frants, R. R., Hewitt, J. E., Collen, D., Belayew, A. <strong>Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element.</strong> Gene 236: 25-32, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10433963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10433963</a>] [<a href="https://doi.org/10.1016/s0378-1119(99)00267-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10433963">Gabriels et al. (1999)</a> found an identical copy of DUX4 in each of the 3.3-kb repeat elements remaining in the FSHD patient. Using in vitro transcription/translation, they detected products with apparent molecular masses of 38 kD and 75 kD on SDS-PAGE, corresponding to the DUX4 monomer and dimer, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10433963+7987304" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By PCR of FSHD primary myoblast RNA, <a href="#7" class="mim-tip-reference" title="Dixit, M., Ansseau, E., Tassin, A., Winokur, S., Shi, R., Qian, H., Sauvage, S., Matteotti, C., van Acker, A. M., Leo, O., Figlewicz, D., Barro, M., Laoudj-Chenivesse, D., Belayew, A., Coppee, F., Chen, Y.-W. <strong>DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1.</strong> Proc. Nat. Acad. Sci. 104: 18157-18162, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17984056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17984056</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17984056[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0708659104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17984056">Dixit et al. (2007)</a> identified 2 DUX4 splice variants that differed due to inclusion or exclusion of an intron in their 3-prime UTRs. The deduced DUX4 protein contains 424 amino acids, larger than the protein initially reported (<a href="#10" class="mim-tip-reference" title="Gabriels, J., Beckers, M.-C., Ding, H., De Vriese, A., Plaisance, S., van der Maarel, S. M., Padberg, G. W., Frants, R. R., Hewitt, J. E., Collen, D., Belayew, A. <strong>Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element.</strong> Gene 236: 25-32, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10433963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10433963</a>] [<a href="https://doi.org/10.1016/s0378-1119(99)00267-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10433963">Gabriels et al., 1999</a>) due to corrections of sequencing errors. PCR analysis detected the 5-prime end of DUX4 mRNA in both FSHD and control myoblasts, whereas the 3-prime end specific to the most distal unit of DUX4, which includes a polyadenylation sequence, was detected only in FSHD myoblasts. Western blot analysis of transfected cells revealed a 52-kD DUX4 protein. DUX4 protein was detected in FSHD samples, but not controls. <a href="#7" class="mim-tip-reference" title="Dixit, M., Ansseau, E., Tassin, A., Winokur, S., Shi, R., Qian, H., Sauvage, S., Matteotti, C., van Acker, A. M., Leo, O., Figlewicz, D., Barro, M., Laoudj-Chenivesse, D., Belayew, A., Coppee, F., Chen, Y.-W. <strong>DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1.</strong> Proc. Nat. Acad. Sci. 104: 18157-18162, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17984056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17984056</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17984056[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0708659104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17984056">Dixit et al. (2007)</a> concluded that only the DUX4 gene in the most distal D4Z4 element is likely to be transcribed into a polyadenylated RNA and to be translated in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10433963+17984056" 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="#15" class="mim-tip-reference" title="Kowaljow, V., Marcowycz, A., Ansseau, E., Conde, C. B., Sauvage, S., Matteotti, C., Arias, C., Corona, E. D., Nunez, N. G., Leo, O., Wattiez, R., Figlewicz, D., Laoudj-Chenivesse, D., Belayew, A., Coppee, F., Rosa, A. L. <strong>The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein.</strong> Neuromusc. Disord. 17: 611-623, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17588759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17588759</a>] [<a href="https://doi.org/10.1016/j.nmd.2007.04.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17588759">Kowaljow et al. (2007)</a> found that DUX4 transcripts had only short poly(A) tails and did not fractionate with mRNAs containing long poly(A) tails. RT-PCR detected DUX4 expression in cultured FSHD patient myoblasts and in human fetal and adult rhabdomyosarcoma cell lines, but not in control myoblasts. Immunofluorescence analysis of DUX4-transfected cell lines showed a nuclear staining pattern that partly overlapped with the nuclear envelope. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17588759" 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="#27" class="mim-tip-reference" title="Snider, L., Asawachaicharn, A., Tyler, A. E., Geng, L. N., Petek, L. M., Maves, L., Miller, D. G., Lemmers, R. J. L. F., Winokur, S. T., Tawil, R., van der Maarel, S. M., Filippova, G. N., Tapscott, S. J. <strong>RNA transcripts, miRNA-sized fragments and proteins produced from D4Z4 units: new candidates for the pathophysiology of facioscapulohumeral dystrophy.</strong> Hum. Molec. Genet. 18: 2414-2430, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19359275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19359275</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19359275[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/ddp180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19359275">Snider et al. (2009)</a> found that the D4Z4 region is subject to highly complex splicing and mRNA processing. Sequencing of the 2 residual D4Z4 repeats in an individual with FSHD and the disease-associated haplotype 4qA161 suggested the presence of major and minor ORFs, including the DUX4 ORF, that overlap in different reading frames and in both orientations. Many of the potential ORFs in the 2 D4Z4 repeats, but not the DUX4 ORF, differ significantly due to sequence variations. RT-PCR confirmed expression of full-length DUX4 transcripts at low levels in human embryonic and mesenchymal stem cells, and DUX4 protein was detected in undifferentiated human embryonic and mesenchymal stem cells. However, transcripts including only the 5-prime or 3-prime portions of DUX4 were detected at higher abundance than the full-length transcript in fibroblasts and muscle cells from FSHD and control individuals. Transcripts containing only the 5-prime portion of the DUX4 ORF were polyadenylated and capped in FSHD muscle cells, and they were predicted to encode a truncated protein containing only the paired homeodomains. The majority of these transcripts had a repeated sequence, suggesting splicing between the 2 D4Z4 units. Transcripts containing only the 3-prime portion of the DUX4 ORF were polyadenylated and uncapped in FSHD muscle cells, and they were predicted to encode a 76-amino acid protein containing only the highly conserved C-terminal region. Transfection studies demonstrated expression of the DUX4 isoform containing only the C-terminal domain and suggested that it originated from an internal ribosomal initiation site. RT-PCR also detected several sense and antisense transcripts originating from the D4Z4 repeats in muscle cells from FSHD and control individuals. Northern blot analysis revealed that microRNA-like fragments were generated from the DUX4 transcript in FSHD and control fibroblasts and muscle cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19359275" 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="#28" class="mim-tip-reference" title="Snider, L., Geng, L. N., Lemmers, R. J. L. F., Kyba, M., Ware, C. B., Nelson, A. M., Tawil, R., Filippova, G. N., van der Maarel, S. M., Tapscott, S. J., Miller, D. G. <strong>Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene.</strong> PLoS Genet. 6: e1001181, 2010. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21060811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21060811</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21060811[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/10.1371/journal.pgen.1001181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21060811">Snider et al. (2010)</a> stated that they had previously identified a short DUX4 transcript (DUX4-s), generated by splicing at a noncanonical donor sequence. The deduced protein contains 2 homeobox domains, but lacks the C-terminal end found in full-length DUX4 (DUX4-fl). RT-PCR of normal human tissues detected abundant DUX4-fl expression in testis, but not in any other tissue examined. DUX4-s was detected in ovary, heart, and skeletal muscle, with weaker expression in liver. No DUX4-s expression was detected in testis, kidney, or cerebellum. Within cells and cell lines, DUX4-fl was detected in induced pluripotent stem cells and in some human embryonic stem cell lines. Differentiated fibroblasts and embryoid bodies expressed DUX4-s only. Immunohistochemical analysis of human testis detected DUX4-fl in spermatogonia and primary spermatocytes and in more differentiated cells in seminiferous tubules. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21060811" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="geneStructure" class="mim-anchor"></a>
|
|
<h4 href="#mimGeneStructureFold" id="mimGeneStructureToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimGeneStructureToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimGeneStructureFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><a href="#7" class="mim-tip-reference" title="Dixit, M., Ansseau, E., Tassin, A., Winokur, S., Shi, R., Qian, H., Sauvage, S., Matteotti, C., van Acker, A. M., Leo, O., Figlewicz, D., Barro, M., Laoudj-Chenivesse, D., Belayew, A., Coppee, F., Chen, Y.-W. <strong>DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1.</strong> Proc. Nat. Acad. Sci. 104: 18157-18162, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17984056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17984056</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17984056[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0708659104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17984056">Dixit et al. (2007)</a> reported that the DUX4 promoter region contains putative CATT, GC, TACAA, and E boxes. The 3-prime end of the DUX4 gene contains an alternatively spliced exon located between the stop codon and the end of the D4Z4 unit. In addition, the 3-prime end of the DUX4 gene in the most distal D4Z4 unit contains a second intron and a single polyadenylation signal, both of which are located telomeric to the D4Z4 unit. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17984056" 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="#28" class="mim-tip-reference" title="Snider, L., Geng, L. N., Lemmers, R. J. L. F., Kyba, M., Ware, C. B., Nelson, A. M., Tawil, R., Filippova, G. N., van der Maarel, S. M., Tapscott, S. J., Miller, D. G. <strong>Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene.</strong> PLoS Genet. 6: e1001181, 2010. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21060811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21060811</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21060811[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/10.1371/journal.pgen.1001181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21060811">Snider et al. (2010)</a> determined that the DUX4 gene contains at least 7 exons, with exons 3 through 7 outside the D4Z4 repeat region. The 4qA haplotype includes alternate polyadenylation sites in exons 3 and 7. The 4qB haplotype does not show these polyadenylation sites and may include more than 7 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21060811" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="mapping" class="mim-anchor"></a>
|
|
<h4 href="#mimMappingFold" id="mimMappingToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimMappingToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimMappingFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p>By genomic sequence analysis, <a href="#10" class="mim-tip-reference" title="Gabriels, J., Beckers, M.-C., Ding, H., De Vriese, A., Plaisance, S., van der Maarel, S. M., Padberg, G. W., Frants, R. R., Hewitt, J. E., Collen, D., Belayew, A. <strong>Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element.</strong> Gene 236: 25-32, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10433963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10433963</a>] [<a href="https://doi.org/10.1016/s0378-1119(99)00267-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10433963">Gabriels et al. (1999)</a> mapped the DUX4 gene to chromosome 4q35. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10433963" 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>Using luciferase reporter assays, <a href="#10" class="mim-tip-reference" title="Gabriels, J., Beckers, M.-C., Ding, H., De Vriese, A., Plaisance, S., van der Maarel, S. M., Padberg, G. W., Frants, R. R., Hewitt, J. E., Collen, D., Belayew, A. <strong>Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element.</strong> Gene 236: 25-32, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10433963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10433963</a>] [<a href="https://doi.org/10.1016/s0378-1119(99)00267-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10433963">Gabriels et al. (1999)</a> demonstrated DUX4 promoter activity that was dependent on a TACAA box and a GC box. They suggested that DUX4 may play a role in FSHD because partial deletions of the D4Z4 region might alter DUX4 expression in FSHD patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10433963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By comparing genomewide expression profiles of muscle biopsies from patients with FSHD to those of 11 other neuromuscular disorders, <a href="#7" class="mim-tip-reference" title="Dixit, M., Ansseau, E., Tassin, A., Winokur, S., Shi, R., Qian, H., Sauvage, S., Matteotti, C., van Acker, A. M., Leo, O., Figlewicz, D., Barro, M., Laoudj-Chenivesse, D., Belayew, A., Coppee, F., Chen, Y.-W. <strong>DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1.</strong> Proc. Nat. Acad. Sci. 104: 18157-18162, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17984056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17984056</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17984056[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0708659104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17984056">Dixit et al. (2007)</a> identified 5 genes, including the paired homeodomain transcription factor PITX1 (<a href="/entry/602149">602149</a>), that were specifically upregulated in FSHD patients. DUX4 expression was upregulated in FSHD myoblasts at both the mRNA and protein levels. DUX4 activated expression of a reporter gene fused to the PITX1 promoter and of endogenous Pitx1 in DUX4-transfected C2C12 mouse myoblasts. In electrophoretic mobility shift assays, DUX4 specifically interacted with a 30-bp sequence containing a conserved TAAT core motif in the PITX1 promoter. Mutations of the TAAT core affected Pitx1 activation in C2C12 cells and DUX4 binding in vitro. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17984056" 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="#15" class="mim-tip-reference" title="Kowaljow, V., Marcowycz, A., Ansseau, E., Conde, C. B., Sauvage, S., Matteotti, C., Arias, C., Corona, E. D., Nunez, N. G., Leo, O., Wattiez, R., Figlewicz, D., Laoudj-Chenivesse, D., Belayew, A., Coppee, F., Rosa, A. L. <strong>The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein.</strong> Neuromusc. Disord. 17: 611-623, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17588759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17588759</a>] [<a href="https://doi.org/10.1016/j.nmd.2007.04.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17588759">Kowaljow et al. (2007)</a> found that overexpression of DUX4 in several cell lines resulted in apoptotic changes, including activation of caspase-3 (CASP3; <a href="/entry/600636">600636</a>) and caspase-7 (CASP7; <a href="/entry/601761">601761</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17588759" 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 transfection studies, <a href="#27" class="mim-tip-reference" title="Snider, L., Asawachaicharn, A., Tyler, A. E., Geng, L. N., Petek, L. M., Maves, L., Miller, D. G., Lemmers, R. J. L. F., Winokur, S. T., Tawil, R., van der Maarel, S. M., Filippova, G. N., Tapscott, S. J. <strong>RNA transcripts, miRNA-sized fragments and proteins produced from D4Z4 units: new candidates for the pathophysiology of facioscapulohumeral dystrophy.</strong> Hum. Molec. Genet. 18: 2414-2430, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19359275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19359275</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19359275[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/ddp180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19359275">Snider et al. (2009)</a> showed that full-length DUX4 reduced the expression of reporter genes driven by CKM (<a href="/entry/123310">123310</a>), desmin (DES; <a href="/entry/125660">125660</a>), or a multimerized E box. Full-length DUX4 also reduced expression of endogenous myosin heavy chain (see <a href="/entry/160730">160730</a>) in transfected C2C12 mouse myoblasts. Expression of the full-length DUX4 protein or isoforms containing only the N- or C-terminal domains inhibited myogenesis in C2C12 cells. Several DUX4 transcripts incapable of translation also inhibited C2C12 differentiation. Expression of transcripts encoding full-length DUX4 inhibited zebrafish development past gastrulation or caused severe developmental abnormalities in the surviving embryos. Expression of transcripts encoding the C-terminal DUX4 peptide did not alter morphologic development of zebrafish, but blocked myogenesis at a step between Myod (<a href="/entry/159970">159970</a>) transcription and activation of Myod target genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19359275" 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="#34" class="mim-tip-reference" title="Wallace, L. M., Garwick, S. E., Mei, W., Belayew, A., Coppee, F., Ladner, K. J., Guttridge, D., Yang, J., Harper, S. Q. <strong>DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53-dependent myopathy in vivo.</strong> Ann. Neurol. 69: 540-552, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21446026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21446026</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21446026[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/10.1002/ana.22275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21446026">Wallace et al. (2011)</a> showed that apoptotic changes observed in DUX4-expressing HEK293 cells were eliminated by an inactivating mutation in the first DNA-binding homeobox domain of DUX4. The development of lesions in DUX4-injected mouse muscle was also abrogated by mutation of the DUX4 homeobox domain. Pharmacologic inhibition of p53 (TP53; <a href="/entry/191170">191170</a>) mitigated DUX4 toxicity in HEK293 cells, and muscle from p53-null mice were resistant to DUX4-induced damage. <a href="#34" class="mim-tip-reference" title="Wallace, L. M., Garwick, S. E., Mei, W., Belayew, A., Coppee, F., Ladner, K. J., Guttridge, D., Yang, J., Harper, S. Q. <strong>DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53-dependent myopathy in vivo.