3581 lines
304 KiB
Text
3581 lines
304 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
|
|
|
|
- *605185 - DELTA-LIKE CANONICAL NOTCH LIGAND 4; DLL4
|
|
|
|
|
|
- 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=605185"><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">*605185</span>
|
|
<br />
|
|
<strong>Table of Contents</strong>
|
|
</p>
|
|
|
|
<nav>
|
|
<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
|
|
|
|
<li role="presentation">
|
|
<a href="#title"><strong>Title</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#text"><strong>Text</strong></a>
|
|
</li>
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#description">Description</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#cloning">Cloning and Expression</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#biochemicalFeatures">Biochemical Features</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#mapping">Mapping</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#geneFunction">Gene Function</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#molecularGenetics">Molecular Genetics</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#animalModel">Animal Model</a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
|
|
</li>
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="/allelicVariants/605185">Table View</a>
|
|
</li>
|
|
|
|
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#references"><strong>References</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#contributors"><strong>Contributors</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#creationDate"><strong>Creation Date</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#editHistory"><strong>Edit History</strong></a>
|
|
</li>
|
|
|
|
</ul>
|
|
|
|
</nav>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimFloatingLinksMenu">
|
|
|
|
<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
|
|
<h4 class="panel-title">
|
|
<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
|
|
<div style="display: table-row">
|
|
<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
|
|
|
|
<div style="display: table-cell;">External Links</div>
|
|
</div>
|
|
</a>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
|
|
<div id="mimExternalLinksFold" class="collapse in">
|
|
|
|
<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000128917;t=ENST00000249749" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=54567" 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=605185" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000128917;t=ENST00000249749" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_019074" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_019074" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
|
|
|
|
|
|
<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=605185" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
<div><a href="https://hprd.org/summary?hprd_id=05540&isoform_id=05540_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.proteinatlas.org/search/DLL4" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/protein/8568084,8926615,9506545,10567110,11463872,13431490,37182906,76827108,119612872,189054058,1249613891" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.uniprot.org/uniprotkb/Q9NR61" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
|
|
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
|
|
|
<div style="display: table-cell;">Gene Info</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
<div><a href="http://biogps.org/#goto=genereport&id=54567" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000128917;t=ENST00000249749" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=DLL4" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=DLL4" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+54567" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
|
|
|
|
|
|
|
|
<dd><a href="http://v1.marrvel.org/search/gene/DLL4" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
|
|
|
|
|
|
|
|
<dd><a href="https://monarchinitiative.org/NCBIGene:54567" 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/54567" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr15&hgg_gene=ENST00000249749.7&hgg_start=40929340&hgg_end=40939073&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
|
|
|
<div style="display: table-cell;">Clinical Resources</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://medlineplus.gov/genetics/gene/dll4" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=605185[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=605185[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.deciphergenomics.org/gene/DLL4/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000128917" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.ebi.ac.uk/gwas/search?query=DLL4" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
|
|
|
|
|
|
|
|
<div><a href="https://www.gwascentral.org/search?q=DLL4" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=DLL4" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=DLL4&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.pharmgkb.org/gene/PA27366" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
|
|
|
<div style="display: table-cell;">Animal Models</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.alliancegenome.org/gene/HGNC:2910" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://flybase.org/reports/FBgn0000463.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.mousephenotype.org/data/genes/MGI:1859388" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="http://v1.marrvel.org/search/gene/DLL4#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
