3933 lines
356 KiB
Text
3933 lines
356 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
|
|
|
|
- *616186 - H19/IGF2-IMPRINTING CONTROL REGION
|
|
|
|
|
|
- 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=616186"><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">*616186</span>
|
|
<br />
|
|
<strong>Table of Contents</strong>
|
|
</p>
|
|
|
|
<nav>
|
|
<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
|
|
|
|
<li role="presentation">
|
|
<a href="#title"><strong>Title</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#text"><strong>Text</strong></a>
|
|
</li>
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#description">Description</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#geneStructure">Gene Structure</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#mapping">Mapping</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#geneFunction">Gene Function</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#molecularGenetics">Molecular Genetics</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#evolution">Evolution</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#animalModel">Animal Model</a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
|
|
</li>
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="/allelicVariants/616186">Table View</a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#references"><strong>References</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#contributors"><strong>Contributors</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#creationDate"><strong>Creation Date</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#editHistory"><strong>Edit History</strong></a>
|
|
</li>
|
|
|
|
</ul>
|
|
|
|
</nav>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimFloatingLinksMenu">
|
|
|
|
<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
|
|
<h4 class="panel-title">
|
|
<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
|
|
<div style="display: table-row">
|
|
<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
|
|
|
|
<div style="display: table-cell;">External Links</div>
|
|
</div>
|
|
</a>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
|
|
<div id="mimExternalLinksFold" class="collapse in">
|
|
|
|
<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=105259599" 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=616186" 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://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=616186" 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="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=105259599" 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.genome.jp/dbget-bin/www_bget?hsa+105259599" 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="https://monarchinitiative.org/NCBIGene:105259599" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/gene/105259599" 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>
|
|
</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="#mimMedlinePlusGeneticsFold" id="mimMedlinePlusGeneticsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Consumer-friendly information about the effects of genetic variation on human health."><span id="mimMedlinePlusGeneticsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>MedlinePlus Genetics</div>
|
|
<div id="mimMedlinePlusGeneticsFold" class="collapse">
|
|
<div style="margin-left: 0.5em;"><a href="https://medlineplus.gov/genetics/gene/h19" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">H19 gene </a></div><div style="margin-left: 0.5em;"><a href="https://medlineplus.gov/genetics/gene/igf2" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">IGF2 gene </a></div>
|
|
</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=616186[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>
|
|
</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.ncbi.nlm.nih.gov/gene/105259599/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=105259599" 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>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
<span>
|
|
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
|
|
|
|
</span>
|
|
</span>
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
|
|
|
|
<div>
|
|
|
|
<a id="title" class="mim-anchor"></a>
|
|
|
|
<div>
|
|
<a id="number" class="mim-anchor"></a>
|
|
<div class="text-right">
|
|
|
|
|
|
|
|
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
|
|
|
|
<strong>SNOMEDCT:</strong> 81780002<br />
|
|
|
|
|
|
<strong>ICD10CM:</strong> Q87.3<br />
|
|
|
|
|
|
|
|
|
|
|
|
">ICD+</a>
|
|
|
|
</div>
|
|
<div>
|
|
<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
616186
|
|
</span>
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
<div>
|
|
<a id="preferredTitle" class="mim-anchor"></a>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
H19/IGF2-IMPRINTING CONTROL REGION
|
|
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
ICR1<br />
|
|
H19 ICR
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/11/71?start=-3&limit=10&highlight=71">11p15.5</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:1998202-2003509&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'})">11:1,998,202-2,003,509</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=130650,180860,194071" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/11/71?start=-3&limit=10&highlight=71">
|
|
11p15.5
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Beckwith-Wiedemann syndrome
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/130650"> 130650 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Silver-Russell syndrome 1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/180860"> 180860 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Wilms tumor 2
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/194071"> 194071 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Somatic mutation">SMu</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/616186" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/616186" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
|
|
|
|
|
|
|
|
<div>
|
|
<p />
|
|
</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>Chromosome 11p15 contains 2 neighboring imprinted domains, one associated with the H19 (<a href="/entry/103280">103280</a>) and IGF2 (<a href="/entry/147470">147470</a>) genes, and the other associated with the KCNQ1 gene (<a href="/entry/607542">607542</a>). Each domain is controlled by its own imprinting control region, designated ICR1 or ICR2 (see <a href="/entry/607542">607542</a>), respectively. ICR1, which is located just upstream of the H19 gene, regulates imprinted expression of the maternally expressed noncoding RNA H19 and the paternally expressed gene IGF2, which encodes a growth factor. ICR1 is a differentially methylated region (DMR) that is methylated exclusively on the paternal allele. On the maternal allele, unmethylated ICR1 bound by CTCF (<a href="/entry/604167">604167</a>) forms a chromatin insulator that prevents IGF2 promoter activation by the enhancer downstream of H19, resulting in silencing of IGF2 and activation of H19. On the paternal allele, methylation-sensitive CTCF cannot bind to methylated ICR1, resulting in activation of IGF2 and silencing of H19. CTCF also maintains the unmethylated status of ICR1 on the maternal allele (summary by <a href="#11" class="mim-tip-reference" title="Higashimoto, K., Jozaki, K., Kosho, T., Matsubara, K., Fuke, T., Yamada, D., Yatsuki, H., Maeda, T., Ohtsuka, Y., Nishioka, K., Joh, K., Koseki, H., Ogata, T., Soejima, H. <strong>A novel de novo point mutation of the OCT-binding site in the IGF2/H19-imprinting control region in a Beckwith-Wiedemann syndrome patient.</strong> Clin. Genet. 86: 539-544, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24299031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24299031</a>] [<a href="https://doi.org/10.1111/cge.12318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24299031">Higashimoto et al., 2014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24299031" 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="#11" class="mim-tip-reference" title="Higashimoto, K., Jozaki, K., Kosho, T., Matsubara, K., Fuke, T., Yamada, D., Yatsuki, H., Maeda, T., Ohtsuka, Y., Nishioka, K., Joh, K., Koseki, H., Ogata, T., Soejima, H. <strong>A novel de novo point mutation of the OCT-binding site in the IGF2/H19-imprinting control region in a Beckwith-Wiedemann syndrome patient.</strong> Clin. Genet. 86: 539-544, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24299031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24299031</a>] [<a href="https://doi.org/10.1111/cge.12318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24299031">Higashimoto et al. (2014)</a> noted that ICR1 contains 2 different repetitive sequences (A and B) and 7 CTCF-binding sites. It also contains binding motifs for OCT (see <a href="/entry/164175">164175</a>), SOX (see <a href="/entry/602148">602148</a>), and ZFP57 (<a href="/entry/612192">612192</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24299031" 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>ICR1 is located just upstream of the H19 gene on chromosome 11p15.5. The H19 gene is telomeric to ICR1, and the IGF2 gene is centromeric to ICR1 (<a href="#11" class="mim-tip-reference" title="Higashimoto, K., Jozaki, K., Kosho, T., Matsubara, K., Fuke, T., Yamada, D., Yatsuki, H., Maeda, T., Ohtsuka, Y., Nishioka, K., Joh, K., Koseki, H., Ogata, T., Soejima, H. <strong>A novel de novo point mutation of the OCT-binding site in the IGF2/H19-imprinting control region in a Beckwith-Wiedemann syndrome patient.</strong> Clin. Genet. 86: 539-544, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24299031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24299031</a>] [<a href="https://doi.org/10.1111/cge.12318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24299031">Higashimoto et al., 2014</a>). This genomic arrangement is conserved on mouse chromosome 7 (<a href="#34" class="mim-tip-reference" title="Zemel, S., Bartolomei, M. S., Tilghman, S. M. <strong>Physical linkage of two mammalian imprinted genes, H19 and insulin-like growth factor 2.</strong> Nature Genet. 2: 61-65, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1303252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1303252</a>] [<a href="https://doi.org/10.1038/ng0992-61" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1303252">Zemel et al., 1992</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=24299031+1303252" 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>In mouse, the imprinted H19 gene lies at the end of a cluster of imprinted genes. <a href="#15" class="mim-tip-reference" title="Leighton, P. A., Ingram, R. S., Eggenschwiler, J., Efstratiadis, A., Tilghman, S. M. <strong>Disruption of imprinting caused by deletion of the H19 gene region in mice.</strong> Nature 375: 34-39, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7536897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7536897</a>] [<a href="https://doi.org/10.1038/375034a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7536897">Leighton et al. (1995)</a> found that imprinting of the insulin-2 (Ins2; see <a href="/entry/176730">176730</a>) gene and the Igf2 gene, which lie about 100 kb upstream of H19, can be disrupted by maternal inheritance of a targeted deletion of the H19 gene and its flanking sequence. Animals inheriting the H19 mutation from their mothers were 27% heavier than those inheriting from their fathers. Paternal inheritance of the disruption had no effect, which presumably reflects the normally silent state of the paternal gene. The somatic overgrowth of heterozygotes for the maternal deletion was attributed to a gain-of-function of the Igf2 gene rather than a loss of function of H19. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7536897" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The expression of the IGF2 and H19 genes is imprinted. Although these neighboring genes share an enhancer, H19 is expressed only from the maternal allele, and IGF2 only from the paternally inherited allele. The region of paternal-specific methylation upstream of H19 appears to be the site of an epigenetic mark that is required for the imprinting of these genes. A deletion within this region results in loss of imprinting of both H19 and IGF2 (<a href="#29" class="mim-tip-reference" title="Thorvaldsen, J. L., Duran, K. L., Bartolomei, M. S. <strong>Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2.</strong> Genes Dev. 12: 3693-3702, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9851976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9851976</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9851976[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/gad.12.23.3693" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9851976">Thorvaldsen et al., 1998</a>). <a href="#2" class="mim-tip-reference" title="Bell, A. C., Felsenfeld, G. <strong>Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene.</strong> Nature 405: 482-485, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839546</a>] [<a href="https://doi.org/10.1038/35013100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839546">Bell and Felsenfeld (2000)</a> showed that this methylated region contains an element that blocks enhancer activity. The activity of this element is dependent upon the vertebrate enhancer-blocking protein CTCF (<a href="/entry/604167">604167</a>). Methylation of CpGs within the CTCF binding sites eliminates binding of CTCF in vitro, and deletion of these sites results in loss of enhancer-blocking activity in vivo, thereby allowing gene expression. This CTCF-dependent enhancer-blocking element acts as an insulator. <a href="#2" class="mim-tip-reference" title="Bell, A. C., Felsenfeld, G. <strong>Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene.</strong> Nature 405: 482-485, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839546</a>] [<a href="https://doi.org/10.1038/35013100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839546">Bell and Felsenfeld (2000)</a> suggested that it controls imprinting of IGF2. The activity of this insulator is restricted to the maternal allele by specific DNA methylation of the paternal allele. <a href="#2" class="mim-tip-reference" title="Bell, A. C., Felsenfeld, G. <strong>Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene.</strong> Nature 405: 482-485, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839546</a>] [<a href="https://doi.org/10.1038/35013100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839546">Bell and Felsenfeld (2000)</a> concluded that DNA methylation can control gene expression by modulating enhancer access to the gene promoter through regulation of an enhancer boundary. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10839546+9851976" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The unmethylated ICR acts as a chromatin boundary that blocks the interaction of IGF2 with enhancers that lie 3-prime of H19 (<a href="#33" class="mim-tip-reference" title="Webber, A., Ingram, R. S., Levorse, J. M., Tilghman, S. M. <strong>Location of enhancers is essential for imprinting of H19 and Igf2 genes.</strong> Nature 391: 711-715, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9490417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9490417</a>] [<a href="https://doi.org/10.1038/35655" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9490417">Webber et al., 1998</a>; <a href="#10" class="mim-tip-reference" title="Hark, A. T., Tilghman, S. M. <strong>Chromatin conformation of the H19 epigenetic mark.</strong> Hum. Molec. Genet. 7: 1979-1985, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9811943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9811943</a>] [<a href="https://doi.org/10.1093/hmg/7.12.1979" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9811943">Hark and Tilghman, 1998</a>). This enhancer-blocking activity would then be lost when the region was methylated, thereby allowing expression of IGF2 paternally. Using transgenic mice and tissue culture, <a href="#9" class="mim-tip-reference" title="Hark, A. T., Schoenherr, C. J., Katz, D. J., Ingram, R. S., Levrose, J. M., Tilghman, S. M. <strong>CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus.</strong> Nature 405: 486-489, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839547</a>] [<a href="https://doi.org/10.1038/35013106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839547">Hark et al. (2000)</a> demonstrated that the unmethylated ICRs from mouse and human H19 exhibit enhancer-blocking activity. They showed that CTCF binds to several sites in the unmethylated ICR that are essential for enhancer blocking. Consistent with this model, CTCF binding is abolished by DNA methylation. Within the human ICR, there is a CpG-rich 45-bp sequence in B repeats that is 60% identical to 2 sites in the hypersensitive region HS1 and 3 sites in HS2. Within this is a 14-bp core that has a high degree of similarity to a binding site for CTCF (FII) within the chicken beta-globin insulator. <a href="#9" class="mim-tip-reference" title="Hark, A. T., Schoenherr, C. J., Katz, D. J., Ingram, R. S., Levrose, J. M., Tilghman, S. M. <strong>CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus.</strong> Nature 405: 486-489, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839547</a>] [<a href="https://doi.org/10.1038/35013106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839547">Hark et al. (2000)</a> demonstrated that DNA methylation inhibited binding of CTCF to human B1 sites and showed that CTCF sites are not symmetric, and that the protein makes important contacts with some of the cytosine residues on the top DNA strand. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10839547+9490417+9811943" 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="Srivastava, M., Hsieh, S., Grinberg, A., Williams-Simons, L., Huang, S.-P., Pfeifer, K. <strong>H19 and Igf2 monoallelic expression is regulated in two distinct ways by a shared cis acting regulatory region upstream of H19.