</strong> Ann. Neurol. 69: 540-552, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21446026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21446026</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21446026[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/10.1002/ana.22275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21446026">Wallace et al. (2011)</a> concluded that DUX4-induced myopathy is dependent on p53-mediated apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21446026" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By gene expression array analysis, <a href="#11" class="mim-tip-reference" title="Geng, L. N., Yao, Z., Snider, L., Fong, A. P., Cech, J. N., Young, J. M., van der Maarel, S. M., Ruzzo, W. L., Gentleman, R. C., Tawil, R., Tapscott, S. J. <strong>DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy.</strong> Dev. Cell 22: 38-51, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22209328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22209328</a>] [<a href="https://doi.org/10.1016/j.devcel.2011.11.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22209328">Geng et al. (2012)</a> found that DUX4-fl induced expression of several genes associated with germline and early stem-cell development and suppressed genes involved in innate immune response. DUX4-fl bound specifically to a long terminal repeat element from a class of MaLR retrotransposons. DUX4-s bound the same element, but it did not activate gene expression, and it functioned as a dominant-negative inhibitor of DUX4-fl when coexpressed. Although DUX4 expression was below the level of detection in several FSHD muscle biopsy samples by RT-PCR, expression of DUX4-fl-regulated genes was significantly upregulated compared with control muscle samples. Furthermore, knockdown of DUX4-fl expression in FSHD muscle cells via small interfering RNA or coexpression of DUX4-s reduced the expression of DUX4-fl target genes. DEFB103A (<a href="/entry/606611">606611</a>) and DEFB103B, which encode negative regulators of innate immunity, were among the DUX4-fl target genes upregulated in FSHD muscle. Overexpression of DEFB103 in differentiating muscle cells reduced expression of genes associated with muscle differentiation and inflammatory response. <a href="#11" class="mim-tip-reference" title="Geng, L. N., Yao, Z., Snider, L., Fong, A. P., Cech, J. N., Young, J. M., van der Maarel, S. M., Ruzzo, W. L., Gentleman, R. C., Tawil, R., Tapscott, S. J. <strong>DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy.</strong> Dev. Cell 22: 38-51, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22209328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22209328</a>] [<a href="https://doi.org/10.1016/j.devcel.2011.11.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22209328">Geng et al. (2012)</a> concluded that even low-level DUX4 overexpression can have a profound effect on gene expression and result in FSHD, and they proposed that DEFB103 may contribute to FSHD pathology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22209328" 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>D4Z4 Macrosatellite Repeat</em></strong></p><p>
|
|
<a href="#12" class="mim-tip-reference" title="Hewitt, J. E., Lyle, R., Clark, L. N., Valleley, E. M., Wright, T. J., Wijmenga, C., van Deutekom, J. C. T., Francis, F., Sharpe, P. T., Hofker, M., Frants, R. R., Williamson, R. <strong>Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy.</strong> Hum. Molec. Genet. 3: 1287-1295, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7987304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7987304</a>] [<a href="https://doi.org/10.1093/hmg/3.8.1287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7987304">Hewitt et al. (1994)</a> determined the sequence of D4Z4 and showed that each copy of the repeat contains 2 homeoboxes and 2 previously described repetitive sequences, LSau and a GC-rich low copy repeat designated hhspm3. By Southern blot analysis, FISH, and isolation of cDNA and genomic clones, <a href="#12" class="mim-tip-reference" title="Hewitt, J. E., Lyle, R., Clark, L. N., Valleley, E. M., Wright, T. J., Wijmenga, C., van Deutekom, J. C. T., Francis, F., Sharpe, P. T., Hofker, M., Frants, R. R., Williamson, R. <strong>Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy.</strong> Hum. Molec. Genet. 3: 1287-1295, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7987304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7987304</a>] [<a href="https://doi.org/10.1093/hmg/3.8.1287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7987304">Hewitt et al. (1994)</a> showed that there are repeat sequences similar to D4Z4 at other locations in the human genome. Southern blot analysis of primate genomic DNA indicated that the copy number of D4Z4-like repeats has increased markedly within the last 25 million years. Two cDNA clones were isolated and found to contain stop codons and frameshifts within the homeodomains. An STS was produced to the cDNAs, and analysis of a somatic cell hybrid panel suggested that they mapped to chromosome 14. No cDNA clones mapping to the 4q35 D4Z4 repeat were identified, although the possibility that these repeats encode a protein could not be ruled out. Although D4Z4 may not encode a protein, there is association between deletions within this locus and FSHD1 (<a href="/entry/158900">158900</a>). The D4Z4 repeats contain LSau repeats and are adjacent to 68-bp Sau3A repeats. Both of these sequences are associated with heterochromatic regions of DNA, regions known to be involved in the phenomenon of 'position effect' variegation. <a href="#12" class="mim-tip-reference" title="Hewitt, J. E., Lyle, R., Clark, L. N., Valleley, E. M., Wright, T. J., Wijmenga, C., van Deutekom, J. C. T., Francis, F., Sharpe, P. T., Hofker, M., Frants, R. R., Williamson, R. <strong>Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy.</strong> Hum. Molec. Genet. 3: 1287-1295, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7987304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7987304</a>] [<a href="https://doi.org/10.1093/hmg/3.8.1287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7987304">Hewitt et al. (1994)</a> postulated that deletion of D4Z4 sequences produced a position effect that is involved in the pathogenesis of FSHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7987304" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#35" class="mim-tip-reference" title="Winokur, S. T., Schutte, B., Weiffenbach, B., Washington, S. S., McElligott, D., Chakravarti, A., Wasmuth, J. H., Altherr, M. R. <strong>A radiation hybrid map of 15 loci on the distal long arm of chromosome 4, the region containing the gene responsible for facioscapulohumeral muscular dystrophy (FSHD).</strong> Am. J. Hum. Genet. 53: 874-880, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8213815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8213815</a>]" pmid="8213815">Winokur et al. (1993)</a> also postulated that FSHD may be due to a position effect. <a href="#1" class="mim-tip-reference" title="Bengtsson, U., Altherr, M. R., Wasmuth, J. J., Winokur, S. T. <strong>High resolution fluorescence in situ hybridization to linearly extended DNA visually maps a tandem repeat associated with facioscapulohumeral muscular dystrophy immediately adjacent to the telomere of 4q.</strong> Hum. Molec. Genet. 3: 1801-1805, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849703</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1801" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849703">Bengtsson et al. (1994)</a> reported results indicating that the tandem array of 3.2-kb repeats, disrupted in FSHD, lies immediately adjacent to the telomere of 4q and that the gene responsible for FSHD is probably located proximal to the tandem repeat. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7849703+8213815" 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 highly homologous polymorphic repeat array is located near the telomere of 10q, but a specific BlnI site within each chromosome 10-derived repeat unit allows discrimination between the arrays (<a href="#6" class="mim-tip-reference" title="Deidda, G., Cacurri, S., Piazzo, N., Felicetti, L. <strong>Direct detection of 4q35 rearrangements implicated in facioscapulohumeral muscular dystrophy (FSHD).</strong> J. Med. Genet. 33: 361-365, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8733043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8733043</a>] [<a href="https://doi.org/10.1136/jmg.33.5.361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8733043">Deidda et al., 1996</a>). This BlnI site-dependent discrimination demonstrated the presence of 10-type repeats on chromosome 4 and, vice versa, 4-type repeats on chromosome 10, suggesting a dynamic exchange between these chromosomes. <a href="#29" class="mim-tip-reference" title="van der Maarel, S. M., Deidda, G., Lemmers, R. J. L. F., van Overveld, P. G. M., van der Wielen, M., Hewitt, J. E., Sandkuijl, L., Bakker, B., van Ommen, G.-J. B., Padberg, G. W., Frants, R. R. <strong>De novo facioscapulohumeral muscular dystrophy: frequent somatic mosaicism, sex-dependent phenotype, and the role of mitotic transchromosomal repeat interaction between chromosomes 4 and 10.</strong> Am. J. Hum. Genet. 66: 26-35, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10631134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10631134</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10631134[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/302730" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10631134">Van der Maarel et al. (2000)</a> found that the repeat deletion was significantly enhanced by supernumerary homologous repeat arrays. They demonstrated that a numerical excess of 4-type repeats on chromosome 10 was a significant, if not the major, predisposing factor for the occurrence of the FSHD-type deletion. Mitotic interchromosomal gene conversion or translocation between fully homologous repeat arrays may be a major mechanism for FSHD mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8733043+10631134" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="van Deutekom, J. C. T., Bakker, E., Lemmers, R. J. L. F., van der Wielen, M. J. R., Bik, E., Hofker, M. H., Padberg, G. W., Frants, R. R. <strong>Evidence for subtelomeric exchange of 3.3 kb tandemly repeated units between chromosomes 4q35 and 10q26: implications for genetic counselling and etiology of FSHD1.</strong> Hum. Molec. Genet. 5: 1997-2003, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968754</a>] [<a href="https://doi.org/10.1093/hmg/5.12.1997" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8968754">Van Deutekom et al. (1996)</a> reported exchange of subtelomeric repeated DNA units between chromosomes 4q35 and 10q26 in at least 20% of the Dutch population. These subtelomeric rearrangements generated novel DNA restriction fragments and complicated the use of restriction fragment analysis for DNA diagnosis of FSHD. The high frequency of interchromosomal exchanges of 3.3-kb repeat units suggested to <a href="#30" class="mim-tip-reference" title="van Deutekom, J. C. T., Bakker, E., Lemmers, R. J. L. F., van der Wielen, M. J. R., Bik, E., Hofker, M. H., Padberg, G. W., Frants, R. R. <strong>Evidence for subtelomeric exchange of 3.3 kb tandemly repeated units between chromosomes 4q35 and 10q26: implications for genetic counselling and etiology of FSHD1.</strong> Hum. Molec. Genet. 5: 1997-2003, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968754</a>] [<a href="https://doi.org/10.1093/hmg/5.12.1997" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8968754">van Deutekom et al. (1996)</a> that these units probably do not contain part of the FSHD gene and supported position effect variegation as the most likely mechanism for FSHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8968754" 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 3-dimensional immuno-FISH, <a href="#21" class="mim-tip-reference" title="Masny, P. S., Bengtsson, U., Chung, S.-A., Martin, J. H., van Engelen, B., van der Maarel, S. M., Winokur, S. T. <strong>Localization of 4q35.2 to the nuclear periphery: is FSHD a nuclear envelope disease?</strong> Hum. Molec. Genet. 13: 1857-1871, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15238509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15238509</a>] [<a href="https://doi.org/10.1093/hmg/ddh205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15238509">Masny et al. (2004)</a> determined that the FSHD region at chromosome 4q35.2 localized to the nuclear periphery in several cell types throughout the cell cycle. FSHD region chromatin localization to the nuclear envelope was lost in lamin A/C (<a href="/entry/150330">150330</a>)-null fibroblasts, suggesting that lamin A/C is required for proper localization, and both normal and D4Z4-deleted alleles localized to the nuclear periphery. <a href="#21" class="mim-tip-reference" title="Masny, P. S., Bengtsson, U., Chung, S.-A., Martin, J. H., van Engelen, B., van der Maarel, S. M., Winokur, S. T. <strong>Localization of 4q35.2 to the nuclear periphery: is FSHD a nuclear envelope disease?</strong> Hum. Molec. Genet. 13: 1857-1871, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15238509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15238509</a>] [<a href="https://doi.org/10.1093/hmg/ddh205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15238509">Masny et al. (2004)</a> suggested that FSHD likely arises from improper interactions with transcription factors or chromatin modifiers at the nuclear envelope. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15238509" 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>Within the D4Z4 locus, <a href="#26" class="mim-tip-reference" title="Petrov, A., Pirozhkova, I., Carnac, G., Laoudj, D., Lipinski, M., Vassetzky, Y. S. <strong>Chromatin loop domain organization within the 4q35 locus in facioscapulohumeral dystrophy patients versus normal human myoblasts.</strong> Proc. Nat. Acad. Sci. 103: 6982-6987, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16632607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16632607</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16632607[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0511235103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16632607">Petrov et al. (2006)</a> identified 2 DNA loop domains anchored to the nuclear matrix via nuclear scaffold/matrix attached regions (S/MARs). Myoblasts derived from patients with FSHD showed a significant decrease in association of S/MARs with the nuclear matrix compared to control myoblasts. Biochemical mapping showed that in normal myoblasts the D4Z4 array was located in a DNA loop domain distinct from the DNA loop domain where FRG1 (<a href="/entry/601278">601278</a>) and FRG2 (<a href="/entry/609032">609032</a>) were located, whereas in damaged FSHD chromosome, the partially deleted D4Z4 array and FRG1 and FRG2 were located within the same DNA loop domain. <a href="#26" class="mim-tip-reference" title="Petrov, A., Pirozhkova, I., Carnac, G., Laoudj, D., Lipinski, M., Vassetzky, Y. S. <strong>Chromatin loop domain organization within the 4q35 locus in facioscapulohumeral dystrophy patients versus normal human myoblasts.</strong> Proc. Nat. Acad. Sci. 103: 6982-6987, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16632607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16632607</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16632607[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0511235103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16632607">Petrov et al. (2006)</a> suggested that S/MARs regulate chromatin accessibility and expression of genes implicated in FSHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16632607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Petrov, A., Allinne, J., Pirozhkova, I., Laoudj, D., Lipinski, M., Vassetzky, Y. S. <strong>A nuclear matrix attachment site in the 4q35 locus has an enhancer-blocking activity in vivo: implications for the facio-scapulo-humeral dystrophy.</strong> Genome Res. 18: 39-45, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18032730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18032730</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18032730[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/10.1101/gr.6620908" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18032730">Petrov et al. (2008)</a> proposed that FR-MAR, an S/MAR positioned 5-prime of the D4Z4 repeat array, may function in normal cells as an insulator element to protect upstream genes from the effect of D4Z4. Using reporter gene assays, they found that D4Z4 repeats showed enhancer function and elevated transcription from the FRG1 promoter in all transfected cell lines examined. Deletion analysis located the strongest enhancer activity to the 5-prime end of the D4Z4 unit. FR-MAR blocked this enhancer function. FR-MAR also associated with the nuclear matrix in normal myoblasts, but not in FSHD myoblasts. <a href="#25" class="mim-tip-reference" title="Petrov, A., Allinne, J., Pirozhkova, I., Laoudj, D., Lipinski, M., Vassetzky, Y. S. <strong>A nuclear matrix attachment site in the 4q35 locus has an enhancer-blocking activity in vivo: implications for the facio-scapulo-humeral dystrophy.</strong> Genome Res. 18: 39-45, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18032730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18032730</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18032730[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/10.1101/gr.6620908" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18032730">Petrov et al. (2008)</a> concluded that FR-MAR functions as an insulator to protect the FRG genes from the enhancer activity present in each D4Z4 repeat unit. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18032730" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By in vitro cellular studies with a single D4Z4 repeat, <a href="#23" class="mim-tip-reference" title="Ottaviani, A., Rival-Gervier, S., Boussouar, A., Foerster, A. M., Rondier, D., Sacconi, S., Desnuelle, C., Gilson, E., Magdinier, F. <strong>The D4Z4 macrosatellite repeat acts as a CTCF and A-type lamins-dependent insulator in facio-scapulo-humeral dystrophy.</strong> PLoS Genet. 