|
|
|
|
|
|
|
|
|
|
<div><a href="http://www.informatics.jax.org/marker/MGI:1859388" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.ncbi.nlm.nih.gov/gene/54567/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=54567" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
|
|
<div id="mimWormbaseGeneFold" class="collapse">
|
|
<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00001106;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00001106 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00004963;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00004963 </a></div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://zfin.org/ZDB-GENE-041014-73" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
|
|
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
|
|
|
<div style="display: table-cell;">Cellular Pathways</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:54567" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://reactome.org/content/query?q=DLL4&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
|
|
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
<span>
|
|
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
|
|
|
|
</span>
|
|
</span>
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
|
|
|
|
<div>
|
|
|
|
<a id="title" class="mim-anchor"></a>
|
|
|
|
<div>
|
|
<a id="number" class="mim-anchor"></a>
|
|
<div class="text-right">
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
<div>
|
|
<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
605185
|
|
</span>
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
<div>
|
|
<a id="preferredTitle" class="mim-anchor"></a>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
DELTA-LIKE CANONICAL NOTCH LIGAND 4; DLL4
|
|
|
|
</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">
|
|
DELTA-LIKE 4
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=DLL4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">DLL4</a></em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/15/112?start=-3&limit=10&highlight=112">15q15.1</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr15:40929340-40939073&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'})">15:40,929,340-40,939,073</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/15/112?start=-3&limit=10&highlight=112">
|
|
15q15.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Adams-Oliver syndrome 6
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/616589"> 616589 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/605185" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/605185" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="text" class="mim-anchor"></a>
|
|
|
|
|
|
|
|
<h4>
|
|
|
|
<span class="mim-font">
|
|
<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="description" class="mim-anchor"></a>
|
|
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimDescriptionFold" class="collapse in ">
|
|
<span class="mim-text-font">
|
|
<p>Notch (see <a href="/entry/190198">190198</a>) signaling controls cell fate specification in a variety of cell contexts during embryonic and postnatal development. DLL4 is a transmembrane ligand for Notch receptors that shows restricted expression to endothelial cells (ECs), in particular to arteries and capillaries, and is involved in vascular development (<a href="#16" class="mim-tip-reference" title="Suchting, S., Freitas, C., le Noble, F., Benedito, R., Breant, C., Duarte, A., Eichmann, A. <strong>The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching.</strong> Proc. Nat. Acad. Sci. 104: 3225-3230, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17296941/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17296941</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17296941[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.0611177104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17296941">Suchting et al., 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17296941" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="cloning" class="mim-anchor"></a>
|
|
<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimCloningFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><a href="#14" class="mim-tip-reference" title="Shutter, J. R., Scully, S., Fan, W., Richards, W. G., Kitajewski, J., Deblandre, G. A., Kintner, C. R., Stark, K. L. <strong>Dll4, a novel Notch ligand expressed in arterial endothelium.</strong> Genes Dev. 14: 1313-1318, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10837024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10837024</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10837024[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="10837024">Shutter et al. (2000)</a> identified Dll4 as a mouse EST encoding a polypeptide with homology to the DSL family of Notch ligands. By searching a DNA sequence database with the mouse Dll4 sequence, they identified a partial human brain DLL4 cDNA. Using this partial DLL4 cDNA, <a href="#14" class="mim-tip-reference" title="Shutter, J. R., Scully, S., Fan, W., Richards, W. G., Kitajewski, J., Deblandre, G. A., Kintner, C. R., Stark, K. L. <strong>Dll4, a novel Notch ligand expressed in arterial endothelium.