</strong> Genes Dev. 14: 1186-1195, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10817754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10817754</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10817754[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="10817754">Srivastava et al. (2000)</a> used a loxP/cre recombinase-based strategy to delete the ICR upstream of H19 in mice in a conditional manner to determine the temporal requirement of the upstream region in initiating and maintaining the imprinted expression of H19 and Igf2. Analysis of allele-specific expression of H19 and Igf2 and DNA methylation at the H19 promoter demonstrated that this region controls the monoallelic expression of the 2 genes in different ways, suggesting that it harbors 2 functionally distinct regulatory elements. Continued presence of the region is required to silence maternal Igf2 in accordance with its proposed role as an insulator. However, it does not have a direct role in keeping the paternal H19 promoter silenced. Instead, on the paternal chromosome, the upstream element mediates epigenetic modifications of the H19 promoter region during development, leading to transcriptional silencing of H19. Thereafter, its presence is redundant for preventing transcription. This temporal requirement of the silencing element appears to be a unique cis activity in the mammalian system. However, it is likely that other cis-acting elements, positive and negative, have the ability to effect stable changes in the chromatin structure and are not constantly required to give signals to the transcriptional machinery. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10817754" 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="Takai, D., Gonzales, F. A., Tsai, Y. C., Thayer, M. J., Jones, P. A. <strong>Large scale mapping of methylcytosines in CTCF-binding sites in the human H19 promoter and aberrant hypomethylation in human bladder cancer.</strong> Hum. Molec. Genet. 10: 2619-2626, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11726548/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11726548</a>] [<a href="https://doi.org/10.1093/hmg/10.23.2619" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11726548">Takai et al. (2001)</a> found that all the CTCF-binding sites in H19 except for the sixth were hypermethylated, whereas only the sixth binding site showed allele-specific methylation in normal human embryonic ureteral tissue. In human-mouse somatic-cell-hybrid clones containing a single copy of human chromosome 11, they observed a correlation between methylation of the sixth CTCF-binding site and expression of IGF2. The authors also reported hypomethylation of the paternal allele in 2 of 6 informative cases of human bladder cancer. The authors proposed that only the sixth CTCF-binding site may act as a key regulatory domain for switching between H19 or IGF2 expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11726548" 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="#5" class="mim-tip-reference" title="Du, M., Beatty, L. G., Zhou, W., Lew, J., Schoenherr, C., Weksberg, R., Sadowski, P. D. <strong>Insulator and silencer sequences in the imprinted region of human chromosome 11p15.5.</strong> Hum. Molec. Genet. 12: 1927-1939, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12874112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12874112</a>] [<a href="https://doi.org/10.1093/hmg/ddg194" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12874112">Du et al. (2003)</a> confirmed the existence of insulators in the H19 DMR and reported 2 insulators in the IGF2 gene. The authors demonstrated binding of CTCF to all the insulator sequences detected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12874112" 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="Ulaner, G. A., Vu, T. H., Li, T., Hu, J.-F., Yao, X.-M., Yang, Y., Gorlick, R., Meyers, P., Healey, J., Ladanyi, M., Hoffman, A. R. <strong>Loss of imprinting of IGF2 and H19 in osteosarcoma is accompanied by reciprocal methylation changes of a CTCF-binding site.</strong> Hum. Molec. Genet. 12: 535-549, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12588801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12588801</a>] [<a href="https://doi.org/10.1093/hmg/ddg034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12588801">Ulaner et al. (2003)</a> showed that osteosarcoma tumors with IGF2/H19 maintenance of imprinting (MOI) exhibited allele-specific differential methylation of a CTCF-binding site upstream of H19. Loss of imprinting (LOI) of IGF2 or H19 in osteosarcoma occurred in a mutually exclusive manner and occurred with monoallelic expression of the other gene. Bisulfite sequencing revealed that IGF2 LOI occurred with biallelic CpG methylation of the CTCF-binding site, while H19 LOI occurred with biallelic hypomethylation of this site. The authors proposed a model in which incomplete gain or loss of methylation at this CTCF-binding site during tumorigenesis may explain the complex and often conflicting expression patterns of IGF2 and H19 in tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12588801" 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="Sandovici, I., Leppert, M., Hawk, P. R., Suarez, A., Linares, Y., Sapienza, C. <strong>Familial aggregation of abnormal methylation of parental alleles at the IGF2/H19 and IGF2R differentially methylated regions.</strong> Hum. Molec. Genet. 12: 1569-1578, 2003. Note: Erratum: Hum. Molec. Genet. 13: 781 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12812984/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12812984</a>] [<a href="https://doi.org/10.1093/hmg/ddg167" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12812984">Sandovici et al. (2003)</a> examined allelic methylation ratios at DMRs within the IGF2/H19 and IGF2R loci in a panel of 48 three-generation families. There was familial clustering of individuals with abnormal methylation ratios at the IGF2/H19 DMR, as well as stability of this trait over a period of nearly 2 decades, consistent with the possibility that constitutional LOI at this locus may be due largely to genetic factors. At the IGF2R DMR, more variability in the allelic methylation ratios was observed over time, but there was also familial clustering of abnormal methylation ratios. <a href="#22" class="mim-tip-reference" title="Sandovici, I., Leppert, M., Hawk, P. R., Suarez, A., Linares, Y., Sapienza, C. <strong>Familial aggregation of abnormal methylation of parental alleles at the IGF2/H19 and IGF2R differentially methylated regions.</strong> Hum. Molec. Genet. 12: 1569-1578, 2003. Note: Erratum: Hum. Molec. Genet. 13: 781 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12812984/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12812984</a>] [<a href="https://doi.org/10.1093/hmg/ddg167" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12812984">Sandovici et al. (2003)</a> concluded that shared genetic factors may be responsible for a major fraction of interindividual variability in parental origin-dependent epigenetic modifications; however, temporal changes also occur in isolated cases, as well as within multiple individuals in the same family, indicating that environmental factors may also play a role. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12812984" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Fedoriw, A. M., Stein, P., Svoboda, P., Schultz, R. M., Bartolomei, M. S. <strong>Transgenic RNAi reveals essential function for CTCF in H19 gene imprinting.</strong> Science 303: 238-240, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14716017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14716017</a>] [<a href="https://doi.org/10.1126/science.1090934" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14716017">Fedoriw et al. (2004)</a> used a transgenic RNA interference-based approach to generate oocytes with reduced amounts of CTCF protein, and found increased methylation of the H19 differentially methylated domain and decreased developmental competence of CTCF-deficient oocytes. <a href="#7" class="mim-tip-reference" title="Fedoriw, A. M., Stein, P., Svoboda, P., Schultz, R. M., Bartolomei, M. S. <strong>Transgenic RNAi reveals essential function for CTCF in H19 gene imprinting.</strong> Science 303: 238-240, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14716017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14716017</a>] [<a href="https://doi.org/10.1126/science.1090934" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14716017">Fedoriw et al. (2004)</a> concluded that CTCF protects H19 differentially methylated domain from de novo methylation during oocyte growth and is required for normal preimplantation development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14716017" 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 analyzing 3 deletions of the H19 locus, <a href="#32" class="mim-tip-reference" title="Vernucci, M., Cerrato, F., Pedone, P. V., Dandolo, L., Bruni, C. B., Riccio, A. <strong>Developmentally regulated functions of the H19 differentially methylated domain.</strong> Hum. Molec. Genet. 13: 353-361, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14681296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14681296</a>] [<a href="https://doi.org/10.1093/hmg/ddh028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14681296">Vernucci et al. (2004)</a> investigated the mechanism regulating imprinted expression of the Igf2 gene during liver tumorigenesis in mouse embryos. The role of the H19 DMR in controlling Igf2 expression changed during tumorigenesis. The H19 DMR was required on the paternal chromosome for Igf2 activation in the early stages, while its maternal allele was necessary for maintaining Igf2 imprinting only in the late stages. A positive regulatory function for paternal H19 DMR was also evident in normal neonatal liver, but its relevance for Igf2 expression became higher in the second postnatal week. <a href="#32" class="mim-tip-reference" title="Vernucci, M., Cerrato, F., Pedone, P. V., Dandolo, L., Bruni, C. B., Riccio, A. <strong>Developmentally regulated functions of the H19 differentially methylated domain.</strong> Hum. Molec. Genet. 13: 353-361, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14681296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14681296</a>] [<a href="https://doi.org/10.1093/hmg/ddh028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14681296">Vernucci et al. (2004)</a> proposed a model in which both methylated and nonmethylated parental copies of the H19 DMR have active roles in regulating Igf2 expression in the liver, and these activities are under developmental control. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14681296" 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>It is believed that chromosomes interact with each other to regulate transcription in trans. To explore systematically the epigenetic dimension of such interactions, <a href="#35" class="mim-tip-reference" title="Zhao, Z., Tavoosidana, G., Sjolinder, M., Gondor, A., Mariano, P., Wang, S., Kanduri, C., Lezcano, M., Sandhu, K. S., Singh, U., Pant, V., Tiwari, V., Kurukuti, S., Ohlsson, R. <strong>Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra- and interchromosomal interactions.</strong> Nature Genet. 38: 1341-1347, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17033624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17033624</a>] [<a href="https://doi.org/10.1038/ng1891" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17033624">Zhao et al. (2006)</a> devised a strategy termed circular chromosome conformation capture (4C). This approach enabled high-throughput screening of physical interactions between chromosomes without a preconceived idea of the interacting partners. The authors identified 114 unique sequences from all autosomes, several of which interact primarily with the maternally inherited H19 imprinting control region. Imprinted domains were strongly overrepresented in the library of 4C sequences, further highlighting the epigenetic nature of these interactions. Moreover, <a href="#35" class="mim-tip-reference" title="Zhao, Z., Tavoosidana, G., Sjolinder, M., Gondor, A., Mariano, P., Wang, S., Kanduri, C., Lezcano, M., Sandhu, K. S., Singh, U., Pant, V., Tiwari, V., Kurukuti, S., Ohlsson, R. <strong>Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra- and interchromosomal interactions.</strong> Nature Genet. 38: 1341-1347, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17033624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17033624</a>] [<a href="https://doi.org/10.1038/ng1891" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17033624">Zhao et al. (2006)</a> found that the direct interaction between differentially methylated regions was linked to epigenetic regulation of transcription in trans. They found that the patterns of interactions specific to the maternal H19 imprinting control region underwent reprogramming during in vitro maturation of embryonic stem cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17033624" 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>Gene transcription may be regulated by remote enhancer or insulator regions through chromosome looping. Using a modification of chromosome conformation capture and fluorescence in situ hybridization, <a href="#16" class="mim-tip-reference" title="Ling, J. Q., Li, T., Hu, J. F., Vu, T. H., Chen, H. L., Qiu, X. W., Cherry, A. M., Hoffman, A. R. <strong>CTCF mediates interchromosomal colocalization between Igf2/H19 and Wsb1/Nf1.</strong> Science 312: 269-272, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16614224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16614224</a>] [<a href="https://doi.org/10.1126/science.1123191" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16614224">Ling et al. (2006)</a> found that 1 allele of the Igf2/H19 ICR on mouse chromosome 7 colocalized with 1 allele of Wsb1 (<a href="/entry/610091">610091</a>)/Nf1 (<a href="/entry/613113">613113</a>) on chromosome 11. Omission of Ctcf or deletion of the maternal ICR abrogated this association and altered Wsb1/Nf1 gene expression. <a href="#16" class="mim-tip-reference" title="Ling, J. Q., Li, T., Hu, J. F., Vu, T. H., Chen, H. L., Qiu, X. W., Cherry, A. M., Hoffman, A. R. <strong>CTCF mediates interchromosomal colocalization between Igf2/H19 and Wsb1/Nf1.</strong> Science 312: 269-272, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16614224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16614224</a>] [<a href="https://doi.org/10.1126/science.1123191" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16614224">Ling et al. (2006)</a> concluded that their findings demonstrated that CTCF mediates an interchromosomal association, perhaps by directing distant DNA segments to a common transcription factory, and the data provided a model for long-range allele-specific associations between gene regions on different chromosomes that suggested a framework for DNA recombination and RNA trans-splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16614224" 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="#31" class="mim-tip-reference" title="Venkatraman, A., He, X. C., Thorvaldsen, J. L., Sugimura, R., Perry, J. M., Tao, F., Zhao, M., Christenson, M. K., Sanchez, R., Yu, J. Y., Peng, L., Haug, J. S., Paulson, A., Li, H., Zhong, X., Clemens, T. L., Bartolomei, M. S., Li, L. <strong>Maternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence.</strong> Nature 500: 345-349, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23863936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23863936</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23863936[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/nature12303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23863936">Venkatraman et al. (2013)</a> demonstrated upregulation of growth-restricting imprinted genes, including in the H19-Igf2 locus, in long-term hematopoietic stem cells and their downregulation upon hematopoietic stem cell activation and proliferation. The H19 DMR, serving as the imprinting control region, determines the reciprocal expression of H19 from the maternal allele and Igf2 from the paternal allele. In addition, H19 serves as a source of miR675, which restricts Igf1r expression (<a href="#14" class="mim-tip-reference" title="Keniry, A., Oxley, D., Monnier, P., Kyba, M., Dandolo, L., Smits, G., Reik, W. <strong>The H19 lincRNA is a developmental reservoir of miR-675 that suppresses growth and Igf1r.</strong> Nature Cell Biol. 14: 659-665, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22684254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22684254</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22684254[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/ncb2521" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22684254">Keniry et al., 2012</a>). <a href="#31" class="mim-tip-reference" title="Venkatraman, A., He, X. C., Thorvaldsen, J. L., Sugimura, R., Perry, J. M., Tao, F., Zhao, M., Christenson, M. K., Sanchez, R., Yu, J. Y., Peng, L., Haug, J. S., Paulson, A., Li, H., Zhong, X., Clemens, T. L., Bartolomei, M. S., Li, L. <strong>Maternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence.</strong> Nature 500: 345-349, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23863936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23863936</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23863936[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/nature12303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23863936">Venkatraman et al. (2013)</a> demonstrated that conditional deletion of the maternal but not the paternal H19 DMR reduced adult hematopoietic stem cell quiescence, a state required for long-term maintenance of hematopoietic stem cells, and compromised hematopoietic stem cell function. Maternal-specific H19 DMR deletion resulted in activation of the Igf2-Igfr1 pathway, as shown by the translocation of phosphorylated FoxO3 (<a href="/entry/602681">602681</a>), an inactive form, from nucleus to cytoplasm and the release of FoxO3-mediated cell cycle arrest, thus leading to increased activation, proliferation, and eventual exhaustion of hematopoietic stem cells. Mechanistically, maternal-specific H19 DMR deletion led to Igf2 upregulation and increased translation of Igf1r, which is normally suppressed by H19-derived miR675. Similarly, genetic inactivation of Igf1r partly rescued the H19 DMR deletion phenotype. <a href="#31" class="mim-tip-reference" title="Venkatraman, A., He, X. C., Thorvaldsen, J. L., Sugimura, R., Perry, J. M., Tao, F., Zhao, M., Christenson, M. K., Sanchez, R., Yu, J. Y., Peng, L., Haug, J. S., Paulson, A., Li, H., Zhong, X., Clemens, T. L., Bartolomei, M. S., Li, L. <strong>Maternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence.</strong> Nature 500: 345-349, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23863936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23863936</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23863936[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/nature12303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23863936">Venkatraman et al. (2013)</a> concluded that their work established a role for this form of epigenetic control at the H19-IGF2 locus in maintaining adult stem cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22684254+23863936" 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>Beckwith-Wiedemann Syndrome</em></strong></p><p>