5: e1000394, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19247430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19247430</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19247430[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/10.1371/journal.pgen.1000394" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19247430">Ottaviani et al. (2009)</a> demonstrated that D4Z4 acts both as a transcriptional insulator protecting against the repressive influence of various chromosomal contexts and as an enhancer insulator interfering with enhancer-promoter communication. The addition of D4Z4 element repeats progressively abolished the insulation activity, suggesting that the repeat element loosens its anti-silencing activity upon multimerization. Further studies showed that the insulator function of D4Z4 is dependent on CTCF (<a href="/entry/604167">604167</a>) and LMNA (<a href="/entry/150330">150330</a>). The findings demonstrated a novel mode of chromatin regulation controlled by the number of D4Z4 repeats. <a href="#23" class="mim-tip-reference" title="Ottaviani, A., Rival-Gervier, S., Boussouar, A., Foerster, A. M., Rondier, D., Sacconi, S., Desnuelle, C., Gilson, E., Magdinier, F. <strong>The D4Z4 macrosatellite repeat acts as a CTCF and A-type lamins-dependent insulator in facio-scapulo-humeral dystrophy.</strong> PLoS Genet. 5: e1000394, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19247430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19247430</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19247430[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/10.1371/journal.pgen.1000394" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19247430">Ottaviani et al. (2009)</a> proposed that reduction of the D4Z4 array in FSHD patients results in a gain-of-function effect by allowing the binding of CTCF and provoking changes in the biologic function of D4Z4 such that it switches from a repressor to an insulator protecting the expression of the FSHD gene(s). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19247430" 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="Dmitriev, P., Petrov, A., Ansseau, E., Stankevicins, L., Charron, S., Kim, E., Bos, T. J., Robert, T., Turki, A., Coppee, F., Belayew, A., Lazar, V., Carnac, G., Laoudj, D., Lipinski, M., Vassetzky, Y. S. <strong>The Kruppel-like factor 15 as a molecular link between myogenic factors and a chromosome 4q transcriptional enhancer implicated in facioscapulohumeral dystrophy.</strong> J. Biol. Chem. 286: 44620-44631, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21937448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21937448</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21937448[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/10.1074/jbc.M111.254052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21937448">Dmitriev et al. (2011)</a> showed that KLF15 (<a href="/entry/606465">606465</a>) bound an enhancer element within the D4Z4 repeat unit. Binding of KLF15 to 2 sites within the D4Z4 enhancer drove expression of FRG2 and DUX4C (DUX4L9; <a href="/entry/615581">615581</a>), which are located over 40 kb centromeric to the D4Z4 repeat array. KLF15 expression was upregulated following differentiation of normal human myoblasts and following expression of MYOD (<a href="/entry/159970">159970</a>), and it was upregulated in FSHD myoblasts, myotubes, and muscle biopsies. FSHD cells also showed upregulated expression of MYOD and the KLF15 target gene PPARG (<a href="/entry/601487">601487</a>), in addition to DUX4C and FRG2. <a href="#8" class="mim-tip-reference" title="Dmitriev, P., Petrov, A., Ansseau, E., Stankevicins, L., Charron, S., Kim, E., Bos, T. J., Robert, T., Turki, A., Coppee, F., Belayew, A., Lazar, V., Carnac, G., Laoudj, D., Lipinski, M., Vassetzky, Y. S. <strong>The Kruppel-like factor 15 as a molecular link between myogenic factors and a chromosome 4q transcriptional enhancer implicated in facioscapulohumeral dystrophy.</strong> J. Biol. Chem. 286: 44620-44631, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21937448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21937448</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21937448[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/10.1074/jbc.M111.254052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21937448">Dmitriev et al. (2011)</a> concluded that MYOD-dependent KLF15 expression is involved in partial activation of the differentiation program in FSHD myoblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21937448" 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>4qA and 4qB Polymorphic Segment</em></strong></p><p>
|
|
Human 4qter and 10qter share a high degree of similarity, including the D4Z4 repeat array; however, contractions affecting the 10qter repeat are nonpathogenic. <a href="#32" class="mim-tip-reference" title="van Geel, M., Dickson, M. C., Beck, A. F., Bolland, D. J., Frants, R. R., van der Maarel, S. M., de Jong, P. J., Hewitt, J. E. <strong>Genomic analysis of human chromosome 10q and 4q telomeres suggests a common origin.</strong> Genomics 79: 210-217, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11829491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11829491</a>] [<a href="https://doi.org/10.1006/geno.2002.6690" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11829491">Van Geel et al. (2002)</a> detected a polymorphic segment of 10 kb directly distal to D4Z4, which they called alleles 4qA and 4qB. <a href="#17" class="mim-tip-reference" title="Lemmers, R. J. L. F., de Kievit, P., Sandkuijl, L., Padberg, G. W., van Ommen, G.-J. B., Frants, R. R., van der Maarel, S. M. <strong>Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere. (Letter)</strong> Nature Genet. 32: 235-236, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12355084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12355084</a>] [<a href="https://doi.org/10.1038/ng999" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12355084">Lemmers et al. (2002)</a> reported that although the 2 alleles are equally common in the general population, FSHD is associated solely with the 4qA allele. They suggested that this was the first example of an intrinsically benign subtelomeric polymorphism predisposing to the development of human disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12355084+11829491" 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="#16" class="mim-tip-reference" title="Lemmers, R. J. F. L., Wohlgemuth, M., Frants, R. R., Padberg, G. W., Morava, E., van der Maarel, S. M. <strong>Contractions of D4Z4 on 4qB subtelomeres do not cause facioscapulohumeral muscular dystrophy.</strong> Am. J. Hum. Genet. 75: 1124-1130, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15467981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15467981</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15467981[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/426035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15467981">Lemmers et al. (2004)</a> concluded that contractions of D4Z4 on 4qB subtelomeres do not cause FSHD. The 2 allelic variants of 4q, 4qA and 4qB, exist in the region distal to D4Z4. Although both variants are almost equally present in the population, FSHD is associated exclusively with the 4qA allele. <a href="#16" class="mim-tip-reference" title="Lemmers, R. J. F. L., Wohlgemuth, M., Frants, R. R., Padberg, G. W., Morava, E., van der Maarel, S. M. <strong>Contractions of D4Z4 on 4qB subtelomeres do not cause facioscapulohumeral muscular dystrophy.</strong> Am. J. Hum. Genet. 75: 1124-1130, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15467981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15467981</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15467981[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/426035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15467981">Lemmers et al. (2004)</a> identified 3 families with FSHD in which each proband carried 2 FSHD-sized alleles and was heterozygous for the 4qA/4qB polymorphism. Segregation analysis demonstrated that FSHD-sized 4qB alleles are not associated with disease, since these were present in unaffected family members. Thus, in addition to a contraction of D4Z4, additional cis-acting elements on 4qA may be required for the development of FSHD. Alternatively, 4qB subtelomeres may contain elements that prevent FSHD pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15467981" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Lemmers, R. J. L. F., Wohlgemuth, M., van der Gaag, K. J., van der Vliet, P. J., van Teijlingen, C. M. M., de Knijff, P., Padberg, G. W., Frants, R. R., van der Maarel, S. M. <strong>Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy.</strong> Am. J. Hum. Genet. 81: 884-894, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17924332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17924332</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17924332[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/521986" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17924332">Lemmers et al. (2007)</a> hypothesized that allele-specific sequence differences among 4qA, 4qB, and 10q alleles underlie the 4qA specificity of FSHD. By examining sequence variations in the FSHD locus, they demonstrated that the subtelomeric domain of 4q can be subdivided into 9 distinct haplotypes, of which 3 carry the distal 4qA variation. They showed that repeat contractions in 2 of the 9 haplotypes, 1 of which is a 4qA haplotype, are not associated with FSHD. They showed that each of these haplotypes has its unique sequence signature, and proposed that specific SNPs in the disease haplotype are essential for the development of FSHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17924332" 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>Changes in Gene Expression Related to D4Z4</em></strong></p><p>
|
|
<a href="#31" class="mim-tip-reference" title="van Deutekom, J. C. T., Lemmers, R. J. L. F., Grewal, P. K., van Geel, M., Romberg, S., Dauwerse, H. G., Wright, T. J., Padberg, G. W., Hofker, M. H., Hewitt, J. E., Frants, R. R. <strong>Identification of the first gene (FRG1) from the FSHD region on human chromosome 4q35.</strong> Hum. Molec. Genet. 5: 581-590, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8733123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8733123</a>] [<a href="https://doi.org/10.1093/hmg/5.5.581" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8733123">Van Deutekom et al. (1996)</a> identified the FRG1 gene that mapped 100 kb centromeric of the repeated units on chromosome 4q35 that are deleted in FSHD. They identified a polymorphism in exon 1 of this gene and used RT-PCR to amplify reverse transcribed mRNA from lymphocytes and muscle biopsies of patients and controls. These studies indicated that both alleles were transcribed and gave no evidence of 'position effect' variegation leading to repression of allelic transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8733123" 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="Gabellini, D., Green, M. R., Tupler, R. <strong>Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle.</strong> Cell 110: 339-348, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12176321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12176321</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)00826-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12176321">Gabellini et al. (2002)</a> found that in FSHD muscle, genes located upstream of D4Z4 on 4q35, including FRG1, FRG2, and ANT1 (<a href="/entry/103220">103220</a>), are inappropriately overexpressed. They showed that an element within D4Z4 specifically binds a multiprotein complex consisting of transcriptional repressor YY1 (<a href="/entry/600013">600013</a>), HMGB2 (<a href="/entry/163906">163906</a>), and nucleolin (NCL; <a href="/entry/164035">164035</a>). This multiprotein complex binds D4Z4 in vitro and in vivo and mediates transcriptional repression of 4q35 genes. <a href="#9" class="mim-tip-reference" title="Gabellini, D., Green, M. R., Tupler, R. <strong>Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle.</strong> Cell 110: 339-348, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12176321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12176321</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)00826-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12176321">Gabellini et al. (2002)</a> proposed that deletion of D4Z4 leads to the inappropriate transcriptional derepression of 4q35 genes, resulting in disease. In normal individuals, the presence of a threshold number of D4Z4 repeats leads to repression of 4q35 genes by virtue of the DNA-bound multiprotein complex that actively suppresses gene expression. In FSHD patients, deletion of an integral number of D4Z4 repeats reduces the number of bound repressor complexes and consequently decreases or abolishes transcriptional repression of 4q35 genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12176321" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Jiang, G., Yang, F., van Overveld, P. G. M., Vedanarayanan, V., van der Maarel, S., Ehrlich, M. <strong>Testing the position-effect variegation hypothesis for facioscapulohumeral muscular dystrophy by analysis of histone modification and gene expression in subtelomeric 4q.</strong> Hum. Molec. Genet. 12: 2909-2921, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14506132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14506132</a>] [<a href="https://doi.org/10.1093/hmg/ddg323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14506132">Jiang et al. (2003)</a> found that H4 acetylation levels of a nonrepeated region adjacent to the 4q35 and 10q26 D4Z4 arrays in normal and FSHD lymphoid cells were like those in unexpressed euchromatin, rather than like constitutive heterochromatin. The control and FSHD cells also displayed similar H4 hyperacetylation (like that of expressed genes) at the 5-prime regions of 4q35 candidate genes FRG1 and ANT1. There was no position-dependent increase in transcript levels from these genes in FSHD skeletal muscle samples compared with controls. <a href="#13" class="mim-tip-reference" title="Jiang, G., Yang, F., van Overveld, P. G. M., Vedanarayanan, V., van der Maarel, S., Ehrlich, M. <strong>Testing the position-effect variegation hypothesis for facioscapulohumeral muscular dystrophy by analysis of histone modification and gene expression in subtelomeric 4q.</strong> Hum. Molec. Genet. 12: 2909-2921, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14506132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14506132</a>] [<a href="https://doi.org/10.1093/hmg/ddg323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14506132">Jiang et al. (2003)</a> proposed a model for FSHD in which differential long-distance cis looping depends upon the presence of a 4q35 D4Z4 array with less than a threshold number of copies of the 3.3-kb repeat. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14506132" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Perini, G., Tupler, R. <strong>Altered gene silencing and human diseases.</strong> Clin. Genet. 69: 1-7, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16451126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16451126</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2005.00540.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16451126">Perini and Tupler (2006)</a> suggested that FSHD might be considered a useful model for the study of position effect in humans. The D4Z4 deletion might result in stochastic variation in gene expression in muscle cells and explain the asymmetric involvement of muscles, the great variability of clinical expression between and within families, and the apparent threshold effect whereby there is a requirement for the deletion of a certain number of copies of D4Z4 to develop FSHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16451126" 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="#22" class="mim-tip-reference" title="Osborne, R. J., Welle, S., Venance, S. L., Thornton, C. A., Tawil, R. <strong>Expression profile of FSHD supports a link between retinal vasculopathy and muscular dystrophy.</strong> Neurology 68: 569-577, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17151338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17151338</a>] [<a href="https://doi.org/10.1212/01.wnl.0000251269.31442.d9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17151338">Osborne et al. (2007)</a> detected no change in expression of the FRG1, FRG2, or ANT1 genes in muscle biopsies from 19 FSHD patients compared to controls. Further studies of the 8-Mb region proximal to the D4Z4 array showed no significant changes in gene expression, no evidence of a position effect, and no evidence of unequal allele-specific expression. However, microarray analysis of global gene expression in FSHD muscle identified 11 upregulated genes with a role in vascular smooth muscle or endothelial cells, suggesting a possible link between muscular dystrophy and vasculopathy in FSHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17151338" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Bosnakovski, D., Xu, Z., Gang, E. J., Galindo, C. L., Liu, M., Simsek, T., Garner, H. R., Agha-Mohammadi, S., Tassin, A., Coppee, F., Belayew, A., Perlingeiro, R. R., Kyba, M. <strong>An isogenic myoblast expression screen identifies DUX4-mediated FSHD-associated molecular pathologies.</strong> EMBO J. 27: 2766-2779, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18833193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18833193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18833193[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/emboj.2008.201" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18833193">Bosnakovski et al. (2008)</a> conditionally expressed cDNAs for FSHD candidate genes within the D4Z4 repeat, DUX4, FRG1, FRG2, and ANT1, in mouse C2C12 myoblasts at both high and low expression levels and found that only DUX4 was overtly toxic, as indicated by cellular ATP content, morphologic changes, and apoptosis. DUX4 showed variable toxicity when expressed in mouse fibroblasts or embryoid bodies. DUX4 localized to C2C12 cell nuclei within 2 hours of induction. Microarray analysis revealed altered expression in a broad range of genes, with greatest changes in those involved in growth and development and signal transduction. Expression of Myod was also downregulated at an early time point. Oxidative stress and heat shock genes were downregulated at later time points, suggesting that they may be secondary targets. The DUX4 homeodomains are most similar to those of PAX3 (<a href="/entry/606597">606597</a>) and PAX7 (<a href="/entry/167410">167410</a>), and overexpression of these genes rescued viability and proliferation in DUX4-expressing C2C12 cells. <a href="#2" class="mim-tip-reference" title="Bosnakovski, D., Xu, Z., Gang, E. J., Galindo, C. L., Liu, M., Simsek, T., Garner, H. R., Agha-Mohammadi, S., Tassin, A., Coppee, F., Belayew, A., Perlingeiro, R. R., Kyba, M. <strong>An isogenic myoblast expression screen identifies DUX4-mediated FSHD-associated molecular pathologies.