</strong> Genes Dev. 14: 1313-1318, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10837024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10837024</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10837024[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="10837024">Shutter et al. (2000)</a> isolated a full-length human DLL4 coding sequence. The predicted 685-amino acid DLL4 protein exhibits all of the hallmarks of the Delta family of Notch ligands. It has an extracellular region containing 8 EGF-like repeats and a DSL domain involved in Notch binding, as well as a transmembrane domain and a cytoplasmic tail that lacks catalytic motifs. Human DLL4 shares 87% amino acid sequence identity with mouse Dll4. Northern blot analysis of mouse tissues detected highest Dll4 expression in lung, followed by heart, kidney, skeletal muscle, and brain; Dll4 expression was barely detectable in spleen and testis. Northern blot analysis of whole mouse embryos demonstrated increased expression of Dll4 from embryonic day 7 through 17. Analysis by RT-PCR revealed a low level of Dll4 expression in all tissues examined, with higher levels in lung, brown and white adipose, and adrenal. In situ hybridization of mouse tissues showed a strikingly specific expression pattern. In both embryonic and adult tissues, the predominant site of Dll4 expression was the vascular endothelium. <a href="#14" class="mim-tip-reference" title="Shutter, J. R., Scully, S., Fan, W., Richards, W. G., Kitajewski, J., Deblandre, G. A., Kintner, C. R., Stark, K. L. <strong>Dll4, a novel Notch ligand expressed in arterial endothelium.</strong> Genes Dev. 14: 1313-1318, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10837024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10837024</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10837024[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="10837024">Shutter et al. (2000)</a> found a similar expression pattern for human DLL4 by in situ analysis. They suggested that DLL4 is involved in the regulation of vascular biology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10837024" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="biochemicalFeatures" class="mim-anchor"></a>
|
|
<h4 href="#mimBiochemicalFeaturesFold" id="mimBiochemicalFeaturesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimBiochemicalFeaturesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Biochemical Features</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimBiochemicalFeaturesFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Crystal Structure</em></strong></p><p>
|
|
<a href="#10" class="mim-tip-reference" title="Luca, V. C., Jude, K. M., Pierce, N. W., Nachury, M. V., Fischer, S., Garcia, K. C. <strong>Structural basis for Notch1 engagement of delta-like 4.</strong> Science 347: 847-853, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25700513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25700513</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25700513[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1261093" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25700513">Luca et al. (2015)</a> determined the crystal structure of the interacting regions of the NOTCH1-DLL4 complex at 2.3-angstrom resolution. The complex reveals a 2-site, antiparallel binding orientation assisted by NOTCH1 O-linked glycosylation. NOTCH1 EGF-like repeats 11 and 12 interact with the DLL4 Delta/Serrate/Lag2 (DSL) domain and module at the N terminus of Notch ligand (MNNL) domains, respectively. Threonine and serine residues on NOTCH1 are functionalized with O-fucose and O-glucose, which act as surrogate amino acids by making specific and essential contacts to residues on DLL4. The elucidation of a direct chemical role for O-glycans in NOTCH1 ligand engagement demonstrates how, by relying on posttranslational modifications of their ligand binding sites, Notch proteins have linked their functional capacity to developmentally regulated biosynthetic pathways. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25700513" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="mapping" class="mim-anchor"></a>
|
|
<h4 href="#mimMappingFold" id="mimMappingToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimMappingToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimMappingFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p>By radiation hybrid mapping, <a href="#14" class="mim-tip-reference" title="Shutter, J. R., Scully, S., Fan, W., Richards, W. G., Kitajewski, J., Deblandre, G. A., Kintner, C. R., Stark, K. L. <strong>Dll4, a novel Notch ligand expressed in arterial endothelium.</strong> Genes Dev. 14: 1313-1318, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10837024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10837024</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10837024[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="10837024">Shutter et al. (2000)</a> mapped the DLL4 gene to 15q21.1. By FISH, they mapped the mouse Dll4 gene to 2E3, a region sharing homology of synteny with human 15q. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10837024" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Stumpf, A. M. <strong>Personal Communication.</strong> Baltimore, Md. 03/16/2020."None>Stumpf (2020)</a> mapped the DLL4 gene to chromosome 15q15.1 based on an alignment of the DLL4 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AF253468" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AF253468</a>) with the genomic sequence (GRCh38).</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="geneFunction" class="mim-anchor"></a>