|
|
In mice, a targeted deletion showed that imprinting of the paternally expressed Igf2 and maternally expressed H19 genes is controlled by a 2-kb DMR located 5-prime of H19 (<a href="#29" class="mim-tip-reference" title="Thorvaldsen, J. L., Duran, K. L., Bartolomei, M. S. <strong>Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2.</strong> Genes Dev. 12: 3693-3702, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9851976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9851976</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9851976[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/gad.12.23.3693" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9851976">Thorvaldsen et al., 1998</a>). The H19 DMR sequence in human differs from the homologous mouse region in that it is organized into 2 repeat units, each consisting of 2 types of direct repeats, and containing 7 potential binding sites for CTCF. <a href="#26" class="mim-tip-reference" title="Sparago, A., Cerrato, F., Vernucci, M., Ferrero, G. B., Silengo, M. C., Riccio, A. <strong>Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome.</strong> Nature Genet. 36: 958-960, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15314640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15314640</a>] [<a href="https://doi.org/10.1038/ng1410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15314640">Sparago et al. (2004)</a> analyzed 7 individuals with Beckwith-Wiedemann syndrome (BWS; <a href="/entry/130650">130650</a>) and H19 hypermethylation for the presence of deletions in the H19 DMR and showed that inherited microdeletions in the H19 DMR that abolished 2 CTCF target sites caused this disorder. Maternal transmission of the deletions resulted in hypermethylation of the H19 DMR, biallelic IGF2 expression, H19 silencing, and BWS syndrome, indicative of loss of function of the IGF2/H19 ICR. In 3 sibs with BWS and Wilms tumor and 2 unaffected sibs from a 3-generation family, <a href="#21" class="mim-tip-reference" title="Prawitt, D., Enklaar, T., Gartner-Rupprecht, B., Spangenberg, C., Oswald, M., Lausch, E., Schmidtke, P., Reutzel, D., Fees, S., Lucito, R., Korzon, M., Brozek, I., Limon, J., Housman, D. E., Pelletier, J., Zabel, B. <strong>Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms' tumor.</strong> Proc. Nat. Acad. Sci. 102: 4085-4090, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15743916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15743916</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15743916[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.0500037102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15743916">Prawitt et al. (2005)</a> identified a 2.2-kbp microdeletion in the H19/IGF2 ICR1 that abolished 3 CTCF target sites. Maternal inheritance of the deletion was associated with IGF2 loss of imprinting and upregulation of IGF2 mRNA. However, in at least 1 affected family member a second lesion was identified, duplication of maternal 11p15, which was accompanied by a further increase in IGF2 mRNA levels (35-fold higher than control values). <a href="#21" class="mim-tip-reference" title="Prawitt, D., Enklaar, T., Gartner-Rupprecht, B., Spangenberg, C., Oswald, M., Lausch, E., Schmidtke, P., Reutzel, D., Fees, S., Lucito, R., Korzon, M., Brozek, I., Limon, J., Housman, D. E., Pelletier, J., Zabel, B. <strong>Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms' tumor.</strong> Proc. Nat. Acad. Sci. 102: 4085-4090, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15743916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15743916</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15743916[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.0500037102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15743916">Prawitt et al. (2005)</a> suggested that the combined effects of the BWS ICR1 microdeletion and 11p15 duplication were necessary for the manifestation of BWS in this family. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15743916+15314640+9851976" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Demars, J., Shmela, M. E., Rossignol, S., Okabe, J., Netchine, I., Azzi, S., Cabrol, S., Le Caignec, C., David, A., Le Bouc, Y., El-Osta, A., Gicquel, C. <strong>Analysis of the IGF2/H19 imprinting control region uncovers new genetic defects, including mutations of OCT-binding sequences, in patients with 11p15 fetal growth disorders.</strong> Hum. Molec. Genet. 19: 803-814, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20007505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20007505</a>] [<a href="https://doi.org/10.1093/hmg/ddp549" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20007505">Demars et al. (2010)</a> investigated the CTCF gene and the ICR1 domain in 21 BWS patients with ICR1 gain of methylation and 16 SRS patients with ICR1 loss of methylation. There were 4 constitutional ICR1 genetic defects in BWS patients, including a familial case. Three of those defects were imprinting defects consisting of small deletions and a single mutation, which did not involve one of the CTCF binding sites. Moreover, 2 of those defects affected OCT (PLXNA2; <a href="/entry/601054">601054</a>)-binding sequences, which may normally maintain the unmethylated state of the maternal allele. A single-nucleotide variation was identified in a SRS patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20007505" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 brothers with BWS, <a href="#20" class="mim-tip-reference" title="Poole, R. L., Leith, D. J., Docherty, L. E., Shmela, M. E., Gicquel, C., Splitt, M., Temple, I. K., Mackay, D. J. G. <strong>Beckwith-Wiedemann syndrome caused by maternally inherited mutation of an OCT-binding motif in the IGF2/H19-imprinting control region, ICR1.</strong> Europ. J. Hum. Genet. 20: 240-243, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21863054/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21863054</a>] [<a href="https://doi.org/10.1038/ejhg.2011.166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21863054">Poole et al. (2012)</a> identified a heterozygous A-to-C transversion in the A2 repeat of ICR1 that was demonstrated to alter the binding of nuclear factors, most likely OCT4 (POU5F1; <a href="/entry/164177">164177</a>). The mutation was inherited from the unaffected mother, who carried it on the paternal allele. The patients had hypermethylation of the ICR1 region. DNA sequencing of 9 additional patients with BWS and H19 hypermethylation did not identify mutations in the H19 ICR or promoter region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21863054" 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>Silver-Russell Syndrome</em></strong></p><p>
|
|
Given the crucial role of the 11p15 imprinted region in the control of fetal growth, <a href="#8" class="mim-tip-reference" title="Gicquel, C., Rossignol, S., Cabrol, S., Houang, M., Steunou, V., Barbu, V., Danton, F., Thibaud, N., Le Merrer, M., Burglen, L., Bertrand, A.-M., Netchine, I., Le Bouc, Y. <strong>Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome.</strong> Nature Genet. 37: 1003-1007, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16086014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16086014</a>] [<a href="https://doi.org/10.1038/ng1629" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16086014">Gicquel et al. (2005)</a> hypothesized that dysregulation of genes at 11p15 might be involved in syndromic intrauterine growth retardation. In the telomeric imprinting center region (ICR1) of the 11p15 region in several individuals with clinically typical Silver-Russell syndrome, they identified an epimutation (demethylation). The epigenetic defect was associated with, and probably responsible for, relaxation of imprinting and biallelic expression of H19 and downregulation of IGF2. These findings provided new insight into the pathogenesis of SRS and strongly suggested that the 11p15 imprinted region, in addition to the imprinted region of 7p13-p11.2 and 7q31-qter, is involved in SRS. The loss of paternal methylation in individuals with SRS may have resulted from a deficient acquisition of methylation during spermatogenesis or from a lack of maintenance of methylation after fertilization. The 5 individuals with SRS that carried the epimutation had only a partial loss of methylation, and 4 of them had body asymmetry. These data suggested that the loss of methylation occurred after fertilization and resulted in a mosaic distribution of the epimutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16086014" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Bartholdi, D., Krajewska-Walasek, M., Ounap, K., Gaspar, H., Chrzanowska, K. H., Ilyana, H., Kayserili, H., Lurie, I. W., Schinzel, A., Baumer, A. <strong>Epigenetic mutations of the imprinted IGF2-H19 domain in Silver-Russell syndrome (SRS): results from a large cohort of patients with SRS and SRS-like phenotypes. (Letter)</strong> J. Med. Genet. 46: 192-197, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19066168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19066168</a>] [<a href="https://doi.org/10.1136/jmg.2008.061820" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19066168">Bartholdi et al. (2009)</a> observed hypomethylation at ICR1 on chromosome 11p15 in 41 (38.5%) of 106 patients with Silver-Russell syndrome (SRS; <a href="/entry/180860">180860</a>). The majority of patients showed hypomethylation of both the H19 DMR and IGF2, but 10 showed selective hypomethylation of the H19 DMR, and 2 showed selective hypomethylation of IGF2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19066168" 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>Wilms Tumor</em></strong></p><p>
|
|
<a href="#24" class="mim-tip-reference" title="Scott, R. H., Douglas, J., Baskcomb, L., Huxter, N., Barker, K., Hanks, S., Craft, A., Gerrard, M., Kohler, J. A., Levitt, G. A., Picton, S., Pizer, B., and 10 others. <strong>Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor.</strong> Nature Genet. 40: 1329-1334, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18836444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18836444</a>] [<a href="https://doi.org/10.1038/ng.243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18836444">Scott et al. (2008)</a> identified constitutional abnormalities at chromosome 11p15 in 13 (3%) of 437 individuals with sporadic Wilms tumor without features of overgrowth syndromes (WT2; <a href="/entry/194071">194071</a>). Six patients had paternal uniparental disomy of 11p15 and 6 had hypermethylation at the H19 DMR. There were 2 familial cases. In 1 family, 2 sibs had a microdeletion of the H19 DMR (<a href="/entry/103280#0002">103280.0002</a>) that was inherited from the unaffected mother; 1 sib had isolated Wilms tumor and the other had features of BWS. In a second family, a mother and 2 daughters had a microinsertion in the H19 DMR (<a href="/entry/103280#0003">103280.0003</a>), inherited from the unaffected grandmother. No abnormalities were detected in 220 controls. Analysis of tumor tissue showed that the level of H19 DMR hypermethylation was greater in tumor compared to lymphocytes, suggesting that the tumors developed by clonal expansion of cells harboring the 11p15 defect. There was no evidence of additional tumor-specific 11p15 abnormalities affecting the wildtype allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18836444" 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>Comparisons between eutherians and marsupials have suggested limited conservation of the molecular mechanisms that control genomic imprinting in mammals. <a href="#25" class="mim-tip-reference" title="Smits, G., Mungall, A. J., Griffiths-Jones, S., Smith, P., Beury, D., Matthews, L., Rogers, J., Pask, A. J., Shaw, G., VandeBerg, J. L., McCarrey, J. R., SAVOIR Consortium, Renfree, M. B., Reik, W., Dunham, I. <strong>Conservation of the H19 noncoding RNA and H19-IGF2 imprinting mechanism in therians.</strong> Nature Genet. 40: 971-976, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18587395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18587395</a>] [<a href="https://doi.org/10.1038/ng.168" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18587395">Smits et al. (2008)</a> studied the evolution of the imprinted IGF2 (<a href="/entry/147470">147470</a>)-H19 locus in therians. Although marsupial orthologs of protein-coding exons were easily identified, the use of evolutionarily conserved regions and low-stringency Bl2seq comparisons was required to delineate a candidate H19 noncoding RNA sequence. The therian H19 orthologs showed miR675 and exon structure conservation, suggesting functional selection on both features. Transcription start site sequences and poly(A) signals are also conserved. As in eutherians, marsupial H19 is maternally expressed and paternal methylation upstream of the gene originates in the male germline, encompasses a CTCF (<a href="/entry/604167">604167</a>) insulator, and spreads somatically into the H19 gene. <a href="#25" class="mim-tip-reference" title="Smits, G., Mungall, A. J., Griffiths-Jones, S., Smith, P., Beury, D., Matthews, L., Rogers, J., Pask, A. J., Shaw, G., VandeBerg, J. L., McCarrey, J. R., SAVOIR Consortium, Renfree, M. B., Reik, W., Dunham, I. <strong>Conservation of the H19 noncoding RNA and H19-IGF2 imprinting mechanism in therians.</strong> Nature Genet. 40: 971-976, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18587395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18587395</a>] [<a href="https://doi.org/10.1038/ng.168" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18587395">Smits et al. (2008)</a> concluded that the conservation in all therians of the mechanism controlling imprinting of the IGF2-H19 locus suggests a sequential model of imprinting evolution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18587395" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="animalModel" class="mim-anchor"></a>
|
|
<h4 href="#mimAnimalModelFold" id="mimAnimalModelToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimAnimalModelToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimAnimalModelFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><a href="#13" class="mim-tip-reference" title="Jones, B. K., Levorse, J., Tilghman, S. M. <strong>Deletion of a nuclease-sensitive region between the Igf2 and H19 genes leads to Igf2 misregulation and increased adiposity.</strong> Hum. Molec. Genet. 10: 807-814, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11285246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11285246</a>] [<a href="https://doi.org/10.1093/hmg/10.8.807" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11285246">Jones et al. (2001)</a> described a 12-kb deletion of a region 5-prime of the ICR that was hypersensitive to nuclease digestion in chromatin. Its deletion resulted in a biallelic decrease in expression of Igf2, but not H19, in the brains of transgenic mice, consistent with the hypothesis that it encodes a positive regulatory element. In addition, the deletion resulted in a minor relaxation of Igf2 imprinting in skeletal muscle and tongue. Lastly, the reduction in Igf2 expression in the adult mouse was accompanied by increased fat deposition and occasional obesity. Overweight animals were hypophagic, suggesting that Igf2 affects fat metabolism rather than feeding behavior in adult mice. Although the essential DNA methyltransferases had been discovered, proteins that regulate the sequence-specific establishment and maintenance of allelic methylation had not been identified. One candidate regulator of methylation was the zinc finger protein CTCF, which binds to the ICR of the genes IGF2 and H19. The unmethylated maternal ICR is a chromatin boundary that prevents distant enhancers from activating IGF2. In vitro experiments had suggested that CTCF mediates boundary activity of the maternal ICR, and that methylation of the paternal ICR abolishes this activity by preventing CTCF binding. Using mice with point mutations in all 4 CTCF sites in the ICR, <a href="#23" class="mim-tip-reference" title="Schoenherr, C. J., Levorse, J. M., Tilghman, S. M. <strong>CTCF maintains differential methylation at the Igf2/H19 locus.</strong> Nature Genet. 33: 66-69, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12461525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12461525</a>] [<a href="https://doi.org/10.1038/ng1057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12461525">Schoenherr et al. (2003)</a> showed that maternally transmitted mutant ICRs in neonatal mice acquired a substantial but heterogeneous degree of methylation. Mutant ICRs in oocytes and blastocysts were not methylated, however, indicating that binding of CTCF is not required to establish the unmethylated ICR during oogenesis. The authors also showed that the mutant ICR lacked enhancer-blocking activity, as the expression of IGF2 is activated on mutant maternal chromosomes. Conversely, maternal H19 expression was reduced, suggesting a positive role for CTCF in the transcription of that gene. This was said to be the first in vivo demonstration of the multiple functions of CTCF in an ICR. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12461525+11285246" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Lopes, S., Lewis, A., Hajkova, P., Dean, W., Oswald, J., Forne, T., Murrell, A., Constancia, M., Bartolomei, M., Walter, J., Reik, W. <strong>Epigenetic modifications in an imprinting cluster are controlled by a hierarchy of DMRs suggesting long-range chromatin interactions.