</strong> EMBO J. 27: 2766-2779, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18833193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18833193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18833193[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/emboj.2008.201" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18833193">Bosnakovski et al. (2008)</a> concluded that DUX4 may cause FSHD by interfering with normal PAX3 or PAX7 function in muscle satellite cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18833193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Lemmers, R. J. L. F., van der Vliet, P. J., Klooster, R., Sacconi, S., Camano, P., Dauwerse, J. G., Snider, L., Straasheijm, K. R., van Ommen, G. J., Padberg, G. W., Miller, D. G., Tapscott, S. J., Tawil, R., Frants, R. R., van der Maarel, S. M. <strong>A unifying genetic model for facioscapulohumeral muscular dystrophy.</strong> Science 329: 1650-1653, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20724583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20724583</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20724583[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/10.1126/science.1189044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20724583">Lemmers et al. (2010)</a> showed that FSHD patients carry specific single-nucleotide polymorphisms in the chromosomal region distal to the last D4Z4 repeat. This FSHD-predisposing configuration creates a canonic polyadenylation signal for transcripts derived from DUX4, a double homeobox gene that straddles the last repeat unit and the adjacent sequence. Transfection studies revealed that DUX4 transcripts are efficiently polyadenylated and are more stable when expressed from permissive chromosomes. <a href="#19" class="mim-tip-reference" title="Lemmers, R. J. L. F., van der Vliet, P. J., Klooster, R., Sacconi, S., Camano, P., Dauwerse, J. G., Snider, L., Straasheijm, K. R., van Ommen, G. J., Padberg, G. W., Miller, D. G., Tapscott, S. J., Tawil, R., Frants, R. R., van der Maarel, S. M. <strong>A unifying genetic model for facioscapulohumeral muscular dystrophy.</strong> Science 329: 1650-1653, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20724583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20724583</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20724583[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/10.1126/science.1189044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20724583">Lemmers et al. (2010)</a> concluded that their findings suggest that FSHD arises through a toxic gain of function attributable to the stabilized distal DUX4 transcript. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20724583" 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="Cabianca, D. S., Casa, V., Bodega, B., Xynos, A., Ginelli, E., Tanaka, Y., Gabellini, D. <strong>A long ncRNA links copy number variation to a polycomb/trithorax epigenetic switch in FSHD muscular dystrophy.</strong> Cell 149: 819-831, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22541069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22541069</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22541069[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2012.03.035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22541069">Cabianca et al. (2012)</a> found that derepression of chromosome 4q35 genes in FSHD cells was associated with expression of a long noncoding RNA, DBET (<a href="/entry/614865">614865</a>), from the FSHD locus. DBET recruited the histone methyltransferase Ash1l (ASH1; <a href="/entry/607999">607999</a>) for gene repression in an apparent positive-feedback loop. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22541069" 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>D4Z4 and Facioscapulohumeral Muscular Dystrophy 2</em></strong></p><p>
|
|
In affected members of 15 (79%) of 19 families with facioscapulohumeral muscular dystrophy-2 (FSHD2; <a href="/entry/158901">158901</a>), <a href="#18" class="mim-tip-reference" title="Lemmers, R. J. L. F., Tawil, R., Petek, L. M., Balog, J., Block, G. J., Santen, G. W. E., Amell, A. M., van der Vliet, P. J., Almomani, R., Straasheijm, K. R., Krom, Y. D., Klooster, R., and 18 others. <strong>Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.</strong> Nature Genet. 44: 1370-1374, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23143600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23143600</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23143600[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.2454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23143600">Lemmers et al. (2012)</a> identified heterozygous loss-of-function mutations in the SMCHD1 gene (see, e.g., <a href="/entry/614982#0001">614982.0001</a>-<a href="/entry/614982#0005">614982.0005</a>). The mutations in 7 families were initially identified by exome sequencing and confirmed by Sanger sequencing. The mutational spectrum included small deletions, splice site mutations, and missense mutations, resulting in haploinsufficiency. Patients showed D4Z4 hypomethylation to levels less than 25% (normal being about 50%), and protein blot analysis in several patients showed decreased SMCHD1 protein in fibroblasts. Affected individuals were also heterozygous or homozygous for an FSHD1 (<a href="/entry/158900">158900</a>)-permissive D4Z4 haplotype that contains a polyadenylation signal to stabilize DUX4 mRNA in skeletal muscle. Primary myotubes from a normal individual with a normal-sized and methylated D4Z4 array on a permissive haplotype showed no DUX4 mRNA. However, decreasing SMCHD1 expression to about 50% using RNA interference resulted in transcriptional activation of DUX4 and a variegated pattern of DUX4 protein expression in the myotubes. The pattern of variegated DUX4 expression that resulted was similar to that observed in FSHD1 and FSHD2 myotube cultures. The findings indicated that SMCHD1 activity is necessary for D4Z4 hypermethylation and somatic repression of DUX4, and that reduction of SMCHD1 results in D4Z4 arrays that express DUX4 when a permissive haplotype is present. The SMCHD1 mutation and the permissive D4Z4 haplotype segregated independently in the families, indicating digenic inheritance. Of the 26 individuals with hypomethylation at D4Z4, a SMCHD1 mutation, and a permissive D4Z4 haplotype, 5 (19%) were asymptomatic, indicating incomplete penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23143600" 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="cytogenetics" class="mim-anchor"></a>
|
|
<h4 href="#mimCytogeneticsFold" id="mimCytogeneticsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimCytogeneticsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Cytogenetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimCytogeneticsFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p>In 2 cases of Ewing-like sarcomas (see <a href="/entry/612219">612219</a>), <a href="#14" class="mim-tip-reference" title="Kawamura-Saito, M., Yamazaki, Y., Kaneko, K., Kawaguchi, N., Kanda, H., Mukai, H., Gotoh, T., Motoi, T., Fukayama, M., Aburatani, H., Takizawa, T., Nakamura, T. <strong>Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation.</strong> Hum. Molec. Genet. 15: 2125-2137, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16717057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16717057</a>] [<a href="https://doi.org/10.1093/hmg/ddl136" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16717057">Kawamura-Saito et al. (2006)</a> identified the chromosomal translocation t(4;19)(q35;q13). The breakpoint at chromosome 19q13 was within exon 20 of the CIC gene (<a href="/entry/612082">612082</a>), and the breakpoint at chromosome 4q35 was within the DUX4 coding region in the D4Z4 repeat region. The translocation resulted in a CIC-DUX4 fusion transcript that was translated into a chimeric protein containing most of the CIC sequence, including the HMG box and TLE (see <a href="/entry/600189">600189</a>)-binding sites, fused in frame to the C terminus of DUX4. The chimeric protein did not contain the N-terminal DNA-binding homeodomains of DUX4. No reciprocal DUX4-CIC transcripts were observed. The CIC-DUX4 transcript induced anchorage-independent growth when transfected into mouse fibroblasts. Although CIC is a transcriptional repressor, the CIC-DUX4 transcript enhanced transcription of a reporter gene when transfected into HeLa cells. Microarray analysis revealed altered gene expression following transfection of CIC-DUX4 into a human osteosarcoma cell line, including significantly upregulated expression of ERM (ETV5; <a href="/entry/601600">601600</a>) and ETV1 (<a href="/entry/600541">600541</a>). Chromatin immunoprecipitation analysis and electrophoretic mobility shift assays confirmed binding of the chimeric protein to the ERM and ETV1 promoters. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16717057" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="evolution" class="mim-anchor"></a>
|
|
<h4 href="#mimEvolutionFold" id="mimEvolutionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimEvolutionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Evolution</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimEvolutionFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><a href="#5" class="mim-tip-reference" title="Clapp, J., Mitchell, L. M., Bolland, D. J., Fantes, J., Corcoran, A. E., Scotting, P. J., Armour, J. A. L., Hewitt, J. E. <strong>Evolutionary conservation of a coding function for D4Z4, the tandem DNA repeat mutated in facioscapulohumeral muscular dystrophy.</strong> Am. J. Hum. Genet. 81: 264-279, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17668377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17668377</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17668377[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/519311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17668377">Clapp et al. (2007)</a> identified D4Z4 homologs in the genomes of rodents, Afrotheria (superorder of elephants and related species), and other species and showed that the DUX4 ORF is conserved. Phylogenetic analysis suggested that primate and Afrotherian D4Z4 arrays are orthologous and originated from a retrotransposed copy of an intron-containing DUX gene, DUXC. Reverse-transcriptase PCR and RNA fluorescence and tissue in situ hybridization data indicated transcription of the mouse array. <a href="#5" class="mim-tip-reference" title="Clapp, J., Mitchell, L. M., Bolland, D. J., Fantes, J., Corcoran, A. E., Scotting, P. J., Armour, J. A. L., Hewitt, J. E. <strong>Evolutionary conservation of a coding function for D4Z4, the tandem DNA repeat mutated in facioscapulohumeral muscular dystrophy.</strong> Am. J. Hum. Genet. 81: 264-279, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17668377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17668377</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17668377[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/519311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17668377">Clapp et al. (2007)</a> concluded that, together with the conservation of the DUX4 ORF for more than 100 million years, this strongly supports a coding function for D4Z4 and necessitates reexamination of the current models of mechanism for FSHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17668377" 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>Dux, or Duxf3, is the mouse ortholog of human DUX4. <a href="#4" class="mim-tip-reference" title="Chen, Z., Zhang, Y. <strong>Loss of DUX causes minor defects in zygotic genome activation and is compatible with mouse development.</strong> Nature Genet. 51: 947-951, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31133747/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31133747</a>] [<a href="https://doi.org/10.1038/s41588-019-0418-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31133747">Chen and Zhang (2019)</a> found that both Dux zygotic knockout (Z-KO) and Dux maternal and zygotic knockout (MZ-KO) embryos were born at reduced mendelian frequencies but survived to adulthood without obvious abnormalities. RNA-sequencing analyses of 1-cell and late 2-cell Dux MZ-KO embryos revealed that loss of Dux had a minimal effect on zygotic genome activation (ZGA). Although Dux is essential for embryonic stem (ES) cells to enter the 2-cell (2C)-like ES cell state, most Dux targets in 2C-like cells were activated normally in MZ-KO embryos. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31133747" 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="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="Bengtsson1994" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Bengtsson, U., Altherr, M. R., Wasmuth, J. J., Winokur, S. T.
|
|
<strong>High resolution fluorescence in situ hybridization to linearly extended DNA visually maps a tandem repeat associated with facioscapulohumeral muscular dystrophy immediately adjacent to the telomere of 4q.</strong>
|
|
Hum. Molec. Genet. 3: 1801-1805, 1994.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849703</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849703" 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/3.10.1801" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="2" class="mim-anchor"></a>
|
|
<a id="Bosnakovski2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Bosnakovski, D., Xu, Z., Gang, E. J., Galindo, C. L., Liu, M., Simsek, T., Garner, H. R., Agha-Mohammadi, S., Tassin, A., Coppee, F., Belayew, A., Perlingeiro, R. R., Kyba, M.
|
|
<strong>An isogenic myoblast expression screen identifies DUX4-mediated FSHD-associated molecular pathologies.</strong>
|
|
EMBO J. 27: 2766-2779, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18833193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18833193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18833193[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=18833193" 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/emboj.2008.201" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="3" class="mim-anchor"></a>
|
|
<a id="Cabianca2012" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Cabianca, D. S., Casa, V., Bodega, B., Xynos, A., Ginelli, E., Tanaka, Y., Gabellini, D.
|
|
<strong>A long ncRNA links copy number variation to a polycomb/trithorax epigenetic switch in FSHD muscular dystrophy.</strong>
|
|
Cell 149: 819-831, 2012.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22541069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22541069</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22541069[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=22541069" 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.2012.03.035" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="4" class="mim-anchor"></a>
|
|
<a id="Chen2019" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Chen, Z., Zhang, Y.
|
|
<strong>Loss of DUX causes minor defects in zygotic genome activation and is compatible with mouse development.</strong>
|
|
Nature Genet. 51: 947-951, 2019.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31133747/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31133747</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31133747" 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/s41588-019-0418-7" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="5" class="mim-anchor"></a>
|
|
<a id="Clapp2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Clapp, J., Mitchell, L. M., Bolland, D. J., Fantes, J., Corcoran, A. E., Scotting, P. J., Armour, J. A. L., Hewitt, J. E.
|
|
<strong>Evolutionary conservation of a coding function for D4Z4, the tandem DNA repeat mutated in facioscapulohumeral muscular dystrophy.</strong>
|
|
Am. J. Hum. Genet. 81: 264-279, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17668377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17668377</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17668377[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=17668377" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1086/519311" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="6" class="mim-anchor"></a>
|
|
<a id="Deidda1996" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Deidda, G., Cacurri, S., Piazzo, N., Felicetti, L.
|
|
<strong>Direct detection of 4q35 rearrangements implicated in facioscapulohumeral muscular dystrophy (FSHD).</strong>
|
|
J. Med. Genet. 33: 361-365, 1996.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8733043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8733043</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8733043" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1136/jmg.33.5.361" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="7" class="mim-anchor"></a>
|
|
<a id="Dixit2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Dixit, M., Ansseau, E., Tassin, A., Winokur, S., Shi, R., Qian, H., Sauvage, S., Matteotti, C., van Acker, A. M., Leo, O., Figlewicz, D., Barro, M., Laoudj-Chenivesse, D., Belayew, A., Coppee, F., Chen, Y.-W.
|
|
<strong>DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1.</strong>
|
|
Proc. Nat. Acad. Sci. 104: 18157-18162, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17984056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17984056</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17984056[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=17984056" 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.0708659104" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="8" class="mim-anchor"></a>
|
|
<a id="Dmitriev2011" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Dmitriev, P., Petrov, A., Ansseau, E., Stankevicins, L., Charron, S., Kim, E., Bos, T. J., Robert, T., Turki, A., Coppee, F., Belayew, A., Lazar, V., Carnac, G., Laoudj, D., Lipinski, M., Vassetzky, Y. S.
|
|
<strong>The Kruppel-like factor 15 as a molecular link between myogenic factors and a chromosome 4q transcriptional enhancer implicated in facioscapulohumeral dystrophy.</strong>
|
|
J. Biol. Chem. 286: 44620-44631, 2011.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21937448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21937448</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21937448[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=21937448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1074/jbc.M111.254052" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="9" class="mim-anchor"></a>
|
|
<a id="Gabellini2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Gabellini, D., Green, M. R., Tupler, R.
|
|
<strong>Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle.</strong>
|
|
Cell 110: 339-348, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12176321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12176321</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12176321" 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(02)00826-7" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="10" class="mim-anchor"></a>
|
|
<a id="Gabriels1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Gabriels, J., Beckers, M.-C., Ding, H., De Vriese, A., Plaisance, S., van der Maarel, S. M., Padberg, G. W., Frants, R. R., Hewitt, J. E., Collen, D., Belayew, A.