|
|
<h4 href="#mimGeneFunctionFold" id="mimGeneFunctionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimGeneFunctionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimGeneFunctionFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><a href="#14" class="mim-tip-reference" title="Shutter, J. R., Scully, S., Fan, W., Richards, W. G., Kitajewski, J., Deblandre, G. A., Kintner, C. R., Stark, K. L. <strong>Dll4, a novel Notch ligand expressed in arterial endothelium.</strong> Genes Dev. 14: 1313-1318, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10837024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10837024</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10837024[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="10837024">Shutter et al. (2000)</a> demonstrated that mouse Dll4 could activate mouse Notch1 (<a href="/entry/190198">190198</a>) and mouse Notch4 (<a href="/entry/164951">164951</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10837024" 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="Noguera-Troise, I., Daly, C., Papadopoulos, N. J., Coetzee, S., Boland, P., Gale, N. W., Lin, H. C., Yancopoulos, G. D., Thurston, G. <strong>Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis.</strong> Nature 444: 1032-1037, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17183313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17183313</a>] [<a href="https://doi.org/10.1038/nature05355" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17183313">Noguera-Troise et al. (2006)</a> reported that VEGF (<a href="/entry/192240">192240</a>) dynamically regulates tumor endothelial expression of DLL4, which had been shown to be absolutely required for normal embryonic vascular development (<a href="#2" class="mim-tip-reference" title="Duarte, A., Hirashima, M., Benedito, R., Trindade, A., Diniz, P., Bekman, E., Costa, L., Henrique, D., Rossant, J. <strong>Dosage-sensitive requirement for mouse Dll4 in artery development.</strong> Genes Dev. 18: 2474-2478, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15466159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15466159</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15466159[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.1239004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15466159">Duarte et al., 2004</a>; <a href="#3" class="mim-tip-reference" title="Gale, N. W., Dominguez, M. G., Noguera, I., Pan, L., Hughes, V., Valenzuela, D. M., Murphy, A. J., Adams, N. C., Lin, H. C., Holash, J., Thurston, G., Yancopoulos, G. D. <strong>Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development.</strong> Proc. Nat. Acad. Sci. 101: 15949-15954, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15520367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15520367</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15520367[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.0407290101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15520367">Gale et al., 2004</a>; <a href="#8" class="mim-tip-reference" title="Krebs, L. T., Shutter, J. R., Tanigaki, K., Honjo, T., Stark, K. L., Gridley, T. <strong>Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants.</strong> Genes Dev. 18: 2469-2473, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15466160/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15466160</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15466160[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.1239204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15466160">Krebs et al., 2004</a>). To define Dll4 function in tumor angiogenesis, <a href="#12" class="mim-tip-reference" title="Noguera-Troise, I., Daly, C., Papadopoulos, N. J., Coetzee, S., Boland, P., Gale, N. W., Lin, H. C., Yancopoulos, G. D., Thurston, G. <strong>Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis.</strong> Nature 444: 1032-1037, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17183313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17183313</a>] [<a href="https://doi.org/10.1038/nature05355" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17183313">Noguera-Troise et al. (2006)</a> manipulated this pathway in murine tumor models using several approaches. They showed that blockade resulted in markedly increased tumor vascularity, associated with enhanced angiogenic sprouting and branching. Paradoxically, this increased vascularity was nonproductive--as shown by poor perfusion and increased hypoxia, and most importantly, by decreased tumor growth--even for tumors resistant to anti-VEGF therapy. Thus, <a href="#12" class="mim-tip-reference" title="Noguera-Troise, I., Daly, C., Papadopoulos, N. J., Coetzee, S., Boland, P., Gale, N. W., Lin, H. C., Yancopoulos, G. D., Thurston, G. <strong>Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis.</strong> Nature 444: 1032-1037, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17183313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17183313</a>] [<a href="https://doi.org/10.1038/nature05355" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17183313">Noguera-Troise et al. (2006)</a> concluded that VEGF-induced Dll4 acts as a negative regulator of tumor angiogenesis; its blockade results in the striking uncoupling of tumor growth from vessel density, presenting a novel therapeutic approach even for tumors resistant to anti-VEGF therapies. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15466159+15466160+15520367+17183313" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Ridgway, J., Zhang, G., Wu, Y., Stawicki, S., Liang, W.-C., Chanthery, Y., Kowalski, J., Watts, R. J., Callahan, C., Kasman, I., Singh, M., Chien, M., Tan, C., Hongo, J.-A. S., de Sauvage, F., Plowman, G., Yan, M. <strong>Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis.</strong> Nature 444: 1083-1087, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17183323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17183323</a>] [<a href="https://doi.org/10.1038/nature05313" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17183323">Ridgway et al. (2006)</a> showed that DLL4-mediated Notch signaling has a unique role in regulating endothelial cell proliferation and differentiation. Neutralizing DLL4 with a DLL4-selective antibody rendered endothelial cells hyperproliferative, and caused defective cell fate specification or differentiation both in vitro and in vivo. In addition, blocking DLL4 inhibited tumor growth in several tumor models. Remarkably, antibodies against DLL4 and antibodies against VEGF had paradoxically distinct effects on tumor vasculature. <a href="#13" class="mim-tip-reference" title="Ridgway, J., Zhang, G., Wu, Y., Stawicki, S., Liang, W.-C., Chanthery, Y., Kowalski, J., Watts, R. J., Callahan, C., Kasman, I., Singh, M., Chien, M., Tan, C., Hongo, J.-A. S., de Sauvage, F., Plowman, G., Yan, M. <strong>Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis.</strong> Nature 444: 1083-1087, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17183323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17183323</a>] [<a href="https://doi.org/10.1038/nature05313" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17183323">Ridgway et al. (2006)</a> stated that their data also indicated that DLL4-mediated Notch signaling is crucial during active vascularization, but less important for normal vessel maintenance. Furthermore, unlike blocking Notch signaling globally, neutralizing DLL4 had no discernible impact on intestinal goblet cell differentiation, supporting the idea that DLL4-mediated Notch signaling is largely restricted to the vascular compartment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17183323" 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="Hellstrom, M., Phng, L.-K., Hofmann, J. J., Wallgard, E., Coultas, L., Lindblom, P., Alva, J., Nilsson, A.-K., Karlsson, L., Gaiano, N., Yoon, K., Rossant, J., Iruela-Arispe, M. L., Kalen, M., Gerhardt, H., Betsholtz, C. <strong>Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis.</strong> Nature 445: 776-780, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17259973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17259973</a>] [<a href="https://doi.org/10.1038/nature05571" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17259973">Hellstrom et al. (2007)</a> presented evidence that Dll4-Notch1 signaling regulates the formation of appropriate numbers of tip cells to control vessel sprouting and branching in mouse retina. They showed that inhibition of Notch signaling using gamma-secretase inhibitors, genetic inactivation of 1 allele of the endothelial Notch ligand Dll4, or endothelial-specific genetic deletion of Notch1 all promoted increased numbers of tip cells. Conversely, activation of Notch by a soluble jagged1 (<a href="/entry/601920">601920</a>) peptide led to fewer tip cells and vessel branches. Dll4 and reporters of Notch signaling are distributed in a mosaic pattern among endothelial cells of actively sprouting retinal vessels. At this location, Notch1-deleted endothelial cells preferentially assumed tip cell characteristics. <a href="#4" class="mim-tip-reference" title="Hellstrom, M., Phng, L.-K., Hofmann, J. J., Wallgard, E., Coultas, L., Lindblom, P., Alva, J., Nilsson, A.-K., Karlsson, L., Gaiano, N., Yoon, K., Rossant, J., Iruela-Arispe, M. L., Kalen, M., Gerhardt, H., Betsholtz, C. <strong>Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis.</strong> Nature 445: 776-780, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17259973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17259973</a>] [<a href="https://doi.org/10.1038/nature05571" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17259973">Hellstrom et al. (2007)</a> concluded that Dll4-Notch1 signaling between the endothelial cells within the angiogenic sprout restricts tip cell formation in response to VEGF, thereby establishing the adequate ratio between tip and stalk cells required for correct sprouting and branching patterns. The authors further concluded that their model offered an explanation for the dose dependency and haploinsufficiency of the DLL4 gene, and indicated that modulators of DLL4 or Notch signaling, such as gamma-secretase inhibitors developed for Alzheimer disease (<a href="/entry/104300">104300</a>), might find usage as pharmacologic regulators of angiogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17259973" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Ito, T., Schaller, M., Hogaboam, C. M., Standiford, T. J., Sandor, M., Lukacs, N. W., Chensue, S. W., Kunkel, S. L. <strong>TLR9 regulates the mycobacteria-elicited pulmonary granulomatous immune response in mice through DC-derived Notch ligand delta-like 4.</strong> J. Clin. Invest. 