</strong> Hum. Molec. Genet. 12: 295-305, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12554683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12554683</a>] [<a href="https://doi.org/10.1093/hmg/ddg022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12554683">Lopes et al. (2003)</a> examined regional control of DNA methylation in the imprinted Igf2-H19 region in the mouse. Paternal germline-specific methylation was reprogrammed after fertilization in 2 DMRs in Igf2, and was reestablished after implantation. Using a number of knockout strains in the region, the authors found that the DMRs themselves were involved in regional coordination in a hierarchical fashion. Thus the H19 DMR was needed on the maternal allele to protect the Igf2 DMRs 1 and 2 from methylation, and Igf2 DMR1 was needed to protect DMR2 from methylation. This regional coordination occurred exclusively after fertilization during somatic development, and did not involve linear spreading of DNA methylation, suggesting a model in which long-range chromatin interactions are involved in regional epigenetic coordination. Parthenogenesis does not naturally occur in mammals because of the need for unequal expression of imprinted genes from the maternal and paternal alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12554683" 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="Cerrato, F., Dean, W., Davies, K., Kagotani, K., Mitsuya, K., Okumara, K., Riccio, A., Reik, W. <strong>Paternal imprints can be established on the maternal Igf2-H19 locus without altering replication timing of DNA.</strong> Hum. Molec. Genet. 12: 3123-3132, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14532328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14532328</a>] [<a href="https://doi.org/10.1093/hmg/ddg338" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14532328">Cerrato et al. (2003)</a> showed that in the mouse mutant 'minute' (Mnt), which carries a 3-Mb inversion with a breakpoint 25 kb distal to the H19 gene, the Igf2-H19 locus acquired a paternal methylation imprint in the maternal germline. DNA methylation of the H19 DMR was established in oogenesis, maintained during postzygotic development on the maternal allele, and erased in primordial germ cells. The fact that a paternal-type methylation imprint can also be established in the maternal germline suggests that trans-acting factors that target methylation to this imprinted region may likely be the same in both germlines. However, asynchrony of DNA replication of the locus was maintained despite the altered expression and methylation imprint of Igf2 and H19. <a href="#3" class="mim-tip-reference" title="Cerrato, F., Dean, W., Davies, K., Kagotani, K., Mitsuya, K., Okumara, K., Riccio, A., Reik, W. <strong>Paternal imprints can be established on the maternal Igf2-H19 locus without altering replication timing of DNA.</strong> Hum. Molec. Genet. 12: 3123-3132, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14532328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14532328</a>] [<a href="https://doi.org/10.1093/hmg/ddg338" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14532328">Cerrato et al. (2003)</a> concluded that replication asynchrony of this region is neither the determinant factor for, nor a consequence of, epigenetic modifications that are critical for genomic imprinting. Replication asynchrony may thus be regulated differently from methylation imprints and have a separate function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14532328" 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>Imprinted expression at the H19/Igf2 locus depends on a differentially methylated domain (DMD) that acts both as a maternal-specific, methylation-sensitive insulator and as a paternal-specific site of hypermethylation. Four repeats in the DMD bind Ctcf on the maternal allele and may attract methylation on the paternal allele. In mice, <a href="#6" class="mim-tip-reference" title="Engel, N., West, A. G., Felsenfeld, G., Bartolomei, M. S. <strong>Antagonism between DNA hypermethylation and enhancer-blocking activity at the H19 DMD is uncovered by CpG mutations.</strong> Nature Genet. 36: 883-888, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15273688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15273688</a>] [<a href="https://doi.org/10.1038/ng1399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15273688">Engel et al. (2004)</a> introduced point mutations into the DMD to deplete the repeats of CpGs while retaining Ctcf-binding and enhancer-blocking activity. Maternal inheritance of the mutations left H19 expression and Igf2 imprinting intact, consistent with the idea that the DMD acts as an insulator. Conversely, paternal inheritance of these mutations disrupted maintenance of DMD methylation, resulting in biallelic H19 expression. Furthermore, an insulator was established on the paternally inherited mutated allele in vivo, reducing Igf2 expression and resulting in a 40% reduction in size of newborn offspring. <a href="#6" class="mim-tip-reference" title="Engel, N., West, A. G., Felsenfeld, G., Bartolomei, M. S. <strong>Antagonism between DNA hypermethylation and enhancer-blocking activity at the H19 DMD is uncovered by CpG mutations.</strong> Nature Genet. 36: 883-888, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15273688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15273688</a>] [<a href="https://doi.org/10.1038/ng1399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15273688">Engel et al. (2004)</a> concluded that the 9 CpG mutations in the DMD showed that the 2 parental-specific roles of the H19 DMD, i.e., methylation maintenance and insulator assembly, are antagonistic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15273688" 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>Imprinted genes are expressed from only 1 of the parental alleles and are marked epigenetically by DNA methylation and histone modifications. The paternally expressed gene Igf2 is separated by approximately 100 kb from the maternally expressed noncoding gene H19 on mouse distal chromosome 7. Differentially methylated regions in Igf2 and H19 contain chromatin boundaries, silencers, and activators, and regulate the reciprocal expression of the 2 genes in a methylation-sensitive manner by allowing them exclusive access to a shared set of enhancers. <a href="#19" class="mim-tip-reference" title="Murrell, A., Heeson, S., Reik, W. <strong>Interaction between differentially methylated regions partitions the imprinted genes Igf2 and H19 into parent-specific chromatin loops.</strong> Nature Genet. 36: 889-893, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15273689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15273689</a>] [<a href="https://doi.org/10.1038/ng1402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15273689">Murrell et al. (2004)</a> used a GAL4 knockin approach as well as the chromosome conformation capture technique to show that the differentially methylated regions in the imprinted genes Igf2 and H19 interact in mice. These interactions are genetically regulated and partition maternal and paternal chromatin into distinct loops. This generates a simple epigenetic switch for Igf2 through which it moves between an active and a silent chromatin domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15273689" 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>Superovulation (ovarian stimulation) is an assisted reproductive technology (ART) for human subfertility/infertility treatment, which has been correlated with increased frequencies of imprinting disorders such as Angelman (<a href="/entry/105830">105830</a>) and Beckwith-Wiedemann syndromes. <a href="#18" class="mim-tip-reference" title="Market-Velker, B. A., Zhang, L., Magri, L. S., Bonvissuto, A. C., Mann, M. R. W. <strong>Dual effects of superovulation: loss of maternal and paternal imprinted methylation in a dose-dependent manner.</strong> Hum. Molec. Genet. 19: 36-51, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19805400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19805400</a>] [<a href="https://doi.org/10.1093/hmg/ddp465" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19805400">Market-Velker et al. (2010)</a> examined the effects of superovulation on genomic imprinting in individual mouse blastocyst stage embryos. Superovulation perturbed genomic imprinting of both maternally and paternally expressed genes. Loss of Snrpn (<a href="/entry/182279">182279</a>) ICR, Peg3 (<a href="/entry/601483">601483</a>) DMR, and Kcnq1ot1 (<a href="/entry/604115">604115</a>) ICR and gain of H19 ICR imprinted methylation were observed. This perturbation was dose-dependent, with aberrant imprinted methylation more frequent at higher hormone dosage. Maternal as well as paternal H19 ICR methylation was perturbed by superovulation. <a href="#18" class="mim-tip-reference" title="Market-Velker, B. A., Zhang, L., Magri, L. S., Bonvissuto, A. C., Mann, M. R. W. <strong>Dual effects of superovulation: loss of maternal and paternal imprinted methylation in a dose-dependent manner.</strong> Hum. Molec. Genet. 19: 36-51, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19805400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19805400</a>] [<a href="https://doi.org/10.1093/hmg/ddp465" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19805400">Market-Velker et al. (2010)</a> postulated that superovulation may have dual effects during oogenesis, disrupting acquisition of imprints in growing oocytes, as well as maternal-effect gene products subsequently required for imprint maintenance during preimplantation development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19805400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Ideraabdullah, F. Y., Thorvaldsen, J. L., Myers, J. A. <strong>Tissue-specific insulator function at H19/Igf2 revealed by deletions at the imprinting control region.</strong> Hum. Molec. Genet. 23: 6246-6259, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24990148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24990148</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24990148[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/ddu344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24990148">Ideraabdullah et al. (2014)</a> created a line of mice with a 1.3-kb deletion at H19/Igf2 ICR1 that removed 2 Ctcf-binding sites and disrupted spacing between the remaining 2 Ctcf-binding sites. The deletion also removed 2 Oct-binding sites, 1 of 4 Zfp57-binding sites, 2 of 3 proposed nucleosome-positioning sites, and 6 nuclear hormone receptor (see <a href="/entry/139139">139139</a>) sites. Despite the differences in ICR1 between mice and humans, maternal inheritance of the 1.3-kb deletion resulted in pups with transitory elevations in whole-body and tongue weights, similar to observations in BWS patients. Maternal inheritance of the deletion also resulted in loss of Igf2 imprinting in tissues of mesodermal origin only, where a significant amount of Ctcf is poly(ADP-ribosyl)ated. Paternal inheritance of the deletion resulted in biallelic H19 expression in all tissues. Despite causing altered parent-of-origin imprinting, the deletion did not disrupt DNA methylation at the remaining H19/Igf2 ICR1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24990148" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="allelicVariants" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<span href="#mimAllelicVariantsFold" id="mimAllelicVariantsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimAllelicVariantsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
|
|
</span>
|
|
<strong>3 Selected Examples</a>):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div id="mimAllelicVariantsFold" class="collapse in mimTextToggleFold">
|
|
<div>
|
|
<a href="/allelicVariants/616186" class="btn btn-default" role="button"> Table View </a>
|
|
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=616186[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
|
|
|
|
</div>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0001" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 BECKWITH-WIEDEMANN SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
ICR1, 1.8-KB DEL
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000149875" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000149875" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000149875</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p><a href="#26" class="mim-tip-reference" title="Sparago, A., Cerrato, F., Vernucci, M., Ferrero, G. B., Silengo, M. C., Riccio, A. <strong>Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome.</strong> Nature Genet. 36: 958-960, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15314640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15314640</a>] [<a href="https://doi.org/10.1038/ng1410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15314640">Sparago et al. (2004)</a> analyzed 7 individuals with Beckwith-Wiedemann syndrome (BWS; <a href="/entry/130650">130650</a>) with H19 hypermethylation for the presence of deletions in the H19 DMR. In 2 individuals, they found an allele with a 1.8-kb deletion. The 2 mutations were very similar, each deleting 2.5 copies of the B repeat and 1 copy of the A repeat and abolishing 2 CTCF binding sites. The sister of 1 patient died prenatally with signs of BWS. Study of DNA from the autopsy specimen showed that she also had inherited the 1.8-kb deletion from her mother. The mutation was found in the mother of these 2 sibs, in the maternal grandfather, and in an uncle and his daughters. In the second family, <a href="#26" class="mim-tip-reference" title="Sparago, A., Cerrato, F., Vernucci, M., Ferrero, G. B., Silengo, M. C., Riccio, A. <strong>Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome.</strong> Nature Genet. 36: 958-960, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15314640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15314640</a>] [<a href="https://doi.org/10.1038/ng1410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15314640">Sparago et al. (2004)</a> found the mutation in the mother, maternal aunt, and maternal grandfather, indicating that the 1.8-kb deletion is associated with the BWS phenotype only when maternally transmitted. The 1.8-kb deletion was not detected in any of 14 individuals with BWS with defects other than H19 methylation or in any of 50 healthy individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15314640" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0002" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 WILMS TUMOR 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
BECKWITH-WIEDEMANN SYNDROME, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
ICR1, 5.3-KB DEL
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000149876 OR RCV000149877" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000149876, RCV000149877" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000149876...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with isolated Wilms tumor (<a href="/entry/194071">194071</a>), <a href="#24" class="mim-tip-reference" title="Scott, R. H., Douglas, J., Baskcomb, L., Huxter, N., Barker, K., Hanks, S., Craft, A., Gerrard, M., Kohler, J. A., Levitt, G. A., Picton, S., Pizer, B., and 10 others. <strong>Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor.</strong> Nature Genet. 40: 1329-1334, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18836444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18836444</a>] [<a href="https://doi.org/10.1038/ng.243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18836444">Scott et al. (2008)</a> identified a 5.3-kb deletion encompassing all but the telomeric 200 bp of the H19 DMR repeat block, resulting in hypermethylation. The mutation deleted 6 of 7 CTCF (<a href="/entry/604167">604167</a>) target sites. The mutation was inherited from the unaffected mother. A sib with overgrowth features of Beckwith-Wiedemann syndrome (<a href="/entry/130650">130650</a>) also carried the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18836444" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0003" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 WILMS TUMOR 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
ICR1, 1.43-KB TRIPLICATION
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000149878" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000149878" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000149878</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 members of a family with isolated Wilms tumor (<a href="/entry/194071">194071</a>), <a href="#24" class="mim-tip-reference" title="Scott, R. H., Douglas, J., Baskcomb, L., Huxter, N., Barker, K., Hanks, S., Craft, A., Gerrard, M., Kohler, J. A., Levitt, G. A., Picton, S., Pizer, B., and 10 others. <strong>Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor.</strong> Nature Genet. 40: 1329-1334, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18836444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18836444</a>] [<a href="https://doi.org/10.1038/ng.243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18836444">Scott et al. (2008)</a> identified a 1.43-kb triplication in the H19 DMR, resulting in hypermethylation. The mutation was inherited from the unaffected maternal grandmother. The triplication appeared as a 2.9-kb microinsertion and did not disrupt predicted CTCF (<a href="/entry/604167">604167</a>) target sites, but inserted 2 predicted CTCF target sites between the 2 H19 DMR repeat blocks. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18836444" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="references"class="mim-anchor"></a>
|
|
<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span class="mim-font">
|
|
<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div id="mimReferencesFold" class="collapse in mimTextToggleFold">
|
|
<ol>
|
|
|
|
<li>
|
|
<a id="1" class="mim-anchor"></a>
|
|
<a id="Bartholdi2009" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Bartholdi, D., Krajewska-Walasek, M., Ounap, K., Gaspar, H., Chrzanowska, K. H., Ilyana, H., Kayserili, H., Lurie, I. W., Schinzel, A., Baumer, A.