|
|
<strong>Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element.</strong>
|
|
Gene 236: 25-32, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10433963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10433963</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10433963" 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/s0378-1119(99)00267-x" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="11" class="mim-anchor"></a>
|
|
<a id="Geng2012" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Geng, L. N., Yao, Z., Snider, L., Fong, A. P., Cech, J. N., Young, J. M., van der Maarel, S. M., Ruzzo, W. L., Gentleman, R. C., Tawil, R., Tapscott, S. J.
|
|
<strong>DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy.</strong>
|
|
Dev. Cell 22: 38-51, 2012.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22209328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22209328</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22209328" 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.devcel.2011.11.013" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="12" class="mim-anchor"></a>
|
|
<a id="Hewitt1994" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Hewitt, J. E., Lyle, R., Clark, L. N., Valleley, E. M., Wright, T. J., Wijmenga, C., van Deutekom, J. C. T., Francis, F., Sharpe, P. T., Hofker, M., Frants, R. R., Williamson, R.
|
|
<strong>Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy.</strong>
|
|
Hum. Molec. Genet. 3: 1287-1295, 1994.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7987304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7987304</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7987304" 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/3.8.1287" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="13" class="mim-anchor"></a>
|
|
<a id="Jiang2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Jiang, G., Yang, F., van Overveld, P. G. M., Vedanarayanan, V., van der Maarel, S., Ehrlich, M.
|
|
<strong>Testing the position-effect variegation hypothesis for facioscapulohumeral muscular dystrophy by analysis of histone modification and gene expression in subtelomeric 4q.</strong>
|
|
Hum. Molec. Genet. 12: 2909-2921, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14506132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14506132</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14506132" 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/ddg323" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="14" class="mim-anchor"></a>
|
|
<a id="Kawamura-Saito2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Kawamura-Saito, M., Yamazaki, Y., Kaneko, K., Kawaguchi, N., Kanda, H., Mukai, H., Gotoh, T., Motoi, T., Fukayama, M., Aburatani, H., Takizawa, T., Nakamura, T.
|
|
<strong>Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation.</strong>
|
|
Hum. Molec. Genet. 15: 2125-2137, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16717057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16717057</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16717057" 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/ddl136" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="15" class="mim-anchor"></a>
|
|
<a id="Kowaljow2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Kowaljow, V., Marcowycz, A., Ansseau, E., Conde, C. B., Sauvage, S., Matteotti, C., Arias, C., Corona, E. D., Nunez, N. G., Leo, O., Wattiez, R., Figlewicz, D., Laoudj-Chenivesse, D., Belayew, A., Coppee, F., Rosa, A. L.
|
|
<strong>The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein.</strong>
|
|
Neuromusc. Disord. 17: 611-623, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17588759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17588759</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17588759" 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.nmd.2007.04.002" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="16" class="mim-anchor"></a>
|
|
<a id="Lemmers2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Lemmers, R. J. F. L., Wohlgemuth, M., Frants, R. R., Padberg, G. W., Morava, E., van der Maarel, S. M.
|
|
<strong>Contractions of D4Z4 on 4qB subtelomeres do not cause facioscapulohumeral muscular dystrophy.</strong>
|
|
Am. J. Hum. Genet. 75: 1124-1130, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15467981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15467981</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15467981[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=15467981" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1086/426035" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="17" class="mim-anchor"></a>
|
|
<a id="Lemmers2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Lemmers, R. J. L. F., de Kievit, P., Sandkuijl, L., Padberg, G. W., van Ommen, G.-J. B., Frants, R. R., van der Maarel, S. M.
|
|
<strong>Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere. (Letter)</strong>
|
|
Nature Genet. 32: 235-236, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12355084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12355084</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12355084" 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/ng999" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="18" class="mim-anchor"></a>
|
|
<a id="Lemmers2012" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Lemmers, R. J. L. F., Tawil, R., Petek, L. M., Balog, J., Block, G. J., Santen, G. W. E., Amell, A. M., van der Vliet, P. J., Almomani, R., Straasheijm, K. R., Krom, Y. D., Klooster, R., and 18 others.
|
|
<strong>Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.</strong>
|
|
Nature Genet. 44: 1370-1374, 2012.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23143600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23143600</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23143600[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=23143600" 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.2454" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="19" class="mim-anchor"></a>
|
|
<a id="Lemmers2010" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Lemmers, R. J. L. F., van der Vliet, P. J., Klooster, R., Sacconi, S., Camano, P., Dauwerse, J. G., Snider, L., Straasheijm, K. R., van Ommen, G. J., Padberg, G. W., Miller, D. G., Tapscott, S. J., Tawil, R., Frants, R. R., van der Maarel, S. M.
|
|
<strong>A unifying genetic model for facioscapulohumeral muscular dystrophy.</strong>
|
|
Science 329: 1650-1653, 2010.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20724583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20724583</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20724583[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=20724583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.1189044" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="20" class="mim-anchor"></a>
|
|
<a id="Lemmers2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Lemmers, R. J. L. F., Wohlgemuth, M., van der Gaag, K. J., van der Vliet, P. J., van Teijlingen, C. M. M., de Knijff, P., Padberg, G. W., Frants, R. R., van der Maarel, S. M.
|
|
<strong>Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy.</strong>
|
|
Am. J. Hum. Genet. 81: 884-894, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17924332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17924332</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17924332[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=17924332" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1086/521986" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="21" class="mim-anchor"></a>
|
|
<a id="Masny2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Masny, P. S., Bengtsson, U., Chung, S.-A., Martin, J. H., van Engelen, B., van der Maarel, S. M., Winokur, S. T.
|
|
<strong>Localization of 4q35.2 to the nuclear periphery: is FSHD a nuclear envelope disease?</strong>
|
|
Hum. Molec. Genet. 13: 1857-1871, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15238509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15238509</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15238509" 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/ddh205" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="22" class="mim-anchor"></a>
|
|
<a id="Osborne2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Osborne, R. J., Welle, S., Venance, S. L., Thornton, C. A., Tawil, R.
|
|
<strong>Expression profile of FSHD supports a link between retinal vasculopathy and muscular dystrophy.</strong>
|
|
Neurology 68: 569-577, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17151338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17151338</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17151338" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1212/01.wnl.0000251269.31442.d9" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="23" class="mim-anchor"></a>
|
|
<a id="Ottaviani2009" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Ottaviani, A., Rival-Gervier, S., Boussouar, A., Foerster, A. M., Rondier, D., Sacconi, S., Desnuelle, C., Gilson, E., Magdinier, F.
|
|
<strong>The D4Z4 macrosatellite repeat acts as a CTCF and A-type lamins-dependent insulator in facio-scapulo-humeral dystrophy.</strong>
|
|
PLoS Genet. 5: e1000394, 2009. Note: Electronic Article.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19247430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19247430</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19247430[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=19247430" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1371/journal.pgen.1000394" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="24" class="mim-anchor"></a>
|
|
<a id="Perini2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Perini, G., Tupler, R.
|
|
<strong>Altered gene silencing and human diseases.</strong>
|
|
Clin. Genet. 69: 1-7, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16451126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16451126</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16451126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1111/j.1399-0004.2005.00540.x" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="25" class="mim-anchor"></a>
|
|
<a id="Petrov2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Petrov, A., Allinne, J., Pirozhkova, I., Laoudj, D., Lipinski, M., Vassetzky, Y. S.
|
|
<strong>A nuclear matrix attachment site in the 4q35 locus has an enhancer-blocking activity in vivo: implications for the facio-scapulo-humeral dystrophy.</strong>
|
|
Genome Res. 18: 39-45, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18032730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18032730</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18032730[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=18032730" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1101/gr.6620908" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="26" class="mim-anchor"></a>
|
|
<a id="Petrov2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Petrov, A., Pirozhkova, I., Carnac, G., Laoudj, D., Lipinski, M., Vassetzky, Y. S.
|
|
<strong>Chromatin loop domain organization within the 4q35 locus in facioscapulohumeral dystrophy patients versus normal human myoblasts.</strong>
|
|
Proc. Nat. Acad. Sci. 103: 6982-6987, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16632607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16632607</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16632607[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=16632607" 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.0511235103" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="27" class="mim-anchor"></a>
|
|
<a id="Snider2009" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Snider, L., Asawachaicharn, A., Tyler, A. E., Geng, L. N., Petek, L. M., Maves, L., Miller, D. G., Lemmers, R. J. L. F., Winokur, S. T., Tawil, R., van der Maarel, S. M., Filippova, G. N., Tapscott, S. J.
|
|
<strong>RNA transcripts, miRNA-sized fragments and proteins produced from D4Z4 units: new candidates for the pathophysiology of facioscapulohumeral dystrophy.</strong>
|
|
Hum. Molec. Genet. 18: 2414-2430, 2009.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19359275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19359275</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19359275[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=19359275" 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/ddp180" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="28" class="mim-anchor"></a>
|
|
<a id="Snider2010" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Snider, L., Geng, L. N., Lemmers, R. J. L. F., Kyba, M., Ware, C. B., Nelson, A. M., Tawil, R., Filippova, G. N., van der Maarel, S. M., Tapscott, S. J., Miller, D. G.
|
|
<strong>Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene.</strong>
|
|
PLoS Genet. 6: e1001181, 2010. Note: Electronic Article.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21060811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21060811</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21060811[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=21060811" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1371/journal.pgen.1001181" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="29" class="mim-anchor"></a>
|
|
<a id="van der Maarel2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
van der Maarel, S. M., Deidda, G., Lemmers, R. J. L. F., van Overveld, P. G. M., van der Wielen, M., Hewitt, J. E., Sandkuijl, L., Bakker, B., van Ommen, G.-J. B., Padberg, G. W., Frants, R. R.
|
|
<strong>De novo facioscapulohumeral muscular dystrophy: frequent somatic mosaicism, sex-dependent phenotype, and the role of mitotic transchromosomal repeat interaction between chromosomes 4 and 10.</strong>
|
|
Am. J. Hum. Genet. 66: 26-35, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10631134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10631134</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10631134[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=10631134" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1086/302730" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="30" class="mim-anchor"></a>
|
|
<a id="van Deutekom1996" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
van Deutekom, J. C. T., Bakker, E., Lemmers, R. J. L. F., van der Wielen, M. J. R., Bik, E., Hofker, M. H., Padberg, G. W., Frants, R. R.
|
|
<strong>Evidence for subtelomeric exchange of 3.3 kb tandemly repeated units between chromosomes 4q35 and 10q26: implications for genetic counselling and etiology of FSHD1.</strong>
|
|
Hum. Molec. Genet. 5: 1997-2003, 1996.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968754</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8968754" 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/5.12.1997" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="31" class="mim-anchor"></a>
|
|
<a id="van Deutekom1996" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
van Deutekom, J. C. T., Lemmers, R. J. L. F., Grewal, P. K., van Geel, M., Romberg, S., Dauwerse, H. G., Wright, T. J., Padberg, G. W., Hofker, M. H., Hewitt, J. E., Frants, R. R.
|
|
<strong>Identification of the first gene (FRG1) from the FSHD region on human chromosome 4q35.</strong>
|
|
Hum. Molec. Genet. 5: 581-590, 1996.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8733123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8733123</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8733123" 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/5.5.581" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="32" class="mim-anchor"></a>
|
|
<a id="van Geel2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
van Geel, M., Dickson, M. C., Beck, A. F., Bolland, D. J., Frants, R. R., van der Maarel, S. M., de Jong, P. J., Hewitt, J. E.
|
|
<strong>Genomic analysis of human chromosome 10q and 4q telomeres suggests a common origin.</strong>
|
|
Genomics 79: 210-217, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11829491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11829491</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11829491" 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.2002.6690" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="33" class="mim-anchor"></a>
|
|
<a id="van Overveld2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
van Overveld, P. G. M., Enthoven, L., Ricci, E., Rossi, M., Felicetti, L., Jeanpierre, M., Winokur, S. T., Frants, R. R., Padberg, G. W., van der Maarel, S. M.
|
|
<strong>Variable hypomethylation of D4Z4 in facioscapulohumeral muscular dystrophy.</strong>
|
|
Ann. Neurol. 58: 569-576, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16178028/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16178028</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16178028" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/ana.20625" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="34" class="mim-anchor"></a>
|
|
<a id="Wallace2011" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Wallace, L. M., Garwick, S. E., Mei, W., Belayew, A., Coppee, F., Ladner, K. J., Guttridge, D., Yang, J., Harper, S. Q.
|
|
<strong>DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53-dependent myopathy in vivo.</strong>
|
|
Ann. Neurol. 69: 540-552, 2011.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21446026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21446026</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21446026[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=21446026" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/ana.22275" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="35" class="mim-anchor"></a>
|
|
<a id="Winokur1993" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Winokur, S. T., Schutte, B., Weiffenbach, B., Washington, S. S., McElligott, D., Chakravarti, A., Wasmuth, J. H., Altherr, M. R.