|
|
<strong>Epigenetic mutations of the imprinted IGF2-H19 domain in Silver-Russell syndrome (SRS): results from a large cohort of patients with SRS and SRS-like phenotypes. (Letter)</strong>
|
|
J. Med. Genet. 46: 192-197, 2009.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19066168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19066168</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19066168" 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.2008.061820" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="2" class="mim-anchor"></a>
|
|
<a id="Bell2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Bell, A. C., Felsenfeld, G.
|
|
<strong>Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene.</strong>
|
|
Nature 405: 482-485, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839546</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10839546" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/35013100" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="3" class="mim-anchor"></a>
|
|
<a id="Cerrato2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Cerrato, F., Dean, W., Davies, K., Kagotani, K., Mitsuya, K., Okumara, K., Riccio, A., Reik, W.
|
|
<strong>Paternal imprints can be established on the maternal Igf2-H19 locus without altering replication timing of DNA.</strong>
|
|
Hum. Molec. Genet. 12: 3123-3132, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14532328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14532328</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14532328" 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/ddg338" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="4" class="mim-anchor"></a>
|
|
<a id="Demars2010" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Demars, J., Shmela, M. E., Rossignol, S., Okabe, J., Netchine, I., Azzi, S., Cabrol, S., Le Caignec, C., David, A., Le Bouc, Y., El-Osta, A., Gicquel, C.
|
|
<strong>Analysis of the IGF2/H19 imprinting control region uncovers new genetic defects, including mutations of OCT-binding sequences, in patients with 11p15 fetal growth disorders.</strong>
|
|
Hum. Molec. Genet. 19: 803-814, 2010.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20007505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20007505</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20007505" 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/ddp549" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="5" class="mim-anchor"></a>
|
|
<a id="Du2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Du, M., Beatty, L. G., Zhou, W., Lew, J., Schoenherr, C., Weksberg, R., Sadowski, P. D.
|
|
<strong>Insulator and silencer sequences in the imprinted region of human chromosome 11p15.5.</strong>
|
|
Hum. Molec. Genet. 12: 1927-1939, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12874112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12874112</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12874112" 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/ddg194" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="6" class="mim-anchor"></a>
|
|
<a id="Engel2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Engel, N., West, A. G., Felsenfeld, G., Bartolomei, M. S.
|
|
<strong>Antagonism between DNA hypermethylation and enhancer-blocking activity at the H19 DMD is uncovered by CpG mutations.</strong>
|
|
Nature Genet. 36: 883-888, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15273688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15273688</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15273688" 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/ng1399" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="7" class="mim-anchor"></a>
|
|
<a id="Fedoriw2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Fedoriw, A. M., Stein, P., Svoboda, P., Schultz, R. M., Bartolomei, M. S.
|
|
<strong>Transgenic RNAi reveals essential function for CTCF in H19 gene imprinting.</strong>
|
|
Science 303: 238-240, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14716017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14716017</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14716017" 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.1090934" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="8" class="mim-anchor"></a>
|
|
<a id="Gicquel2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Gicquel, C., Rossignol, S., Cabrol, S., Houang, M., Steunou, V., Barbu, V., Danton, F., Thibaud, N., Le Merrer, M., Burglen, L., Bertrand, A.-M., Netchine, I., Le Bouc, Y.
|
|
<strong>Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome.</strong>
|
|
Nature Genet. 37: 1003-1007, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16086014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16086014</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16086014" 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/ng1629" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="9" class="mim-anchor"></a>
|
|
<a id="Hark2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Hark, A. T., Schoenherr, C. J., Katz, D. J., Ingram, R. S., Levrose, J. M., Tilghman, S. M.
|
|
<strong>CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus.</strong>
|
|
Nature 405: 486-489, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839547</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10839547" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/35013106" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="10" class="mim-anchor"></a>
|
|
<a id="Hark1998" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Hark, A. T., Tilghman, S. M.
|
|
<strong>Chromatin conformation of the H19 epigenetic mark.</strong>
|
|
Hum. Molec. Genet. 7: 1979-1985, 1998.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9811943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9811943</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9811943" 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/7.12.1979" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="11" class="mim-anchor"></a>
|
|
<a id="Higashimoto2014" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Higashimoto, K., Jozaki, K., Kosho, T., Matsubara, K., Fuke, T., Yamada, D., Yatsuki, H., Maeda, T., Ohtsuka, Y., Nishioka, K., Joh, K., Koseki, H., Ogata, T., Soejima, H.
|
|
<strong>A novel de novo point mutation of the OCT-binding site in the IGF2/H19-imprinting control region in a Beckwith-Wiedemann syndrome patient.</strong>
|
|
Clin. Genet. 86: 539-544, 2014.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24299031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24299031</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24299031" 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/cge.12318" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="12" class="mim-anchor"></a>
|
|
<a id="Ideraabdullah2014" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Ideraabdullah, F. Y., Thorvaldsen, J. L., Myers, J. A.
|
|
<strong>Tissue-specific insulator function at H19/Igf2 revealed by deletions at the imprinting control region.</strong>
|
|
Hum. Molec. Genet. 23: 6246-6259, 2014.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24990148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24990148</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24990148[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=24990148" 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/ddu344" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="13" class="mim-anchor"></a>
|
|
<a id="Jones2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Jones, B. K., Levorse, J., Tilghman, S. M.
|
|
<strong>Deletion of a nuclease-sensitive region between the Igf2 and H19 genes leads to Igf2 misregulation and increased adiposity.</strong>
|
|
Hum. Molec. Genet. 10: 807-814, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11285246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11285246</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11285246" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/10.8.807" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="14" class="mim-anchor"></a>
|
|
<a id="Keniry2012" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Keniry, A., Oxley, D., Monnier, P., Kyba, M., Dandolo, L., Smits, G., Reik, W.
|
|
<strong>The H19 lincRNA is a developmental reservoir of miR-675 that suppresses growth and Igf1r.</strong>
|
|
Nature Cell Biol. 14: 659-665, 2012.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22684254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22684254</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22684254[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=22684254" 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/ncb2521" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="15" class="mim-anchor"></a>
|
|
<a id="Leighton1995" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Leighton, P. A., Ingram, R. S., Eggenschwiler, J., Efstratiadis, A., Tilghman, S. M.
|
|
<strong>Disruption of imprinting caused by deletion of the H19 gene region in mice.</strong>
|
|
Nature 375: 34-39, 1995.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7536897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7536897</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7536897" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/375034a0" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="16" class="mim-anchor"></a>
|
|
<a id="Ling2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Ling, J. Q., Li, T., Hu, J. F., Vu, T. H., Chen, H. L., Qiu, X. W., Cherry, A. M., Hoffman, A. R.
|
|
<strong>CTCF mediates interchromosomal colocalization between Igf2/H19 and Wsb1/Nf1.</strong>
|
|
Science 312: 269-272, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16614224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16614224</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16614224" 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.1123191" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="17" class="mim-anchor"></a>
|
|
<a id="Lopes2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Lopes, S., Lewis, A., Hajkova, P., Dean, W., Oswald, J., Forne, T., Murrell, A., Constancia, M., Bartolomei, M., Walter, J., Reik, W.
|
|
<strong>Epigenetic modifications in an imprinting cluster are controlled by a hierarchy of DMRs suggesting long-range chromatin interactions.</strong>
|
|
Hum. Molec. Genet. 12: 295-305, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12554683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12554683</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12554683" 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/ddg022" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="18" class="mim-anchor"></a>
|
|
<a id="Market-Velker2010" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Market-Velker, B. A., Zhang, L., Magri, L. S., Bonvissuto, A. C., Mann, M. R. W.
|
|
<strong>Dual effects of superovulation: loss of maternal and paternal imprinted methylation in a dose-dependent manner.</strong>
|
|
Hum. Molec. Genet. 19: 36-51, 2010.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19805400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19805400</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19805400" 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/ddp465" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="19" class="mim-anchor"></a>
|
|
<a id="Murrell2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Murrell, A., Heeson, S., Reik, W.
|
|
<strong>Interaction between differentially methylated regions partitions the imprinted genes Igf2 and H19 into parent-specific chromatin loops.</strong>
|
|
Nature Genet. 36: 889-893, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15273689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15273689</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15273689" 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/ng1402" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="20" class="mim-anchor"></a>
|
|
<a id="Poole2012" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Poole, R. L., Leith, D. J., Docherty, L. E., Shmela, M. E., Gicquel, C., Splitt, M., Temple, I. K., Mackay, D. J. G.
|
|
<strong>Beckwith-Wiedemann syndrome caused by maternally inherited mutation of an OCT-binding motif in the IGF2/H19-imprinting control region, ICR1.</strong>
|
|
Europ. J. Hum. Genet. 20: 240-243, 2012.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21863054/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21863054</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21863054" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/ejhg.2011.166" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="21" class="mim-anchor"></a>
|
|
<a id="Prawitt2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Prawitt, D., Enklaar, T., Gartner-Rupprecht, B., Spangenberg, C., Oswald, M., Lausch, E., Schmidtke, P., Reutzel, D., Fees, S., Lucito, R., Korzon, M., Brozek, I., Limon, J., Housman, D. E., Pelletier, J., Zabel, B.
|
|
<strong>Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms' tumor.</strong>
|
|
Proc. Nat. Acad. Sci. 102: 4085-4090, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15743916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15743916</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15743916[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=15743916" 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.0500037102" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="22" class="mim-anchor"></a>
|
|
<a id="Sandovici2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Sandovici, I., Leppert, M., Hawk, P. R., Suarez, A., Linares, Y., Sapienza, C.
|
|
<strong>Familial aggregation of abnormal methylation of parental alleles at the IGF2/H19 and IGF2R differentially methylated regions.</strong>
|
|
Hum. Molec. Genet. 12: 1569-1578, 2003. Note: Erratum: Hum. Molec. Genet. 13: 781 only, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12812984/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12812984</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12812984" 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/ddg167" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="23" class="mim-anchor"></a>
|
|
<a id="Schoenherr2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Schoenherr, C. J., Levorse, J. M., Tilghman, S. M.
|
|
<strong>CTCF maintains differential methylation at the Igf2/H19 locus.</strong>
|
|
Nature Genet. 33: 66-69, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12461525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12461525</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12461525" 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/ng1057" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="24" class="mim-anchor"></a>
|
|
<a id="Scott2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Scott, R. H., Douglas, J., Baskcomb, L., Huxter, N., Barker, K., Hanks, S., Craft, A., Gerrard, M., Kohler, J. A., Levitt, G. A., Picton, S., Pizer, B., and 10 others.
|
|
<strong>Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor.</strong>
|
|
Nature Genet. 40: 1329-1334, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18836444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18836444</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18836444" 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.243" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="25" class="mim-anchor"></a>
|
|
<a id="Smits2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Smits, G., Mungall, A. J., Griffiths-Jones, S., Smith, P., Beury, D., Matthews, L., Rogers, J., Pask, A. J., Shaw, G., VandeBerg, J. L., McCarrey, J. R., SAVOIR Consortium, Renfree, M. B., Reik, W., Dunham, I.
|
|
<strong>Conservation of the H19 noncoding RNA and H19-IGF2 imprinting mechanism in therians.</strong>
|
|
Nature Genet. 40: 971-976, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18587395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18587395</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18587395" 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.168" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="26" class="mim-anchor"></a>
|
|
<a id="Sparago2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Sparago, A., Cerrato, F., Vernucci, M., Ferrero, G. B., Silengo, M. C., Riccio, A.
|
|
<strong>Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome.</strong>
|
|
Nature Genet. 36: 958-960, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15314640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15314640</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15314640" 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/ng1410" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="27" class="mim-anchor"></a>
|
|
<a id="Srivastava2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Srivastava, M., Hsieh, S., Grinberg, A., Williams-Simons, L., Huang, S.-P., Pfeifer, K.
|
|
<strong>H19 and Igf2 monoallelic expression is regulated in two distinct ways by a shared cis acting regulatory region upstream of H19.</strong>
|
|
Genes Dev. 14: 1186-1195, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10817754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10817754</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10817754[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=10817754" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="28" class="mim-anchor"></a>
|
|
<a id="Takai2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Takai, D., Gonzales, F. A., Tsai, Y. C., Thayer, M. J., Jones, P. A.
|
|
<strong>Large scale mapping of methylcytosines in CTCF-binding sites in the human H19 promoter and aberrant hypomethylation in human bladder cancer.</strong>
|
|
Hum. Molec. Genet. 10: 2619-2626, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11726548/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11726548</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11726548" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/10.23.2619" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="29" class="mim-anchor"></a>
|
|
<a id="Thorvaldsen1998" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Thorvaldsen, J. L., Duran, K. L., Bartolomei, M. S.
|
|
<strong>Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2.</strong>
|
|
Genes Dev. 12: 3693-3702, 1998.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9851976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9851976</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9851976[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=9851976" 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/gad.12.23.3693" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="30" class="mim-anchor"></a>
|
|
<a id="Ulaner2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Ulaner, G. A., Vu, T. H., Li, T., Hu, J.-F., Yao, X.-M., Yang, Y., Gorlick, R., Meyers, P., Healey, J., Ladanyi, M., Hoffman, A. R.
|
|
<strong>Loss of imprinting of IGF2 and H19 in osteosarcoma is accompanied by reciprocal methylation changes of a CTCF-binding site.</strong>
|
|
Hum. Molec. Genet. 12: 535-549, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12588801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12588801</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12588801" 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/ddg034" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="31" class="mim-anchor"></a>
|
|
<a id="Venkatraman2013" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Venkatraman, A., He, X. C., Thorvaldsen, J. L., Sugimura, R., Perry, J. M., Tao, F., Zhao, M., Christenson, M. K., Sanchez, R., Yu, J. Y., Peng, L., Haug, J. S., Paulson, A., Li, H., Zhong, X., Clemens, T. L., Bartolomei, M. S., Li, L.
|
|
<strong>Maternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence.</strong>
|
|
Nature 500: 345-349, 2013.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23863936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23863936</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23863936[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=23863936" 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/nature12303" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="32" class="mim-anchor"></a>
|
|
<a id="Vernucci2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Vernucci, M., Cerrato, F., Pedone, P. V., Dandolo, L., Bruni, C. B., Riccio, A.
|
|
<strong>Developmentally regulated functions of the H19 differentially methylated domain.</strong>
|
|
Hum. Molec. Genet. 13: 353-361, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14681296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14681296</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14681296" 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/ddh028" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="33" class="mim-anchor"></a>
|
|
<a id="Webber1998" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Webber, A., Ingram, R. S., Levorse, J. M., Tilghman, S. M.
|
|
<strong>Location of enhancers is essential for imprinting of H19 and Igf2 genes.</strong>
|
|
Nature 391: 711-715, 1998.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9490417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9490417</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9490417" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/35655" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="34" class="mim-anchor"></a>
|
|
<a id="Zemel1992" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Zemel, S., Bartolomei, M. S., Tilghman, S. M.
|
|
<strong>Physical linkage of two mammalian imprinted genes, H19 and insulin-like growth factor 2.</strong>
|
|
Nature Genet. 2: 61-65, 1992.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1303252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1303252</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1303252" 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/ng0992-61" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="35" class="mim-anchor"></a>
|
|
<a id="Zhao2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Zhao, Z., Tavoosidana, G., Sjolinder, M., Gondor, A., Mariano, P., Wang, S., Kanduri, C., Lezcano, M., Sandhu, K. S., Singh, U., Pant, V., Tiwari, V., Kurukuti, S., Ohlsson, R.
|
|
<strong>Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra- and interchromosomal interactions.</strong>
|
|
Nature Genet. 38: 1341-1347, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17033624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17033624</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17033624" 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/ng1891" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
</ol>
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="contributors" class="mim-anchor"></a>
|
|
|
|
<div class="row">
|
|
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
|
<span class="mim-text-font">
|
|
Contributors:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Patricia A. Hartz - updated : 1/16/2015
|
|
</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">
|
|
Matthew B. Gross : 1/13/2015
|
|
</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">
|
|
mgross : 01/27/2015
|
|
</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">
|
|
mgross : 1/20/2015<br>mcolton : 1/16/2015<br>mgross : 1/15/2015
|
|
</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> 616186
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
H19/IGF2-IMPRINTING CONTROL REGION
|
|
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div >
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
ICR1<br />
|
|
H19 ICR
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
|
|
<strong>SNOMEDCT:</strong> 81780002;
|
|
|
|
|
|
<strong>ICD10CM:</strong> Q87.3;
|
|
|
|
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 11p15.5
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 11:1,998,202-2,003,509 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
11p15.5
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Beckwith-Wiedemann syndrome
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
130650
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Silver-Russell syndrome 1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
180860
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Wilms tumor 2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
194071
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant; Somatic mutation
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Chromosome 11p15 contains 2 neighboring imprinted domains, one associated with the H19 (103280) and IGF2 (147470) genes, and the other associated with the KCNQ1 gene (607542). Each domain is controlled by its own imprinting control region, designated ICR1 or ICR2 (see 607542), respectively. ICR1, which is located just upstream of the H19 gene, regulates imprinted expression of the maternally expressed noncoding RNA H19 and the paternally expressed gene IGF2, which encodes a growth factor. ICR1 is a differentially methylated region (DMR) that is methylated exclusively on the paternal allele. On the maternal allele, unmethylated ICR1 bound by CTCF (604167) forms a chromatin insulator that prevents IGF2 promoter activation by the enhancer downstream of H19, resulting in silencing of IGF2 and activation of H19. On the paternal allele, methylation-sensitive CTCF cannot bind to methylated ICR1, resulting in activation of IGF2 and silencing of H19. CTCF also maintains the unmethylated status of ICR1 on the maternal allele (summary by Higashimoto et al., 2014). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Higashimoto et al. (2014) noted that ICR1 contains 2 different repetitive sequences (A and B) and 7 CTCF-binding sites. It also contains binding motifs for OCT (see 164175), SOX (see 602148), and ZFP57 (612192). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>ICR1 is located just upstream of the H19 gene on chromosome 11p15.5. The H19 gene is telomeric to ICR1, and the IGF2 gene is centromeric to ICR1 (Higashimoto et al., 2014). This genomic arrangement is conserved on mouse chromosome 7 (Zemel et al., 1992). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>In mouse, the imprinted H19 gene lies at the end of a cluster of imprinted genes. Leighton et al. (1995) found that imprinting of the insulin-2 (Ins2; see 176730) gene and the Igf2 gene, which lie about 100 kb upstream of H19, can be disrupted by maternal inheritance of a targeted deletion of the H19 gene and its flanking sequence. Animals inheriting the H19 mutation from their mothers were 27% heavier than those inheriting from their fathers. Paternal inheritance of the disruption had no effect, which presumably reflects the normally silent state of the paternal gene. The somatic overgrowth of heterozygotes for the maternal deletion was attributed to a gain-of-function of the Igf2 gene rather than a loss of function of H19. </p><p>The expression of the IGF2 and H19 genes is imprinted. Although these neighboring genes share an enhancer, H19 is expressed only from the maternal allele, and IGF2 only from the paternally inherited allele. The region of paternal-specific methylation upstream of H19 appears to be the site of an epigenetic mark that is required for the imprinting of these genes. A deletion within this region results in loss of imprinting of both H19 and IGF2 (Thorvaldsen et al., 1998). Bell and Felsenfeld (2000) showed that this methylated region contains an element that blocks enhancer activity. The activity of this element is dependent upon the vertebrate enhancer-blocking protein CTCF (604167). Methylation of CpGs within the CTCF binding sites eliminates binding of CTCF in vitro, and deletion of these sites results in loss of enhancer-blocking activity in vivo, thereby allowing gene expression. This CTCF-dependent enhancer-blocking element acts as an insulator. Bell and Felsenfeld (2000) suggested that it controls imprinting of IGF2. The activity of this insulator is restricted to the maternal allele by specific DNA methylation of the paternal allele. Bell and Felsenfeld (2000) concluded that DNA methylation can control gene expression by modulating enhancer access to the gene promoter through regulation of an enhancer boundary. </p><p>The unmethylated ICR acts as a chromatin boundary that blocks the interaction of IGF2 with enhancers that lie 3-prime of H19 (Webber et al., 1998; Hark and Tilghman, 1998). This enhancer-blocking activity would then be lost when the region was methylated, thereby allowing expression of IGF2 paternally. Using transgenic mice and tissue culture, Hark et al. (2000) demonstrated that the unmethylated ICRs from mouse and human H19 exhibit enhancer-blocking activity. They showed that CTCF binds to several sites in the unmethylated ICR that are essential for enhancer blocking. Consistent with this model, CTCF binding is abolished by DNA methylation. Within the human ICR, there is a CpG-rich 45-bp sequence in B repeats that is 60% identical to 2 sites in the hypersensitive region HS1 and 3 sites in HS2. Within this is a 14-bp core that has a high degree of similarity to a binding site for CTCF (FII) within the chicken beta-globin insulator. Hark et al. (2000) demonstrated that DNA methylation inhibited binding of CTCF to human B1 sites and showed that CTCF sites are not symmetric, and that the protein makes important contacts with some of the cytosine residues on the top DNA strand. </p><p>Srivastava et al. (2000) used a loxP/cre recombinase-based strategy to delete the ICR upstream of H19 in mice in a conditional manner to determine the temporal requirement of the upstream region in initiating and maintaining the imprinted expression of H19 and Igf2. Analysis of allele-specific expression of H19 and Igf2 and DNA methylation at the H19 promoter demonstrated that this region controls the monoallelic expression of the 2 genes in different ways, suggesting that it harbors 2 functionally distinct regulatory elements. Continued presence of the region is required to silence maternal Igf2 in accordance with its proposed role as an insulator. However, it does not have a direct role in keeping the paternal H19 promoter silenced. Instead, on the paternal chromosome, the upstream element mediates epigenetic modifications of the H19 promoter region during development, leading to transcriptional silencing of H19. Thereafter, its presence is redundant for preventing transcription. This temporal requirement of the silencing element appears to be a unique cis activity in the mammalian system. However, it is likely that other cis-acting elements, positive and negative, have the ability to effect stable changes in the chromatin structure and are not constantly required to give signals to the transcriptional machinery. </p><p>Takai et al. (2001) found that all the CTCF-binding sites in H19 except for the sixth were hypermethylated, whereas only the sixth binding site showed allele-specific methylation in normal human embryonic ureteral tissue. In human-mouse somatic-cell-hybrid clones containing a single copy of human chromosome 11, they observed a correlation between methylation of the sixth CTCF-binding site and expression of IGF2. The authors also reported hypomethylation of the paternal allele in 2 of 6 informative cases of human bladder cancer. The authors proposed that only the sixth CTCF-binding site may act as a key regulatory domain for switching between H19 or IGF2 expression. </p><p>Du et al. (2003) confirmed the existence of insulators in the H19 DMR and reported 2 insulators in the IGF2 gene. The authors demonstrated binding of CTCF to all the insulator sequences detected. </p><p>Ulaner et al. (2003) showed that osteosarcoma tumors with IGF2/H19 maintenance of imprinting (MOI) exhibited allele-specific differential methylation of a CTCF-binding site upstream of H19. Loss of imprinting (LOI) of IGF2 or H19 in osteosarcoma occurred in a mutually exclusive manner and occurred with monoallelic expression of the other gene. Bisulfite sequencing revealed that IGF2 LOI occurred with biallelic CpG methylation of the CTCF-binding site, while H19 LOI occurred with biallelic hypomethylation of this site. The authors proposed a model in which incomplete gain or loss of methylation at this CTCF-binding site during tumorigenesis may explain the complex and often conflicting expression patterns of IGF2 and H19 in tumors. </p><p>Sandovici et al. (2003) examined allelic methylation ratios at DMRs within the IGF2/H19 and IGF2R loci in a panel of 48 three-generation families. There was familial clustering of individuals with abnormal methylation ratios at the IGF2/H19 DMR, as well as stability of this trait over a period of nearly 2 decades, consistent with the possibility that constitutional LOI at this locus may be due largely to genetic factors. At the IGF2R DMR, more variability in the allelic methylation ratios was observed over time, but there was also familial clustering of abnormal methylation ratios. Sandovici et al. (2003) concluded that shared genetic factors may be responsible for a major fraction of interindividual variability in parental origin-dependent epigenetic modifications; however, temporal changes also occur in isolated cases, as well as within multiple individuals in the same family, indicating that environmental factors may also play a role. </p><p>Fedoriw et al. (2004) used a transgenic RNA interference-based approach to generate oocytes with reduced amounts of CTCF protein, and found increased methylation of the H19 differentially methylated domain and decreased developmental competence of CTCF-deficient oocytes. Fedoriw et al. (2004) concluded that CTCF protects H19 differentially methylated domain from de novo methylation during oocyte growth and is required for normal preimplantation development. </p><p>By analyzing 3 deletions of the H19 locus, Vernucci et al. (2004) investigated the mechanism regulating imprinted expression of the Igf2 gene during liver tumorigenesis in mouse embryos. The role of the H19 DMR in controlling Igf2 expression changed during tumorigenesis. The H19 DMR was required on the paternal chromosome for Igf2 activation in the early stages, while its maternal allele was necessary for maintaining Igf2 imprinting only in the late stages. A positive regulatory function for paternal H19 DMR was also evident in normal neonatal liver, but its relevance for Igf2 expression became higher in the second postnatal week. Vernucci et al. (2004) proposed a model in which both methylated and nonmethylated parental copies of the H19 DMR have active roles in regulating Igf2 expression in the liver, and these activities are under developmental control. </p><p>It is believed that chromosomes interact with each other to regulate transcription in trans. To explore systematically the epigenetic dimension of such interactions, Zhao et al. (2006) devised a strategy termed circular chromosome conformation capture (4C). This approach enabled high-throughput screening of physical interactions between chromosomes without a preconceived idea of the interacting partners. The authors identified 114 unique sequences from all autosomes, several of which interact primarily with the maternally inherited H19 imprinting control region. Imprinted domains were strongly overrepresented in the library of 4C sequences, further highlighting the epigenetic nature of these interactions. Moreover, Zhao et al. (2006) found that the direct interaction between differentially methylated regions was linked to epigenetic regulation of transcription in trans. They found that the patterns of interactions specific to the maternal H19 imprinting control region underwent reprogramming during in vitro maturation of embryonic stem cells. </p><p>Gene transcription may be regulated by remote enhancer or insulator regions through chromosome looping. Using a modification of chromosome conformation capture and fluorescence in situ hybridization, Ling et al. (2006) found that 1 allele of the Igf2/H19 ICR on mouse chromosome 7 colocalized with 1 allele of Wsb1 (610091)/Nf1 (613113) on chromosome 11. Omission of Ctcf or deletion of the maternal ICR abrogated this association and altered Wsb1/Nf1 gene expression. Ling et al. (2006) concluded that their findings demonstrated that CTCF mediates an interchromosomal association, perhaps by directing distant DNA segments to a common transcription factory, and the data provided a model for long-range allele-specific associations between gene regions on different chromosomes that suggested a framework for DNA recombination and RNA trans-splicing. </p><p>Venkatraman et al. (2013) demonstrated upregulation of growth-restricting imprinted genes, including in the H19-Igf2 locus, in long-term hematopoietic stem cells and their downregulation upon hematopoietic stem cell activation and proliferation. The H19 DMR, serving as the imprinting control region, determines the reciprocal expression of H19 from the maternal allele and Igf2 from the paternal allele. In addition, H19 serves as a source of miR675, which restricts Igf1r expression (Keniry et al., 2012). Venkatraman et al. (2013) demonstrated that conditional deletion of the maternal but not the paternal H19 DMR reduced adult hematopoietic stem cell quiescence, a state required for long-term maintenance of hematopoietic stem cells, and compromised hematopoietic stem cell function. Maternal-specific H19 DMR deletion resulted in activation of the Igf2-Igfr1 pathway, as shown by the translocation of phosphorylated FoxO3 (602681), an inactive form, from nucleus to cytoplasm and the release of FoxO3-mediated cell cycle arrest, thus leading to increased activation, proliferation, and eventual exhaustion of hematopoietic stem cells. Mechanistically, maternal-specific H19 DMR deletion led to Igf2 upregulation and increased translation of Igf1r, which is normally suppressed by H19-derived miR675. Similarly, genetic inactivation of Igf1r partly rescued the H19 DMR deletion phenotype. Venkatraman et al. (2013) concluded that their work established a role for this form of epigenetic control at the H19-IGF2 locus in maintaining adult stem cells. </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>Beckwith-Wiedemann Syndrome</em></strong></p><p>
|
|