|
|
<strong>A radiation hybrid map of 15 loci on the distal long arm of chromosome 4, the region containing the gene responsible for facioscapulohumeral muscular dystrophy (FSHD).</strong>
|
|
Am. J. Hum. Genet. 53: 874-880, 1993.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8213815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8213815</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8213815" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</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">
|
|
Bao Lige - updated : 07/08/2019
|
|
</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">
|
|
Patricia A. Hartz - updated : 1/17/2013<br>Patricia A. Hartz - updated : 10/10/2012<br>Patricia A. Hartz - updated : 2/14/2012<br>Patricia A. Hartz - updated : 9/27/2011<br>Ada Hamosh - updated : 11/10/2010<br>Patricia A. Hartz - updated : 4/14/2010<br>George E. Tiller - updated : 3/30/2010<br>Patricia A. Hartz - updated : 4/9/2008<br>Victor A. McKusick - updated : 8/21/2007
|
|
</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">
|
|
Dawn Watkins-Chow : 6/13/2001
|
|
</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 : 08/16/2019
|
|
</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 : 07/09/2019<br>mgross : 07/08/2019<br>mgross : 12/20/2013<br>mgross : 1/18/2013<br>mgross : 1/18/2013<br>terry : 1/17/2013<br>carol : 12/18/2012<br>mgross : 10/11/2012<br>terry : 10/10/2012<br>mgross : 2/14/2012<br>mgross : 2/14/2012<br>terry : 2/14/2012<br>carol : 10/5/2011<br>terry : 9/28/2011<br>terry : 9/27/2011<br>mgross : 9/15/2011<br>terry : 5/17/2011<br>wwang : 11/24/2010<br>alopez : 11/15/2010<br>terry : 11/10/2010<br>mgross : 4/22/2010<br>terry : 4/14/2010<br>wwang : 4/1/2010<br>terry : 3/30/2010<br>wwang : 6/25/2009<br>mgross : 4/10/2008<br>mgross : 4/10/2008<br>terry : 4/9/2008<br>alopez : 8/21/2007<br>terry : 3/18/2004<br>mcapotos : 12/28/2001<br>carol : 6/14/2001
|
|
</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> 606009
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
DOUBLE HOMEOBOX PROTEIN 4; DUX4
|
|
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
D4Z4 MACROSATELLITE REPEAT, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: DUX4</em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 4q35.2
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 4:190,173,774-190,185,911 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</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><strong><em>DUX4 Gene</em></strong></p><p>
|
|
DUX4 encodes a putative transcription factor that contains 2 homeobox domains. A copy of DUX4 is found within each of up to 100 copies of the D4Z4 macrosatellite repeat in the subtelomeric region of chromosome 4q. Only the last repeat appears to encode a functional DUX4 transcript with a polyadenylation site that lies telomeric and outside the D4Z4 repeat region (summary by Snider et al., 2010). </p><p><strong><em>D4Z4 Microsatellite Repeat</em></strong></p><p>
|
|
Multiple copies of a 3.3-kb repeat, designated D4Z4, exist in the proximal subtelomeric region of 4q35. Each repeat contains a copy of DUX4. The polymorphic D4Z4 repeat array is composed of 11 to 150 repeats in normal individuals. Most patients with facioscapulohumeral muscular dystrophy (FSHD; 158900) carry a D4Z4 repeat array of less than 11 repeats. A similar subtelomeric repeat array configuration occurs on chromosome 10qter (summary by van Overveld et al., 2005). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>While sequencing the 3.3-kb repeat elements remaining in an FSHD patient, Gabriels et al. (1999) identified a putative promoter for an ORF encompassing the 2 homeoboxes reported by Hewitt et al. (1994) and named the putative gene DUX4. DUX4 encodes a deduced 391-amino acid protein containing 2 homeodomains. Gabriels et al. (1999) found an identical copy of DUX4 in each of the 3.3-kb repeat elements remaining in the FSHD patient. Using in vitro transcription/translation, they detected products with apparent molecular masses of 38 kD and 75 kD on SDS-PAGE, corresponding to the DUX4 monomer and dimer, respectively. </p><p>By PCR of FSHD primary myoblast RNA, Dixit et al. (2007) identified 2 DUX4 splice variants that differed due to inclusion or exclusion of an intron in their 3-prime UTRs. The deduced DUX4 protein contains 424 amino acids, larger than the protein initially reported (Gabriels et al., 1999) due to corrections of sequencing errors. PCR analysis detected the 5-prime end of DUX4 mRNA in both FSHD and control myoblasts, whereas the 3-prime end specific to the most distal unit of DUX4, which includes a polyadenylation sequence, was detected only in FSHD myoblasts. Western blot analysis of transfected cells revealed a 52-kD DUX4 protein. DUX4 protein was detected in FSHD samples, but not controls. Dixit et al. (2007) concluded that only the DUX4 gene in the most distal D4Z4 element is likely to be transcribed into a polyadenylated RNA and to be translated in vivo. </p><p>Kowaljow et al. (2007) found that DUX4 transcripts had only short poly(A) tails and did not fractionate with mRNAs containing long poly(A) tails. RT-PCR detected DUX4 expression in cultured FSHD patient myoblasts and in human fetal and adult rhabdomyosarcoma cell lines, but not in control myoblasts. Immunofluorescence analysis of DUX4-transfected cell lines showed a nuclear staining pattern that partly overlapped with the nuclear envelope. </p><p>Snider et al. (2009) found that the D4Z4 region is subject to highly complex splicing and mRNA processing. Sequencing of the 2 residual D4Z4 repeats in an individual with FSHD and the disease-associated haplotype 4qA161 suggested the presence of major and minor ORFs, including the DUX4 ORF, that overlap in different reading frames and in both orientations. Many of the potential ORFs in the 2 D4Z4 repeats, but not the DUX4 ORF, differ significantly due to sequence variations. RT-PCR confirmed expression of full-length DUX4 transcripts at low levels in human embryonic and mesenchymal stem cells, and DUX4 protein was detected in undifferentiated human embryonic and mesenchymal stem cells. However, transcripts including only the 5-prime or 3-prime portions of DUX4 were detected at higher abundance than the full-length transcript in fibroblasts and muscle cells from FSHD and control individuals. Transcripts containing only the 5-prime portion of the DUX4 ORF were polyadenylated and capped in FSHD muscle cells, and they were predicted to encode a truncated protein containing only the paired homeodomains. The majority of these transcripts had a repeated sequence, suggesting splicing between the 2 D4Z4 units. Transcripts containing only the 3-prime portion of the DUX4 ORF were polyadenylated and uncapped in FSHD muscle cells, and they were predicted to encode a 76-amino acid protein containing only the highly conserved C-terminal region. Transfection studies demonstrated expression of the DUX4 isoform containing only the C-terminal domain and suggested that it originated from an internal ribosomal initiation site. RT-PCR also detected several sense and antisense transcripts originating from the D4Z4 repeats in muscle cells from FSHD and control individuals. Northern blot analysis revealed that microRNA-like fragments were generated from the DUX4 transcript in FSHD and control fibroblasts and muscle cells. </p><p>Snider et al. (2010) stated that they had previously identified a short DUX4 transcript (DUX4-s), generated by splicing at a noncanonical donor sequence. The deduced protein contains 2 homeobox domains, but lacks the C-terminal end found in full-length DUX4 (DUX4-fl). RT-PCR of normal human tissues detected abundant DUX4-fl expression in testis, but not in any other tissue examined. DUX4-s was detected in ovary, heart, and skeletal muscle, with weaker expression in liver. No DUX4-s expression was detected in testis, kidney, or cerebellum. Within cells and cell lines, DUX4-fl was detected in induced pluripotent stem cells and in some human embryonic stem cell lines. Differentiated fibroblasts and embryoid bodies expressed DUX4-s only. Immunohistochemical analysis of human testis detected DUX4-fl in spermatogonia and primary spermatocytes and in more differentiated cells in seminiferous tubules. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Dixit et al. (2007) reported that the DUX4 promoter region contains putative CATT, GC, TACAA, and E boxes. The 3-prime end of the DUX4 gene contains an alternatively spliced exon located between the stop codon and the end of the D4Z4 unit. In addition, the 3-prime end of the DUX4 gene in the most distal D4Z4 unit contains a second intron and a single polyadenylation signal, both of which are located telomeric to the D4Z4 unit. </p><p>Snider et al. (2010) determined that the DUX4 gene contains at least 7 exons, with exons 3 through 7 outside the D4Z4 repeat region. The 4qA haplotype includes alternate polyadenylation sites in exons 3 and 7. The 4qB haplotype does not show these polyadenylation sites and may include more than 7 exons. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>By genomic sequence analysis, Gabriels et al. (1999) mapped the DUX4 gene to chromosome 4q35. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Using luciferase reporter assays, Gabriels et al. (1999) demonstrated DUX4 promoter activity that was dependent on a TACAA box and a GC box. They suggested that DUX4 may play a role in FSHD because partial deletions of the D4Z4 region might alter DUX4 expression in FSHD patients. </p><p>By comparing genomewide expression profiles of muscle biopsies from patients with FSHD to those of 11 other neuromuscular disorders, Dixit et al. (2007) identified 5 genes, including the paired homeodomain transcription factor PITX1 (602149), that were specifically upregulated in FSHD patients. DUX4 expression was upregulated in FSHD myoblasts at both the mRNA and protein levels. DUX4 activated expression of a reporter gene fused to the PITX1 promoter and of endogenous Pitx1 in DUX4-transfected C2C12 mouse myoblasts. In electrophoretic mobility shift assays, DUX4 specifically interacted with a 30-bp sequence containing a conserved TAAT core motif in the PITX1 promoter. Mutations of the TAAT core affected Pitx1 activation in C2C12 cells and DUX4 binding in vitro. </p><p>Kowaljow et al. (2007) found that overexpression of DUX4 in several cell lines resulted in apoptotic changes, including activation of caspase-3 (CASP3; 600636) and caspase-7 (CASP7; 601761). </p><p>Using transfection studies, Snider et al. (2009) showed that full-length DUX4 reduced the expression of reporter genes driven by CKM (123310), desmin (DES; 125660), or a multimerized E box. Full-length DUX4 also reduced expression of endogenous myosin heavy chain (see 160730) in transfected C2C12 mouse myoblasts. Expression of the full-length DUX4 protein or isoforms containing only the N- or C-terminal domains inhibited myogenesis in C2C12 cells. Several DUX4 transcripts incapable of translation also inhibited C2C12 differentiation. Expression of transcripts encoding full-length DUX4 inhibited zebrafish development past gastrulation or caused severe developmental abnormalities in the surviving embryos. Expression of transcripts encoding the C-terminal DUX4 peptide did not alter morphologic development of zebrafish, but blocked myogenesis at a step between Myod (159970) transcription and activation of Myod target genes. </p><p>Wallace et al. (2011) showed that apoptotic changes observed in DUX4-expressing HEK293 cells were eliminated by an inactivating mutation in the first DNA-binding homeobox domain of DUX4. The development of lesions in DUX4-injected mouse muscle was also abrogated by mutation of the DUX4 homeobox domain. Pharmacologic inhibition of p53 (TP53; 191170) mitigated DUX4 toxicity in HEK293 cells, and muscle from p53-null mice were resistant to DUX4-induced damage. Wallace et al. (2011) concluded that DUX4-induced myopathy is dependent on p53-mediated apoptosis. </p><p>By gene expression array analysis, Geng et al. (2012) found that DUX4-fl induced expression of several genes associated with germline and early stem-cell development and suppressed genes involved in innate immune response. DUX4-fl bound specifically to a long terminal repeat element from a class of MaLR retrotransposons. DUX4-s bound the same element, but it did not activate gene expression, and it functioned as a dominant-negative inhibitor of DUX4-fl when coexpressed. Although DUX4 expression was below the level of detection in several FSHD muscle biopsy samples by RT-PCR, expression of DUX4-fl-regulated genes was significantly upregulated compared with control muscle samples. Furthermore, knockdown of DUX4-fl expression in FSHD muscle cells via small interfering RNA or coexpression of DUX4-s reduced the expression of DUX4-fl target genes. DEFB103A (606611) and DEFB103B, which encode negative regulators of innate immunity, were among the DUX4-fl target genes upregulated in FSHD muscle. Overexpression of DEFB103 in differentiating muscle cells reduced expression of genes associated with muscle differentiation and inflammatory response. Geng et al. (2012) concluded that even low-level DUX4 overexpression can have a profound effect on gene expression and result in FSHD, and they proposed that DEFB103 may contribute to FSHD pathology. </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>D4Z4 Macrosatellite Repeat</em></strong></p><p>
|
|
Hewitt et al. (1994) determined the sequence of D4Z4 and showed that each copy of the repeat contains 2 homeoboxes and 2 previously described repetitive sequences, LSau and a GC-rich low copy repeat designated hhspm3. By Southern blot analysis, FISH, and isolation of cDNA and genomic clones, Hewitt et al. (1994) showed that there are repeat sequences similar to D4Z4 at other locations in the human genome. Southern blot analysis of primate genomic DNA indicated that the copy number of D4Z4-like repeats has increased markedly within the last 25 million years. Two cDNA clones were isolated and found to contain stop codons and frameshifts within the homeodomains. An STS was produced to the cDNAs, and analysis of a somatic cell hybrid panel suggested that they mapped to chromosome 14. No cDNA clones mapping to the 4q35 D4Z4 repeat were identified, although the possibility that these repeats encode a protein could not be ruled out. Although D4Z4 may not encode a protein, there is association between deletions within this locus and FSHD1 (158900). The D4Z4 repeats contain LSau repeats and are adjacent to 68-bp Sau3A repeats. Both of these sequences are associated with heterochromatic regions of DNA, regions known to be involved in the phenomenon of 'position effect' variegation. Hewitt et al. (1994) postulated that deletion of D4Z4 sequences produced a position effect that is involved in the pathogenesis of FSHD. </p><p>Winokur et al. (1993) also postulated that FSHD may be due to a position effect. Bengtsson et al. (1994) reported results indicating that the tandem array of 3.2-kb repeats, disrupted in FSHD, lies immediately adjacent to the telomere of 4q and that the gene responsible for FSHD is probably located proximal to the tandem repeat. </p><p>A highly homologous polymorphic repeat array is located near the telomere of 10q, but a specific BlnI site within each chromosome 10-derived repeat unit allows discrimination between the arrays (Deidda et al., 1996). This BlnI site-dependent discrimination demonstrated the presence of 10-type repeats on chromosome 4 and, vice versa, 4-type repeats on chromosome 10, suggesting a dynamic exchange between these chromosomes. Van der Maarel et al. (2000) found that the repeat deletion was significantly enhanced by supernumerary homologous repeat arrays. They demonstrated that a numerical excess of 4-type repeats on chromosome 10 was a significant, if not the major, predisposing factor for the occurrence of the FSHD-type deletion. Mitotic interchromosomal gene conversion or translocation between fully homologous repeat arrays may be a major mechanism for FSHD mutations. </p><p>Van Deutekom et al. (1996) reported exchange of subtelomeric repeated DNA units between chromosomes 4q35 and 10q26 in at least 20% of the Dutch population. These subtelomeric rearrangements generated novel DNA restriction fragments and complicated the use of restriction fragment analysis for DNA diagnosis of FSHD. The high frequency of interchromosomal exchanges of 3.3-kb repeat units suggested to van Deutekom et al. (1996) that these units probably do not contain part of the FSHD gene and supported position effect variegation as the most likely mechanism for FSHD. </p><p>Using 3-dimensional immuno-FISH, Masny et al. (2004) determined that the FSHD region at chromosome 4q35.2 localized to the nuclear periphery in several cell types throughout the cell cycle. FSHD region chromatin localization to the nuclear envelope was lost in lamin A/C (150330)-null fibroblasts, suggesting that lamin A/C is required for proper localization, and both normal and D4Z4-deleted alleles localized to the nuclear periphery. Masny et al. (2004) suggested that FSHD likely arises from improper interactions with transcription factors or chromatin modifiers at the nuclear envelope. </p><p>Within the D4Z4 locus, Petrov et al. (2006) identified 2 DNA loop domains anchored to the nuclear matrix via nuclear scaffold/matrix attached regions (S/MARs). Myoblasts derived from patients with FSHD showed a significant decrease in association of S/MARs with the nuclear matrix compared to control myoblasts. Biochemical mapping showed that in