In mice, a targeted deletion showed that imprinting of the paternally expressed Igf2 and maternally expressed H19 genes is controlled by a 2-kb DMR located 5-prime of H19 (Thorvaldsen et al., 1998). The H19 DMR sequence in human differs from the homologous mouse region in that it is organized into 2 repeat units, each consisting of 2 types of direct repeats, and containing 7 potential binding sites for CTCF. Sparago et al. (2004) analyzed 7 individuals with Beckwith-Wiedemann syndrome (BWS; 130650) and H19 hypermethylation for the presence of deletions in the H19 DMR and showed that inherited microdeletions in the H19 DMR that abolished 2 CTCF target sites caused this disorder. Maternal transmission of the deletions resulted in hypermethylation of the H19 DMR, biallelic IGF2 expression, H19 silencing, and BWS syndrome, indicative of loss of function of the IGF2/H19 ICR. In 3 sibs with BWS and Wilms tumor and 2 unaffected sibs from a 3-generation family, Prawitt et al. (2005) identified a 2.2-kbp microdeletion in the H19/IGF2 ICR1 that abolished 3 CTCF target sites. Maternal inheritance of the deletion was associated with IGF2 loss of imprinting and upregulation of IGF2 mRNA. However, in at least 1 affected family member a second lesion was identified, duplication of maternal 11p15, which was accompanied by a further increase in IGF2 mRNA levels (35-fold higher than control values). Prawitt et al. (2005) suggested that the combined effects of the BWS ICR1 microdeletion and 11p15 duplication were necessary for the manifestation of BWS in this family. </p><p>Demars et al. (2010) investigated the CTCF gene and the ICR1 domain in 21 BWS patients with ICR1 gain of methylation and 16 SRS patients with ICR1 loss of methylation. There were 4 constitutional ICR1 genetic defects in BWS patients, including a familial case. Three of those defects were imprinting defects consisting of small deletions and a single mutation, which did not involve one of the CTCF binding sites. Moreover, 2 of those defects affected OCT (PLXNA2; 601054)-binding sequences, which may normally maintain the unmethylated state of the maternal allele. A single-nucleotide variation was identified in a SRS patient. </p><p>In 2 brothers with BWS, Poole et al. (2012) identified a heterozygous A-to-C transversion in the A2 repeat of ICR1 that was demonstrated to alter the binding of nuclear factors, most likely OCT4 (POU5F1; 164177). The mutation was inherited from the unaffected mother, who carried it on the paternal allele. The patients had hypermethylation of the ICR1 region. DNA sequencing of 9 additional patients with BWS and H19 hypermethylation did not identify mutations in the H19 ICR or promoter region. </p><p><strong><em>Silver-Russell Syndrome</em></strong></p><p>
|
|
Given the crucial role of the 11p15 imprinted region in the control of fetal growth, Gicquel et al. (2005) hypothesized that dysregulation of genes at 11p15 might be involved in syndromic intrauterine growth retardation. In the telomeric imprinting center region (ICR1) of the 11p15 region in several individuals with clinically typical Silver-Russell syndrome, they identified an epimutation (demethylation). The epigenetic defect was associated with, and probably responsible for, relaxation of imprinting and biallelic expression of H19 and downregulation of IGF2. These findings provided new insight into the pathogenesis of SRS and strongly suggested that the 11p15 imprinted region, in addition to the imprinted region of 7p13-p11.2 and 7q31-qter, is involved in SRS. The loss of paternal methylation in individuals with SRS may have resulted from a deficient acquisition of methylation during spermatogenesis or from a lack of maintenance of methylation after fertilization. The 5 individuals with SRS that carried the epimutation had only a partial loss of methylation, and 4 of them had body asymmetry. These data suggested that the loss of methylation occurred after fertilization and resulted in a mosaic distribution of the epimutation. </p><p>Bartholdi et al. (2009) observed hypomethylation at ICR1 on chromosome 11p15 in 41 (38.5%) of 106 patients with Silver-Russell syndrome (SRS; 180860). The majority of patients showed hypomethylation of both the H19 DMR and IGF2, but 10 showed selective hypomethylation of the H19 DMR, and 2 showed selective hypomethylation of IGF2. </p><p><strong><em>Wilms Tumor</em></strong></p><p>
|
|
Scott et al. (2008) identified constitutional abnormalities at chromosome 11p15 in 13 (3%) of 437 individuals with sporadic Wilms tumor without features of overgrowth syndromes (WT2; 194071). Six patients had paternal uniparental disomy of 11p15 and 6 had hypermethylation at the H19 DMR. There were 2 familial cases. In 1 family, 2 sibs had a microdeletion of the H19 DMR (103280.0002) that was inherited from the unaffected mother; 1 sib had isolated Wilms tumor and the other had features of BWS. In a second family, a mother and 2 daughters had a microinsertion in the H19 DMR (103280.0003), inherited from the unaffected grandmother. No abnormalities were detected in 220 controls. Analysis of tumor tissue showed that the level of H19 DMR hypermethylation was greater in tumor compared to lymphocytes, suggesting that the tumors developed by clonal expansion of cells harboring the 11p15 defect. There was no evidence of additional tumor-specific 11p15 abnormalities affecting the wildtype allele. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Evolution</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Comparisons between eutherians and marsupials have suggested limited conservation of the molecular mechanisms that control genomic imprinting in mammals. Smits et al. (2008) studied the evolution of the imprinted IGF2 (147470)-H19 locus in therians. Although marsupial orthologs of protein-coding exons were easily identified, the use of evolutionarily conserved regions and low-stringency Bl2seq comparisons was required to delineate a candidate H19 noncoding RNA sequence. The therian H19 orthologs showed miR675 and exon structure conservation, suggesting functional selection on both features. Transcription start site sequences and poly(A) signals are also conserved. As in eutherians, marsupial H19 is maternally expressed and paternal methylation upstream of the gene originates in the male germline, encompasses a CTCF (604167) insulator, and spreads somatically into the H19 gene. Smits et al. (2008) concluded that the conservation in all therians of the mechanism controlling imprinting of the IGF2-H19 locus suggests a sequential model of imprinting evolution. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Jones et al. (2001) described a 12-kb deletion of a region 5-prime of the ICR that was hypersensitive to nuclease digestion in chromatin. Its deletion resulted in a biallelic decrease in expression of Igf2, but not H19, in the brains of transgenic mice, consistent with the hypothesis that it encodes a positive regulatory element. In addition, the deletion resulted in a minor relaxation of Igf2 imprinting in skeletal muscle and tongue. Lastly, the reduction in Igf2 expression in the adult mouse was accompanied by increased fat deposition and occasional obesity. Overweight animals were hypophagic, suggesting that Igf2 affects fat metabolism rather than feeding behavior in adult mice. Although the essential DNA methyltransferases had been discovered, proteins that regulate the sequence-specific establishment and maintenance of allelic methylation had not been identified. One candidate regulator of methylation was the zinc finger protein CTCF, which binds to the ICR of the genes IGF2 and H19. The unmethylated maternal ICR is a chromatin boundary that prevents distant enhancers from activating IGF2. In vitro experiments had suggested that CTCF mediates boundary activity of the maternal ICR, and that methylation of the paternal ICR abolishes this activity by preventing CTCF binding. Using mice with point mutations in all 4 CTCF sites in the ICR, Schoenherr et al. (2003) showed that maternally transmitted mutant ICRs in neonatal mice acquired a substantial but heterogeneous degree of methylation. Mutant ICRs in oocytes and blastocysts were not methylated, however, indicating that binding of CTCF is not required to establish the unmethylated ICR during oogenesis. The authors also showed that the mutant ICR lacked enhancer-blocking activity, as the expression of IGF2 is activated on mutant maternal chromosomes. Conversely, maternal H19 expression was reduced, suggesting a positive role for CTCF in the transcription of that gene. This was said to be the first in vivo demonstration of the multiple functions of CTCF in an ICR. </p><p>Lopes et al. (2003) examined regional control of DNA methylation in the imprinted Igf2-H19 region in the mouse. Paternal germline-specific methylation was reprogrammed after fertilization in 2 DMRs in Igf2, and was reestablished after implantation. Using a number of knockout strains in the region, the authors found that the DMRs themselves were involved in regional coordination in a hierarchical fashion. Thus the H19 DMR was needed on the maternal allele to protect the Igf2 DMRs 1 and 2 from methylation, and Igf2 DMR1 was needed to protect DMR2 from methylation. This regional coordination occurred exclusively after fertilization during somatic development, and did not involve linear spreading of DNA methylation, suggesting a model in which long-range chromatin interactions are involved in regional epigenetic coordination. Parthenogenesis does not naturally occur in mammals because of the need for unequal expression of imprinted genes from the maternal and paternal alleles. </p><p>Cerrato et al. (2003) showed that in the mouse mutant 'minute' (Mnt), which carries a 3-Mb inversion with a breakpoint 25 kb distal to the H19 gene, the Igf2-H19 locus acquired a paternal methylation imprint in the maternal germline. DNA methylation of the H19 DMR was established in oogenesis, maintained during postzygotic development on the maternal allele, and erased in primordial germ cells. The fact that a paternal-type methylation imprint can also be established in the maternal germline suggests that trans-acting factors that target methylation to this imprinted region may likely be the same in both germlines. However, asynchrony of DNA replication of the locus was maintained despite the altered expression and methylation imprint of Igf2 and H19. Cerrato et al. (2003) concluded that replication asynchrony of this region is neither the determinant factor for, nor a consequence of, epigenetic modifications that are critical for genomic imprinting. Replication asynchrony may thus be regulated differently from methylation imprints and have a separate function. </p><p>Imprinted expression at the H19/Igf2 locus depends on a differentially methylated domain (DMD) that acts both as a maternal-specific, methylation-sensitive insulator and as a paternal-specific site of hypermethylation. Four repeats in the DMD bind Ctcf on the maternal allele and may attract methylation on the paternal allele. In mice, Engel et al. (2004) introduced point mutations into the DMD to deplete the repeats of CpGs while retaining Ctcf-binding and enhancer-blocking activity. Maternal inheritance of the mutations left H19 expression and Igf2 imprinting intact, consistent with the idea that the DMD acts as an insulator. Conversely, paternal inheritance of these mutations disrupted maintenance of DMD methylation, resulting in biallelic H19 expression. Furthermore, an insulator was established on the paternally inherited mutated allele in vivo, reducing Igf2 expression and resulting in a 40% reduction in size of newborn offspring. Engel et al. (2004) concluded that the 9 CpG mutations in the DMD showed that the 2 parental-specific roles of the H19 DMD, i.e., methylation maintenance and insulator assembly, are antagonistic. </p><p>Imprinted genes are expressed from only 1 of the parental alleles and are marked epigenetically by DNA methylation and histone modifications. The paternally expressed gene Igf2 is separated by approximately 100 kb from the maternally expressed noncoding gene H19 on mouse distal chromosome 7. Differentially methylated regions in Igf2 and H19 contain chromatin boundaries, silencers, and activators, and regulate the reciprocal expression of the 2 genes in a methylation-sensitive manner by allowing them exclusive access to a shared set of enhancers. Murrell et al. (2004) used a GAL4 knockin approach as well as the chromosome conformation capture technique to show that the differentially methylated regions in the imprinted genes Igf2 and H19 interact in mice. These interactions are genetically regulated and partition maternal and paternal chromatin into distinct loops. This generates a simple epigenetic switch for Igf2 through which it moves between an active and a silent chromatin domain. </p><p>Superovulation (ovarian stimulation) is an assisted reproductive technology (ART) for human subfertility/infertility treatment, which has been correlated with increased frequencies of imprinting disorders such as Angelman (105830) and Beckwith-Wiedemann syndromes. Market-Velker et al. (2010) examined the effects of superovulation on genomic imprinting in individual mouse blastocyst stage embryos. Superovulation perturbed genomic imprinting of both maternally and paternally expressed genes. Loss of Snrpn (182279) ICR, Peg3 (601483) DMR, and Kcnq1ot1 (604115) ICR and gain of H19 ICR imprinted methylation were observed. This perturbation was dose-dependent, with aberrant imprinted methylation more frequent at higher hormone dosage. Maternal as well as paternal H19 ICR methylation was perturbed by superovulation. Market-Velker et al. (2010) postulated that superovulation may have dual effects during oogenesis, disrupting acquisition of imprints in growing oocytes, as well as maternal-effect gene products subsequently required for imprint maintenance during preimplantation development. </p><p>Ideraabdullah et al. (2014) created a line of mice with a 1.3-kb deletion at H19/Igf2 ICR1 that removed 2 Ctcf-binding sites and disrupted spacing between the remaining 2 Ctcf-binding sites. The deletion also removed 2 Oct-binding sites, 1 of 4 Zfp57-binding sites, 2 of 3 proposed nucleosome-positioning sites, and 6 nuclear hormone receptor (see 139139) sites. Despite the differences in ICR1 between mice and humans, maternal inheritance of the 1.3-kb deletion resulted in pups with transitory elevations in whole-body and tongue weights, similar to observations in BWS patients. Maternal inheritance of the deletion also resulted in loss of Igf2 imprinting in tissues of mesodermal origin only, where a significant amount of Ctcf is poly(ADP-ribosyl)ated. Paternal inheritance of the deletion resulted in biallelic H19 expression in all tissues. Despite causing altered parent-of-origin imprinting, the deletion did not disrupt DNA methylation at the remaining H19/Igf2 ICR1. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>3 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 BECKWITH-WIEDEMANN SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ICR1, 1.8-KB DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000149875
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Sparago et al. (2004) analyzed 7 individuals with Beckwith-Wiedemann syndrome (BWS; 130650) with H19 hypermethylation for the presence of deletions in the H19 DMR. In 2 individuals, they found an allele with a 1.8-kb deletion. The 2 mutations were very similar, each deleting 2.5 copies of the B repeat and 1 copy of the A repeat and abolishing 2 CTCF binding sites. The sister of 1 patient died prenatally with signs of BWS. Study of DNA from the autopsy specimen showed that she also had inherited the 1.8-kb deletion from her mother. The mutation was found in the mother of these 2 sibs, in the maternal grandfather, and in an uncle and his daughters. In the second family, Sparago et al. (2004) found the mutation in the mother, maternal aunt, and maternal grandfather, indicating that the 1.8-kb deletion is associated with the BWS phenotype only when maternally transmitted. The 1.8-kb deletion was not detected in any of 14 individuals with BWS with defects other than H19 methylation or in any of 50 healthy individuals. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 WILMS TUMOR 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
BECKWITH-WIEDEMANN SYNDROME, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ICR1, 5.3-KB DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000149876, RCV000149877
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with isolated Wilms tumor (194071), Scott et al. (2008) identified a 5.3-kb deletion encompassing all but the telomeric 200 bp of the H19 DMR repeat block, resulting in hypermethylation. The mutation deleted 6 of 7 CTCF (604167) target sites. The mutation was inherited from the unaffected mother. A sib with overgrowth features of Beckwith-Wiedemann syndrome (130650) also carried the mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 WILMS TUMOR 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ICR1, 1.43-KB TRIPLICATION
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000149878
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 members of a family with isolated Wilms tumor (194071), Scott et al. (2008) identified a 1.43-kb triplication in the H19 DMR, resulting in hypermethylation. The mutation was inherited from the unaffected maternal grandmother. The triplication appeared as a 2.9-kb microinsertion and did not disrupt predicted CTCF (604167) target sites, but inserted 2 predicted CTCF target sites between the 2 H19 DMR repeat blocks. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bartholdi, D., Krajewska-Walasek, M., Ounap, K., Gaspar, H., Chrzanowska, K. H., Ilyana, H., Kayserili, H., Lurie, I. W., Schinzel, A., Baumer, A.