normal myoblasts the D4Z4 array was located in a DNA loop domain distinct from the DNA loop domain where FRG1 (601278) and FRG2 (609032) were located, whereas in damaged FSHD chromosome, the partially deleted D4Z4 array and FRG1 and FRG2 were located within the same DNA loop domain. Petrov et al. (2006) suggested that S/MARs regulate chromatin accessibility and expression of genes implicated in FSHD. </p><p>Petrov et al. (2008) proposed that FR-MAR, an S/MAR positioned 5-prime of the D4Z4 repeat array, may function in normal cells as an insulator element to protect upstream genes from the effect of D4Z4. Using reporter gene assays, they found that D4Z4 repeats showed enhancer function and elevated transcription from the FRG1 promoter in all transfected cell lines examined. Deletion analysis located the strongest enhancer activity to the 5-prime end of the D4Z4 unit. FR-MAR blocked this enhancer function. FR-MAR also associated with the nuclear matrix in normal myoblasts, but not in FSHD myoblasts. Petrov et al. (2008) concluded that FR-MAR functions as an insulator to protect the FRG genes from the enhancer activity present in each D4Z4 repeat unit. </p><p>By in vitro cellular studies with a single D4Z4 repeat, Ottaviani et al. (2009) demonstrated that D4Z4 acts both as a transcriptional insulator protecting against the repressive influence of various chromosomal contexts and as an enhancer insulator interfering with enhancer-promoter communication. The addition of D4Z4 element repeats progressively abolished the insulation activity, suggesting that the repeat element loosens its anti-silencing activity upon multimerization. Further studies showed that the insulator function of D4Z4 is dependent on CTCF (604167) and LMNA (150330). The findings demonstrated a novel mode of chromatin regulation controlled by the number of D4Z4 repeats. Ottaviani et al. (2009) proposed that reduction of the D4Z4 array in FSHD patients results in a gain-of-function effect by allowing the binding of CTCF and provoking changes in the biologic function of D4Z4 such that it switches from a repressor to an insulator protecting the expression of the FSHD gene(s). </p><p>Dmitriev et al. (2011) showed that KLF15 (606465) bound an enhancer element within the D4Z4 repeat unit. Binding of KLF15 to 2 sites within the D4Z4 enhancer drove expression of FRG2 and DUX4C (DUX4L9; 615581), which are located over 40 kb centromeric to the D4Z4 repeat array. KLF15 expression was upregulated following differentiation of normal human myoblasts and following expression of MYOD (159970), and it was upregulated in FSHD myoblasts, myotubes, and muscle biopsies. FSHD cells also showed upregulated expression of MYOD and the KLF15 target gene PPARG (601487), in addition to DUX4C and FRG2. Dmitriev et al. (2011) concluded that MYOD-dependent KLF15 expression is involved in partial activation of the differentiation program in FSHD myoblasts. </p><p><strong><em>4qA and 4qB Polymorphic Segment</em></strong></p><p>
|
|
Human 4qter and 10qter share a high degree of similarity, including the D4Z4 repeat array; however, contractions affecting the 10qter repeat are nonpathogenic. Van Geel et al. (2002) detected a polymorphic segment of 10 kb directly distal to D4Z4, which they called alleles 4qA and 4qB. Lemmers et al. (2002) reported that although the 2 alleles are equally common in the general population, FSHD is associated solely with the 4qA allele. They suggested that this was the first example of an intrinsically benign subtelomeric polymorphism predisposing to the development of human disease. </p><p>Lemmers et al. (2004) concluded that contractions of D4Z4 on 4qB subtelomeres do not cause FSHD. The 2 allelic variants of 4q, 4qA and 4qB, exist in the region distal to D4Z4. Although both variants are almost equally present in the population, FSHD is associated exclusively with the 4qA allele. Lemmers et al. (2004) identified 3 families with FSHD in which each proband carried 2 FSHD-sized alleles and was heterozygous for the 4qA/4qB polymorphism. Segregation analysis demonstrated that FSHD-sized 4qB alleles are not associated with disease, since these were present in unaffected family members. Thus, in addition to a contraction of D4Z4, additional cis-acting elements on 4qA may be required for the development of FSHD. Alternatively, 4qB subtelomeres may contain elements that prevent FSHD pathogenesis. </p><p>Lemmers et al. (2007) hypothesized that allele-specific sequence differences among 4qA, 4qB, and 10q alleles underlie the 4qA specificity of FSHD. By examining sequence variations in the FSHD locus, they demonstrated that the subtelomeric domain of 4q can be subdivided into 9 distinct haplotypes, of which 3 carry the distal 4qA variation. They showed that repeat contractions in 2 of the 9 haplotypes, 1 of which is a 4qA haplotype, are not associated with FSHD. They showed that each of these haplotypes has its unique sequence signature, and proposed that specific SNPs in the disease haplotype are essential for the development of FSHD. </p><p><strong><em>Changes in Gene Expression Related to D4Z4</em></strong></p><p>
|
|
Van Deutekom et al. (1996) identified the FRG1 gene that mapped 100 kb centromeric of the repeated units on chromosome 4q35 that are deleted in FSHD. They identified a polymorphism in exon 1 of this gene and used RT-PCR to amplify reverse transcribed mRNA from lymphocytes and muscle biopsies of patients and controls. These studies indicated that both alleles were transcribed and gave no evidence of 'position effect' variegation leading to repression of allelic transcription. </p><p>Gabellini et al. (2002) found that in FSHD muscle, genes located upstream of D4Z4 on 4q35, including FRG1, FRG2, and ANT1 (103220), are inappropriately overexpressed. They showed that an element within D4Z4 specifically binds a multiprotein complex consisting of transcriptional repressor YY1 (600013), HMGB2 (163906), and nucleolin (NCL; 164035). This multiprotein complex binds D4Z4 in vitro and in vivo and mediates transcriptional repression of 4q35 genes. Gabellini et al. (2002) proposed that deletion of D4Z4 leads to the inappropriate transcriptional derepression of 4q35 genes, resulting in disease. In normal individuals, the presence of a threshold number of D4Z4 repeats leads to repression of 4q35 genes by virtue of the DNA-bound multiprotein complex that actively suppresses gene expression. In FSHD patients, deletion of an integral number of D4Z4 repeats reduces the number of bound repressor complexes and consequently decreases or abolishes transcriptional repression of 4q35 genes. </p><p>Jiang et al. (2003) found that H4 acetylation levels of a nonrepeated region adjacent to the 4q35 and 10q26 D4Z4 arrays in normal and FSHD lymphoid cells were like those in unexpressed euchromatin, rather than like constitutive heterochromatin. The control and FSHD cells also displayed similar H4 hyperacetylation (like that of expressed genes) at the 5-prime regions of 4q35 candidate genes FRG1 and ANT1. There was no position-dependent increase in transcript levels from these genes in FSHD skeletal muscle samples compared with controls. Jiang et al. (2003) proposed a model for FSHD in which differential long-distance cis looping depends upon the presence of a 4q35 D4Z4 array with less than a threshold number of copies of the 3.3-kb repeat. </p><p>Perini and Tupler (2006) suggested that FSHD might be considered a useful model for the study of position effect in humans. The D4Z4 deletion might result in stochastic variation in gene expression in muscle cells and explain the asymmetric involvement of muscles, the great variability of clinical expression between and within families, and the apparent threshold effect whereby there is a requirement for the deletion of a certain number of copies of D4Z4 to develop FSHD. </p><p>Osborne et al. (2007) detected no change in expression of the FRG1, FRG2, or ANT1 genes in muscle biopsies from 19 FSHD patients compared to controls. Further studies of the 8-Mb region proximal to the D4Z4 array showed no significant changes in gene expression, no evidence of a position effect, and no evidence of unequal allele-specific expression. However, microarray analysis of global gene expression in FSHD muscle identified 11 upregulated genes with a role in vascular smooth muscle or endothelial cells, suggesting a possible link between muscular dystrophy and vasculopathy in FSHD. </p><p>Bosnakovski et al. (2008) conditionally expressed cDNAs for FSHD candidate genes within the D4Z4 repeat, DUX4, FRG1, FRG2, and ANT1, in mouse C2C12 myoblasts at both high and low expression levels and found that only DUX4 was overtly toxic, as indicated by cellular ATP content, morphologic changes, and apoptosis. DUX4 showed variable toxicity when expressed in mouse fibroblasts or embryoid bodies. DUX4 localized to C2C12 cell nuclei within 2 hours of induction. Microarray analysis revealed altered expression in a broad range of genes, with greatest changes in those involved in growth and development and signal transduction. Expression of Myod was also downregulated at an early time point. Oxidative stress and heat shock genes were downregulated at later time points, suggesting that they may be secondary targets. The DUX4 homeodomains are most similar to those of PAX3 (606597) and PAX7 (167410), and overexpression of these genes rescued viability and proliferation in DUX4-expressing C2C12 cells. Bosnakovski et al. (2008) concluded that DUX4 may cause FSHD by interfering with normal PAX3 or PAX7 function in muscle satellite cells. </p><p>Lemmers et al. (2010) showed that FSHD patients carry specific single-nucleotide polymorphisms in the chromosomal region distal to the last D4Z4 repeat. This FSHD-predisposing configuration creates a canonic polyadenylation signal for transcripts derived from DUX4, a double homeobox gene that straddles the last repeat unit and the adjacent sequence. Transfection studies revealed that DUX4 transcripts are efficiently polyadenylated and are more stable when expressed from permissive chromosomes. Lemmers et al. (2010) concluded that their findings suggest that FSHD arises through a toxic gain of function attributable to the stabilized distal DUX4 transcript. </p><p>Cabianca et al. (2012) found that derepression of chromosome 4q35 genes in FSHD cells was associated with expression of a long noncoding RNA, DBET (614865), from the FSHD locus. DBET recruited the histone methyltransferase Ash1l (ASH1; 607999) for gene repression in an apparent positive-feedback loop. </p><p><strong><em>D4Z4 and Facioscapulohumeral Muscular Dystrophy 2</em></strong></p><p>
|
|
In affected members of 15 (79%) of 19 families with facioscapulohumeral muscular dystrophy-2 (FSHD2; 158901), Lemmers et al. (2012) identified heterozygous loss-of-function mutations in the SMCHD1 gene (see, e.g., 614982.0001-614982.0005). The mutations in 7 families were initially identified by exome sequencing and confirmed by Sanger sequencing. The mutational spectrum included small deletions, splice site mutations, and missense mutations, resulting in haploinsufficiency. Patients showed D4Z4 hypomethylation to levels less than 25% (normal being about 50%), and protein blot analysis in several patients showed decreased SMCHD1 protein in fibroblasts. Affected individuals were also heterozygous or homozygous for an FSHD1 (158900)-permissive D4Z4 haplotype that contains a polyadenylation signal to stabilize DUX4 mRNA in skeletal muscle. Primary myotubes from a normal individual with a normal-sized and methylated D4Z4 array on a permissive haplotype showed no DUX4 mRNA. However, decreasing SMCHD1 expression to about 50% using RNA interference resulted in transcriptional activation of DUX4 and a variegated pattern of DUX4 protein expression in the myotubes. The pattern of variegated DUX4 expression that resulted was similar to that observed in FSHD1 and FSHD2 myotube cultures. The findings indicated that SMCHD1 activity is necessary for D4Z4 hypermethylation and somatic repression of DUX4, and that reduction of SMCHD1 results in D4Z4 arrays that express DUX4 when a permissive haplotype is present. The SMCHD1 mutation and the permissive D4Z4 haplotype segregated independently in the families, indicating digenic inheritance. Of the 26 individuals with hypomethylation at D4Z4, a SMCHD1 mutation, and a permissive D4Z4 haplotype, 5 (19%) were asymptomatic, indicating incomplete penetrance. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cytogenetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>In 2 cases of Ewing-like sarcomas (see 612219), Kawamura-Saito et al. (2006) identified the chromosomal translocation t(4;19)(q35;q13). The breakpoint at chromosome 19q13 was within exon 20 of the CIC gene (612082), and the breakpoint at chromosome 4q35 was within the DUX4 coding region in the D4Z4 repeat region. The translocation resulted in a CIC-DUX4 fusion transcript that was translated into a chimeric protein containing most of the CIC sequence, including the HMG box and TLE (see 600189)-binding sites, fused in frame to the C terminus of DUX4. The chimeric protein did not contain the N-terminal DNA-binding homeodomains of DUX4. No reciprocal DUX4-CIC transcripts were observed. The CIC-DUX4 transcript induced anchorage-independent growth when transfected into mouse fibroblasts. Although CIC is a transcriptional repressor, the CIC-DUX4 transcript enhanced transcription of a reporter gene when transfected into HeLa cells. Microarray analysis revealed altered gene expression following transfection of CIC-DUX4 into a human osteosarcoma cell line, including significantly upregulated expression of ERM (ETV5; 601600) and ETV1 (600541). Chromatin immunoprecipitation analysis and electrophoretic mobility shift assays confirmed binding of the chimeric protein to the ERM and ETV1 promoters. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Evolution</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Clapp et al. (2007) identified D4Z4 homologs in the genomes of rodents, Afrotheria (superorder of elephants and related species), and other species and showed that the DUX4 ORF is conserved. Phylogenetic analysis suggested that primate and Afrotherian D4Z4 arrays are orthologous and originated from a retrotransposed copy of an intron-containing DUX gene, DUXC. Reverse-transcriptase PCR and RNA fluorescence and tissue in situ hybridization data indicated transcription of the mouse array. Clapp et al. (2007) concluded that, together with the conservation of the DUX4 ORF for more than 100 million years, this strongly supports a coding function for D4Z4 and necessitates reexamination of the current models of mechanism for FSHD. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Dux, or Duxf3, is the mouse ortholog of human DUX4. Chen and Zhang (2019) found that both Dux zygotic knockout (Z-KO) and Dux maternal and zygotic knockout (MZ-KO) embryos were born at reduced mendelian frequencies but survived to adulthood without obvious abnormalities. RNA-sequencing analyses of 1-cell and late 2-cell Dux MZ-KO embryos revealed that loss of Dux had a minimal effect on zygotic genome activation (ZGA). Although Dux is essential for embryonic stem (ES) cells to enter the 2-cell (2C)-like ES cell state, most Dux targets in 2C-like cells were activated normally in MZ-KO embryos. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bengtsson, U., Altherr, M. R., Wasmuth, J. J., Winokur, S. T.
|
|
<strong>High resolution fluorescence in situ hybridization to linearly extended DNA visually maps a tandem repeat associated with facioscapulohumeral muscular dystrophy immediately adjacent to the telomere of 4q.</strong>
|
|
Hum. Molec. Genet. 3: 1801-1805, 1994.
|
|
|
|
|
|
[PubMed: 7849703]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/3.10.1801]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bosnakovski, D., Xu, Z., Gang, E. J., Galindo, C. L., Liu, M., Simsek, T., Garner, H. R., Agha-Mohammadi, S., Tassin, A., Coppee, F., Belayew, A., Perlingeiro, R. R., Kyba, M.
|
|
<strong>An isogenic myoblast expression screen identifies DUX4-mediated FSHD-associated molecular pathologies.</strong>
|
|
EMBO J. 27: 2766-2779, 2008.
|
|
|
|
|
|
[PubMed: 18833193]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/emboj.2008.201]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Cabianca, D. S., Casa, V., Bodega, B., Xynos, A., Ginelli, E., Tanaka, Y., Gabellini, D.
|
|
<strong>A long ncRNA links copy number variation to a polycomb/trithorax epigenetic switch in FSHD muscular dystrophy.</strong>
|
|
Cell 149: 819-831, 2012.
|
|
|
|
|
|
[PubMed: 22541069]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.cell.2012.03.035]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Chen, Z., Zhang, Y.
|
|
<strong>Loss of DUX causes minor defects in zygotic genome activation and is compatible with mouse development.</strong>
|
|
Nature Genet. 51: 947-951, 2019.
|
|
|
|
|
|
[PubMed: 31133747]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/s41588-019-0418-7]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Clapp, J., Mitchell, L. M., Bolland, D. J., Fantes, J., Corcoran, A. E., Scotting, P. J., Armour, J. A. L., Hewitt, J. E.
|
|
<strong>Evolutionary conservation of a coding function for D4Z4, the tandem DNA repeat mutated in facioscapulohumeral muscular dystrophy.</strong>
|
|
Am. J. Hum. Genet. 81: 264-279, 2007.
|
|
|
|
|
|
[PubMed: 17668377]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1086/519311]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Deidda, G., Cacurri, S., Piazzo, N., Felicetti, L.
|
|
<strong>Direct detection of 4q35 rearrangements implicated in facioscapulohumeral muscular dystrophy (FSHD).</strong>
|
|
J. Med. Genet. 33: 361-365, 1996.
|
|
|
|
|
|
[PubMed: 8733043]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1136/jmg.33.5.361]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Dixit, M., Ansseau, E., Tassin, A., Winokur, S., Shi, R., Qian, H., Sauvage, S., Matteotti, C., van Acker, A. M., Leo, O., Figlewicz, D., Barro, M., Laoudj-Chenivesse, D., Belayew, A., Coppee, F., Chen, Y.-W.
|
|
<strong>DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1.</strong>
|
|
Proc. Nat. Acad. Sci. 104: 18157-18162, 2007.
|
|
|
|
|
|
[PubMed: 17984056]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.0708659104]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Dmitriev, P., Petrov, A., Ansseau, E., Stankevicins, L., Charron, S., Kim, E., Bos, T. J., Robert, T., Turki, A., Coppee, F., Belayew, A., Lazar, V., Carnac, G., Laoudj, D., Lipinski, M., Vassetzky, Y. S.
|
|
<strong>The Kruppel-like factor 15 as a molecular link between myogenic factors and a chromosome 4q transcriptional enhancer implicated in facioscapulohumeral dystrophy.</strong>
|
|
J. Biol. Chem. 286: 44620-44631, 2011.
|
|
|
|
|
|
[PubMed: 21937448]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.M111.254052]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gabellini, D., Green, M. R., Tupler, R.
|
|
<strong>Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle.</strong>
|
|
Cell 110: 339-348, 2002.
|
|
|
|
|
|
[PubMed: 12176321]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0092-8674(02)00826-7]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gabriels, J., Beckers, M.-C., Ding, H., De Vriese, A., Plaisance, S., van der Maarel, S. M., Padberg, G. W., Frants, R. R., Hewitt, J. E., Collen, D., Belayew, A.
|
|
<strong>Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element.</strong>
|
|
Gene 236: 25-32, 1999.
|
|
|
|
|
|
[PubMed: 10433963]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0378-1119(99)00267-x]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Geng, L. N., Yao, Z., Snider, L., Fong, A. P., Cech, J. N., Young, J. M., van der Maarel, S. M., Ruzzo, W. L., Gentleman, R. C., Tawil, R., Tapscott, S. J.
|
|
<strong>DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy.</strong>
|
|
Dev. Cell 22: 38-51, 2012.
|
|
|
|
|
|
[PubMed: 22209328]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.devcel.2011.11.013]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hewitt, J. E., Lyle, R., Clark, L. N., Valleley, E. M., Wright, T. J., Wijmenga, C., van Deutekom, J. C. T., Francis, F., Sharpe, P. T., Hofker, M., Frants, R. R., Williamson, R.
|
|
<strong>Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy.</strong>
|
|
Hum. Molec. Genet. 3: 1287-1295, 1994.
|
|
|
|
|
|
[PubMed: 7987304]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/3.8.1287]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Jiang, G., Yang, F., van Overveld, P. G. M., Vedanarayanan, V., van der Maarel, S., Ehrlich, M.
|
|
<strong>Testing the position-effect variegation hypothesis for facioscapulohumeral muscular dystrophy by analysis of histone modification and gene expression in subtelomeric 4q.</strong>
|
|
Hum. Molec. Genet. 12: 2909-2921, 2003.
|
|
|
|
|
|
[PubMed: 14506132]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddg323]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kawamura-Saito, M., Yamazaki, Y., Kaneko, K., Kawaguchi, N., Kanda, H., Mukai, H., Gotoh, T., Motoi, T., Fukayama, M., Aburatani, H., Takizawa, T., Nakamura, T.
|
|
<strong>Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation.</strong>
|
|
Hum. Molec. Genet. 15: 2125-2137, 2006.
|
|
|
|
|
|
[PubMed: 16717057]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddl136]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kowaljow, V., Marcowycz, A., Ansseau, E., Conde, C. B., Sauvage, S., Matteotti, C., Arias, C., Corona, E. D., Nunez, N. G., Leo, O., Wattiez, R., Figlewicz, D., Laoudj-Chenivesse, D., Belayew, A., Coppee, F., Rosa, A. L.
|
|
<strong>The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein.</strong>
|
|
Neuromusc. Disord. 17: 611-623, 2007.
|
|
|
|
|
|
[PubMed: 17588759]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.nmd.2007.04.002]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lemmers, R. J. F. L., Wohlgemuth, M., Frants, R. R., Padberg, G. W., Morava, E., van der Maarel, S. M.
|
|
<strong>Contractions of D4Z4 on 4qB subtelomeres do not cause facioscapulohumeral muscular dystrophy.</strong>
|
|
Am. J. Hum. Genet. 75: 1124-1130, 2004.
|
|
|
|
|
|
[PubMed: 15467981]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1086/426035]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lemmers, R. J. L. F., de Kievit, P., Sandkuijl, L., Padberg, G. W., van Ommen, G.-J. B., Frants, R. R., van der Maarel, S. M.
|
|
<strong>Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere. (Letter)</strong>
|
|
Nature Genet. 32: 235-236, 2002.
|
|
|
|
|
|
[PubMed: 12355084]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng999]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lemmers, R. J. L. F., Tawil, R., Petek, L. M., Balog, J., Block, G. J., Santen, G. W. E., Amell, A. M., van der Vliet, P. J., Almomani, R., Straasheijm, K. R., Krom, Y. D., Klooster, R., and 18 others.
|
|
<strong>Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.</strong>
|
|
Nature Genet. 44: 1370-1374, 2012.
|
|
|
|
|
|
[PubMed: 23143600]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng.2454]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lemmers, R. J. L. F., van der Vliet, P. J., Klooster, R., Sacconi, S., Camano, P., Dauwerse, J. G., Snider, L., Straasheijm, K. R., van Ommen, G. J., Padberg, G. W., Miller, D. G., Tapscott, S. J., Tawil, R., Frants, R. R., van der Maarel, S. M.
|
|
<strong>A unifying genetic model for facioscapulohumeral muscular dystrophy.</strong>
|
|
Science 329: 1650-1653, 2010.
|
|
|
|
|
|
[PubMed: 20724583]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1189044]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lemmers, R. J. L. F., Wohlgemuth, M., van der Gaag, K. J., van der Vliet, P. J., van Teijlingen, C. M. M., de Knijff, P., Padberg, G. W., Frants, R. R., van der Maarel, S. M.
|
|
<strong>Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy.</strong>
|
|
Am. J. Hum. Genet. 81: 884-894, 2007.
|
|
|
|
|
|
[PubMed: 17924332]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1086/521986]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Masny, P. S., Bengtsson, U., Chung, S.-A., Martin, J. H., van Engelen, B., van der Maarel, S. M., Winokur, S. T.
|
|
<strong>Localization of 4q35.2 to the nuclear periphery: is FSHD a nuclear envelope disease?</strong>
|
|
Hum. Molec. Genet. 13: 1857-1871, 2004.
|
|
|
|
|
|
[PubMed: 15238509]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddh205]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Osborne, R. J., Welle, S., Venance, S. L., Thornton, C. A., Tawil, R.
|
|
<strong>Expression profile of FSHD supports a link between retinal vasculopathy and muscular dystrophy.</strong>
|
|
Neurology 68: 569-577, 2007.
|
|
|
|
|
|
[PubMed: 17151338]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1212/01.wnl.0000251269.31442.d9]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ottaviani, A., Rival-Gervier, S., Boussouar, A., Foerster, A. M., Rondier, D., Sacconi, S., Desnuelle, C., Gilson, E., Magdinier, F.
|
|
<strong>The D4Z4 macrosatellite repeat acts as a CTCF and A-type lamins-dependent insulator in facio-scapulo-humeral dystrophy.</strong>
|
|
PLoS Genet. 5: e1000394, 2009. Note: Electronic Article.
|
|
|
|
|
|
[PubMed: 19247430]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1371/journal.pgen.1000394]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Perini, G., Tupler, R.
|
|
<strong>Altered gene silencing and human diseases.</strong>
|
|
Clin. Genet. 69: 1-7, 2006.
|
|
|
|
|
|
[PubMed: 16451126]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1111/j.1399-0004.2005.00540.x]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Petrov, A., Allinne, J., Pirozhkova, I., Laoudj, D., Lipinski, M., Vassetzky, Y. S.
|
|
<strong>A nuclear matrix attachment site in the 4q35 locus has an enhancer-blocking activity in vivo: implications for the facio-scapulo-humeral dystrophy.</strong>
|
|
Genome Res. 18: 39-45, 2008.
|
|
|
|
|
|
[PubMed: 18032730]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1101/gr.6620908]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Petrov, A., Pirozhkova, I., Carnac, G., Laoudj, D., Lipinski, M., Vassetzky, Y. S.
|
|
<strong>Chromatin loop domain organization within the 4q35 locus in facioscapulohumeral dystrophy patients versus normal human myoblasts.</strong>
|
|
Proc. Nat. Acad. Sci. 103: 6982-6987, 2006.
|
|
|
|
|
|
[PubMed: 16632607]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.0511235103]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Snider, L., Asawachaicharn, A., Tyler, A. E., Geng, L. N., Petek, L. M., Maves, L., Miller, D. G., Lemmers, R. J. L. F., Winokur, S. T., Tawil, R., van der Maarel, S. M., Filippova, G. N., Tapscott, S. J.
|
|
<strong>RNA transcripts, miRNA-sized fragments and proteins produced from D4Z4 units: new candidates for the pathophysiology of facioscapulohumeral dystrophy.</strong>
|
|
Hum. Molec. Genet. 18: 2414-2430, 2009.
|
|
|
|
|
|
[PubMed: 19359275]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddp180]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Snider, L., Geng, L. N., Lemmers, R. J. L. F., Kyba, M., Ware, C. B., Nelson, A. M., Tawil, R., Filippova, G. N., van der Maarel, S. M., Tapscott, S. J., Miller, D. G.
|
|
<strong>Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene.</strong>
|
|
PLoS Genet. 6: e1001181, 2010. Note: Electronic Article.
|
|
|
|
|
|
[PubMed: 21060811]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1371/journal.pgen.1001181]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
van der Maarel, S. M., Deidda, G., Lemmers, R. J. L. F., van Overveld, P. G. M., van der Wielen, M., Hewitt, J. E., Sandkuijl, L., Bakker, B., van Ommen, G.-J. B., Padberg, G. W., Frants, R. R.
|
|
<strong>De novo facioscapulohumeral muscular dystrophy: frequent somatic mosaicism, sex-dependent phenotype, and the role of mitotic transchromosomal repeat interaction between chromosomes 4 and 10.</strong>
|
|
Am. J. Hum. Genet. 66: 26-35, 2000.
|
|
|
|
|
|
[PubMed: 10631134]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1086/302730]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
van Deutekom, J. C. T., Bakker, E., Lemmers, R. J. L. F., van der Wielen, M. J. R., Bik, E., Hofker, M. H., Padberg, G. W., Frants, R. R.
|
|
<strong>Evidence for subtelomeric exchange of 3.3 kb tandemly repeated units between chromosomes 4q35 and 10q26: implications for genetic counselling and etiology of FSHD1.</strong>
|
|
Hum. Molec. Genet. 5: 1997-2003, 1996.
|
|
|
|
|
|
[PubMed: 8968754]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/5.12.1997]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
van Deutekom, J. C. T., Lemmers, R. J. L. F., Grewal, P. K., van Geel, M., Romberg, S., Dauwerse, H. G., Wright, T. J., Padberg, G. W., Hofker, M. H., Hewitt, J. E., Frants, R. R.
|
|
<strong>Identification of the first gene (FRG1) from the FSHD region on human chromosome 4q35.</strong>
|
|
Hum. Molec. Genet. 5: 581-590, 1996.
|
|
|
|
|
|
[PubMed: 8733123]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/5.5.581]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
van Geel, M., Dickson, M. C., Beck, A. F., Bolland, D. J., Frants, R. R., van der Maarel, S. M., de Jong, P. J., Hewitt, J. E.
|
|
<strong>Genomic analysis of human chromosome 10q and 4q telomeres suggests a common origin.</strong>
|
|
Genomics 79: 210-217, 2002.
|
|
|
|
|
|
[PubMed: 11829491]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1006/geno.2002.6690]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
van Overveld, P. G. M., Enthoven, L., Ricci, E., Rossi, M., Felicetti, L., Jeanpierre, M., Winokur, S. T., Frants, R. R., Padberg, G. W., van der Maarel, S. M.
|
|
<strong>Variable hypomethylation of D4Z4 in facioscapulohumeral muscular dystrophy.</strong>
|
|
Ann. Neurol. 58: 569-576, 2005.
|
|
|
|
|
|
[PubMed: 16178028]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ana.20625]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Wallace, L. M., Garwick, S. E., Mei, W., Belayew, A., Coppee, F., Ladner, K. J., Guttridge, D., Yang, J., Harper, S. Q.
|
|
<strong>DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53-dependent myopathy in vivo.</strong>
|
|
Ann. Neurol. 69: 540-552, 2011.
|
|
|
|
|
|
[PubMed: 21446026]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ana.22275]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Winokur, S. T., Schutte, B., Weiffenbach, B., Washington, S. S., McElligott, D., Chakravarti, A., Wasmuth, J. H., Altherr, M. R.
|
|
<strong>A radiation hybrid map of 15 loci on the distal long arm of chromosome 4, the region containing the gene responsible for facioscapulohumeral muscular dystrophy (FSHD).</strong>
|
|
Am. J. Hum. Genet. 53: 874-880, 1993.
|
|
|
|
|
|
[PubMed: 8213815]
|
|
|
|
|
|
|
|
</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">
|
|
Bao Lige - updated : 07/08/2019<br>Patricia A. Hartz - updated : 1/17/2013<br>Patricia A. Hartz - updated : 10/10/2012<br>Patricia A. Hartz - updated : 2/14/2012<br>Patricia A. Hartz - updated : 9/27/2011<br>Ada Hamosh - updated : 11/10/2010<br>Patricia A. Hartz - updated : 4/14/2010<br>George E. Tiller - updated : 3/30/2010<br>Patricia A. Hartz - updated : 4/9/2008<br>Victor A. McKusick - updated : 8/21/2007
|
|
</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">
|
|
Dawn Watkins-Chow : 6/13/2001
|
|
</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 : 08/16/2019<br>carol : 07/09/2019<br>mgross : 07/08/2019<br>mgross : 12/20/2013<br>mgross : 1/18/2013<br>mgross : 1/18/2013<br>terry : 1/17/2013<br>carol : 12/18/2012<br>mgross : 10/11/2012<br>terry : 10/10/2012<br>mgross : 2/14/2012<br>mgross : 2/14/2012<br>terry : 2/14/2012<br>carol : 10/5/2011<br>terry : 9/28/2011<br>terry : 9/27/2011<br>mgross : 9/15/2011<br>terry : 5/17/2011<br>wwang : 11/24/2010<br>alopez : 11/15/2010<br>terry : 11/10/2010<br>mgross : 4/22/2010<br>terry : 4/14/2010<br>wwang : 4/1/2010<br>terry : 3/30/2010<br>wwang : 6/25/2009<br>mgross : 4/10/2008<br>mgross : 4/10/2008<br>terry : 4/9/2008<br>alopez : 8/21/2007<br>terry : 3/18/2004<br>mcapotos : 12/28/2001<br>carol : 6/14/2001
|
|
</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>
|
|
|
|
|