|
|
<strong>Epigenetic mutations of the imprinted IGF2-H19 domain in Silver-Russell syndrome (SRS): results from a large cohort of patients with SRS and SRS-like phenotypes. (Letter)</strong>
|
|
J. Med. Genet. 46: 192-197, 2009.
|
|
|
|
|
|
[PubMed: 19066168]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1136/jmg.2008.061820]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bell, A. C., Felsenfeld, G.
|
|
<strong>Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene.</strong>
|
|
Nature 405: 482-485, 2000.
|
|
|
|
|
|
[PubMed: 10839546]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/35013100]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Cerrato, F., Dean, W., Davies, K., Kagotani, K., Mitsuya, K., Okumara, K., Riccio, A., Reik, W.
|
|
<strong>Paternal imprints can be established on the maternal Igf2-H19 locus without altering replication timing of DNA.</strong>
|
|
Hum. Molec. Genet. 12: 3123-3132, 2003.
|
|
|
|
|
|
[PubMed: 14532328]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddg338]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Demars, J., Shmela, M. E., Rossignol, S., Okabe, J., Netchine, I., Azzi, S., Cabrol, S., Le Caignec, C., David, A., Le Bouc, Y., El-Osta, A., Gicquel, C.
|
|
<strong>Analysis of the IGF2/H19 imprinting control region uncovers new genetic defects, including mutations of OCT-binding sequences, in patients with 11p15 fetal growth disorders.</strong>
|
|
Hum. Molec. Genet. 19: 803-814, 2010.
|
|
|
|
|
|
[PubMed: 20007505]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddp549]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Du, M., Beatty, L. G., Zhou, W., Lew, J., Schoenherr, C., Weksberg, R., Sadowski, P. D.
|
|
<strong>Insulator and silencer sequences in the imprinted region of human chromosome 11p15.5.</strong>
|
|
Hum. Molec. Genet. 12: 1927-1939, 2003.
|
|
|
|
|
|
[PubMed: 12874112]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddg194]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Engel, N., West, A. G., Felsenfeld, G., Bartolomei, M. S.
|
|
<strong>Antagonism between DNA hypermethylation and enhancer-blocking activity at the H19 DMD is uncovered by CpG mutations.</strong>
|
|
Nature Genet. 36: 883-888, 2004.
|
|
|
|
|
|
[PubMed: 15273688]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng1399]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Fedoriw, A. M., Stein, P., Svoboda, P., Schultz, R. M., Bartolomei, M. S.
|
|
<strong>Transgenic RNAi reveals essential function for CTCF in H19 gene imprinting.</strong>
|
|
Science 303: 238-240, 2004.
|
|
|
|
|
|
[PubMed: 14716017]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1090934]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gicquel, C., Rossignol, S., Cabrol, S., Houang, M., Steunou, V., Barbu, V., Danton, F., Thibaud, N., Le Merrer, M., Burglen, L., Bertrand, A.-M., Netchine, I., Le Bouc, Y.
|
|
<strong>Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome.</strong>
|
|
Nature Genet. 37: 1003-1007, 2005.
|
|
|
|
|
|
[PubMed: 16086014]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng1629]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hark, A. T., Schoenherr, C. J., Katz, D. J., Ingram, R. S., Levrose, J. M., Tilghman, S. M.
|
|
<strong>CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus.</strong>
|
|
Nature 405: 486-489, 2000.
|
|
|
|
|
|
[PubMed: 10839547]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/35013106]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hark, A. T., Tilghman, S. M.
|
|
<strong>Chromatin conformation of the H19 epigenetic mark.</strong>
|
|
Hum. Molec. Genet. 7: 1979-1985, 1998.
|
|
|
|
|
|
[PubMed: 9811943]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/7.12.1979]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Higashimoto, K., Jozaki, K., Kosho, T., Matsubara, K., Fuke, T., Yamada, D., Yatsuki, H., Maeda, T., Ohtsuka, Y., Nishioka, K., Joh, K., Koseki, H., Ogata, T., Soejima, H.
|
|
<strong>A novel de novo point mutation of the OCT-binding site in the IGF2/H19-imprinting control region in a Beckwith-Wiedemann syndrome patient.</strong>
|
|
Clin. Genet. 86: 539-544, 2014.
|
|
|
|
|
|
[PubMed: 24299031]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1111/cge.12318]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ideraabdullah, F. Y., Thorvaldsen, J. L., Myers, J. A.
|
|
<strong>Tissue-specific insulator function at H19/Igf2 revealed by deletions at the imprinting control region.</strong>
|
|
Hum. Molec. Genet. 23: 6246-6259, 2014.
|
|
|
|
|
|
[PubMed: 24990148]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddu344]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Jones, B. K., Levorse, J., Tilghman, S. M.
|
|
<strong>Deletion of a nuclease-sensitive region between the Igf2 and H19 genes leads to Igf2 misregulation and increased adiposity.</strong>
|
|
Hum. Molec. Genet. 10: 807-814, 2001.
|
|
|
|
|
|
[PubMed: 11285246]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/10.8.807]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Keniry, A., Oxley, D., Monnier, P., Kyba, M., Dandolo, L., Smits, G., Reik, W.
|
|
<strong>The H19 lincRNA is a developmental reservoir of miR-675 that suppresses growth and Igf1r.</strong>
|
|
Nature Cell Biol. 14: 659-665, 2012.
|
|
|
|
|
|
[PubMed: 22684254]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ncb2521]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Leighton, P. A., Ingram, R. S., Eggenschwiler, J., Efstratiadis, A., Tilghman, S. M.
|
|
<strong>Disruption of imprinting caused by deletion of the H19 gene region in mice.</strong>
|
|
Nature 375: 34-39, 1995.
|
|
|
|
|
|
[PubMed: 7536897]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/375034a0]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ling, J. Q., Li, T., Hu, J. F., Vu, T. H., Chen, H. L., Qiu, X. W., Cherry, A. M., Hoffman, A. R.
|
|
<strong>CTCF mediates interchromosomal colocalization between Igf2/H19 and Wsb1/Nf1.</strong>
|
|
Science 312: 269-272, 2006.
|
|
|
|
|
|
[PubMed: 16614224]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1123191]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lopes, S., Lewis, A., Hajkova, P., Dean, W., Oswald, J., Forne, T., Murrell, A., Constancia, M., Bartolomei, M., Walter, J., Reik, W.
|
|
<strong>Epigenetic modifications in an imprinting cluster are controlled by a hierarchy of DMRs suggesting long-range chromatin interactions.</strong>
|
|
Hum. Molec. Genet. 12: 295-305, 2003.
|
|
|
|
|
|
[PubMed: 12554683]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddg022]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Market-Velker, B. A., Zhang, L., Magri, L. S., Bonvissuto, A. C., Mann, M. R. W.
|
|
<strong>Dual effects of superovulation: loss of maternal and paternal imprinted methylation in a dose-dependent manner.</strong>
|
|
Hum. Molec. Genet. 19: 36-51, 2010.
|
|
|
|
|
|
[PubMed: 19805400]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddp465]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Murrell, A., Heeson, S., Reik, W.
|
|
<strong>Interaction between differentially methylated regions partitions the imprinted genes Igf2 and H19 into parent-specific chromatin loops.</strong>
|
|
Nature Genet. 36: 889-893, 2004.
|
|
|
|
|
|
[PubMed: 15273689]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng1402]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Poole, R. L., Leith, D. J., Docherty, L. E., Shmela, M. E., Gicquel, C., Splitt, M., Temple, I. K., Mackay, D. J. G.
|
|
<strong>Beckwith-Wiedemann syndrome caused by maternally inherited mutation of an OCT-binding motif in the IGF2/H19-imprinting control region, ICR1.</strong>
|
|
Europ. J. Hum. Genet. 20: 240-243, 2012.
|
|
|
|
|
|
[PubMed: 21863054]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ejhg.2011.166]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Prawitt, D., Enklaar, T., Gartner-Rupprecht, B., Spangenberg, C., Oswald, M., Lausch, E., Schmidtke, P., Reutzel, D., Fees, S., Lucito, R., Korzon, M., Brozek, I., Limon, J., Housman, D. E., Pelletier, J., Zabel, B.
|
|
<strong>Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms' tumor.</strong>
|
|
Proc. Nat. Acad. Sci. 102: 4085-4090, 2005.
|
|
|
|
|
|
[PubMed: 15743916]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.0500037102]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Sandovici, I., Leppert, M., Hawk, P. R., Suarez, A., Linares, Y., Sapienza, C.
|
|
<strong>Familial aggregation of abnormal methylation of parental alleles at the IGF2/H19 and IGF2R differentially methylated regions.</strong>
|
|
Hum. Molec. Genet. 12: 1569-1578, 2003. Note: Erratum: Hum. Molec. Genet. 13: 781 only, 2004.
|
|
|
|
|
|
[PubMed: 12812984]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddg167]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Schoenherr, C. J., Levorse, J. M., Tilghman, S. M.
|
|
<strong>CTCF maintains differential methylation at the Igf2/H19 locus.</strong>
|
|
Nature Genet. 33: 66-69, 2003.
|
|
|
|
|
|
[PubMed: 12461525]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng1057]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Scott, R. H., Douglas, J., Baskcomb, L., Huxter, N., Barker, K., Hanks, S., Craft, A., Gerrard, M., Kohler, J. A., Levitt, G. A., Picton, S., Pizer, B., and 10 others.
|
|
<strong>Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor.</strong>
|
|
Nature Genet. 40: 1329-1334, 2008.
|
|
|
|
|
|
[PubMed: 18836444]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng.243]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Smits, G., Mungall, A. J., Griffiths-Jones, S., Smith, P., Beury, D., Matthews, L., Rogers, J., Pask, A. J., Shaw, G., VandeBerg, J. L., McCarrey, J. R., SAVOIR Consortium, Renfree, M. B., Reik, W., Dunham, I.
|
|
<strong>Conservation of the H19 noncoding RNA and H19-IGF2 imprinting mechanism in therians.</strong>
|
|
Nature Genet. 40: 971-976, 2008.
|
|
|
|
|
|
[PubMed: 18587395]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng.168]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Sparago, A., Cerrato, F., Vernucci, M., Ferrero, G. B., Silengo, M. C., Riccio, A.
|
|
<strong>Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome.</strong>
|
|
Nature Genet. 36: 958-960, 2004.
|
|
|
|
|
|
[PubMed: 15314640]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng1410]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Srivastava, M., Hsieh, S., Grinberg, A., Williams-Simons, L., Huang, S.-P., Pfeifer, K.
|
|
<strong>H19 and Igf2 monoallelic expression is regulated in two distinct ways by a shared cis acting regulatory region upstream of H19.</strong>
|
|
Genes Dev. 14: 1186-1195, 2000.
|
|
|
|
|
|
[PubMed: 10817754]
|
|
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Takai, D., Gonzales, F. A., Tsai, Y. C., Thayer, M. J., Jones, P. A.
|
|
<strong>Large scale mapping of methylcytosines in CTCF-binding sites in the human H19 promoter and aberrant hypomethylation in human bladder cancer.</strong>
|
|
Hum. Molec. Genet. 10: 2619-2626, 2001.
|
|
|
|
|
|
[PubMed: 11726548]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/10.23.2619]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Thorvaldsen, J. L., Duran, K. L., Bartolomei, M. S.
|
|
<strong>Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2.</strong>
|
|
Genes Dev. 12: 3693-3702, 1998.
|
|
|
|
|
|
[PubMed: 9851976]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1101/gad.12.23.3693]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ulaner, G. A., Vu, T. H., Li, T., Hu, J.-F., Yao, X.-M., Yang, Y., Gorlick, R., Meyers, P., Healey, J., Ladanyi, M., Hoffman, A. R.
|
|
<strong>Loss of imprinting of IGF2 and H19 in osteosarcoma is accompanied by reciprocal methylation changes of a CTCF-binding site.</strong>
|
|
Hum. Molec. Genet. 12: 535-549, 2003.
|
|
|
|
|
|
[PubMed: 12588801]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddg034]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Venkatraman, A., He, X. C., Thorvaldsen, J. L., Sugimura, R., Perry, J. M., Tao, F., Zhao, M., Christenson, M. K., Sanchez, R., Yu, J. Y., Peng, L., Haug, J. S., Paulson, A., Li, H., Zhong, X., Clemens, T. L., Bartolomei, M. S., Li, L.
|
|
<strong>Maternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence.</strong>
|
|
Nature 500: 345-349, 2013.
|
|
|
|
|
|
[PubMed: 23863936]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature12303]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Vernucci, M., Cerrato, F., Pedone, P. V., Dandolo, L., Bruni, C. B., Riccio, A.
|
|
<strong>Developmentally regulated functions of the H19 differentially methylated domain.</strong>
|
|
Hum. Molec. Genet. 13: 353-361, 2004.
|
|
|
|
|
|
[PubMed: 14681296]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddh028]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Webber, A., Ingram, R. S., Levorse, J. M., Tilghman, S. M.
|
|
<strong>Location of enhancers is essential for imprinting of H19 and Igf2 genes.</strong>
|
|
Nature 391: 711-715, 1998.
|
|
|
|
|
|
[PubMed: 9490417]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/35655]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Zemel, S., Bartolomei, M. S., Tilghman, S. M.
|
|
<strong>Physical linkage of two mammalian imprinted genes, H19 and insulin-like growth factor 2.</strong>
|
|
Nature Genet. 2: 61-65, 1992.
|
|
|
|
|
|
[PubMed: 1303252]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng0992-61]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Zhao, Z., Tavoosidana, G., Sjolinder, M., Gondor, A., Mariano, P., Wang, S., Kanduri, C., Lezcano, M., Sandhu, K. S., Singh, U., Pant, V., Tiwari, V., Kurukuti, S., Ohlsson, R.
|
|
<strong>Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra- and interchromosomal interactions.</strong>
|
|
Nature Genet. 38: 1341-1347, 2006.
|
|
|
|
|
|
[PubMed: 17033624]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng1891]
|
|
|
|
|
|
</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">
|
|
Patricia A. Hartz - updated : 1/16/2015
|
|
</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">
|
|
Matthew B. Gross : 1/13/2015
|
|
</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">
|
|
mgross : 01/27/2015<br>mgross : 1/20/2015<br>mcolton : 1/16/2015<br>mgross : 1/15/2015
|
|
</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>
|
|
|
|
|