119: 33-46, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19075396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19075396</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19075396[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI35647" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19075396">Ito et al. (2009)</a> observed altered T helper-17 (Th17; see <a href="/entry/603149">603149</a>) cytokine phenotypes in Tlr9 (<a href="/entry/605474">605474</a>) -/- mice during Mycobacterium antigen-elicited pulmonary granuloma formulation, as well as decreased accumulation of granuloma-associated myeloid dendritic cells (DCs) and profoundly impaired Dll4 expression. DCs, but not macrophages, from wildtype mice promoted differentiation of Th17 cells from mycobacteria-challenged lung Cd4 (<a href="/entry/186940">186940</a>)-positive T cells. Treating wildtype mice with anti-Dll4 during granuloma formation resulted in larger granulomas and lower levels of Th17 cytokines. <a href="#6" class="mim-tip-reference" title="Ito, T., Schaller, M., Hogaboam, C. M., Standiford, T. J., Sandor, M., Lukacs, N. W., Chensue, S. W., Kunkel, S. L. <strong>TLR9 regulates the mycobacteria-elicited pulmonary granulomatous immune response in mice through DC-derived Notch ligand delta-like 4.</strong> J. Clin. Invest. 119: 33-46, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19075396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19075396</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19075396[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI35647" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19075396">Ito et al. (2009)</a> concluded that DLL4 plays an important role in promoting Th17 effector activity during mycobacterial challenge. They suggested that TLR9 may be required for optimal DLL4 expression and regulation of granuloma formation in response to mycobacterial antigen. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19075396" 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="Benedito, R., Rocha, S. F., Woeste, M., Zamykal, M., Radtke, F., Casanovas, O., Duarte, A., Pytowski, B., Adams, R. H. <strong>Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling.</strong> Nature 484: 110-114, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22426001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22426001</a>] [<a href="https://doi.org/10.1038/nature10908" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22426001">Benedito et al. (2012)</a> used inducible loss-of-function genetics in combination with inhibitors in vivo to demonstrate that DLL4 protein expression in retinal tip cells is only weakly modulated by VEGFR2 (<a href="/entry/191306">191306</a>) signaling. Surprisingly, Notch inhibition also had no significant impact on VEGFR2 expression and induced deregulated endothelial sprouting and proliferation even in the absence of VEGFR2, which is the most important VEGFA receptor and is considered to be indispensable for these processes. By contrast, VEGFR3 (<a href="/entry/136352">136352</a>), the main receptor for VEGFC (<a href="/entry/601528">601528</a>), was strongly modulated by Notch. VEGFR3 kinase activity inhibitors but not ligand-blocking antibodies suppressed the sprouting of endothelial cells that had low Notch signaling activity. <a href="#1" class="mim-tip-reference" title="Benedito, R., Rocha, S. F., Woeste, M., Zamykal, M., Radtke, F., Casanovas, O., Duarte, A., Pytowski, B., Adams, R. H. <strong>Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling.</strong> Nature 484: 110-114, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22426001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22426001</a>] [<a href="https://doi.org/10.1038/nature10908" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22426001">Benedito et al. (2012)</a> concluded that their results established that VEGFR2 and VEGFR3 are regulated in a highly differential manner by Notch. They proposed that successful antiangiogenic targeting of these receptors and their ligands will strongly depend on the status of endothelial Notch signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22426001" 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="Wimmer, R. A., Leopoldi, A., Aichinger, M., Wick, N., Hantusch, B., Novatchkova, M., Taubenschmid, J., Hammerle, M., Esk, C., Bagley, J. A., Lindenhofer, D., Chen, G., Boehm, M., Agu, C. A., Yang, F., Fu, B., Zuber, J., Knoblich, J. A., Kerjaschki, D., Penninger, J. M. <strong>Human blood vessel organoids as a model of diabetic vasculopathy.</strong> Nature 565: 505-510, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30651639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30651639</a>] [<a href="https://doi.org/10.1038/s41586-018-0858-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30651639">Wimmer et al. (2019)</a> reported the development of self-organizing 3-dimensional human blood vessel organoids from pluripotent stem cells. These human blood vessel organoids contain endothelial cells and pericytes that self-assemble into capillary networks that are enveloped by a basement membrane. Human blood vessel organoids transplanted into mice formed a stable, perfused vascular tree, including arteries, arterioles, and venules. Exposure of blood vessel organoids to hyperglycemia and inflammatory cytokines in vitro induced thickening of the vascular basement membrane. Human blood vessels exposed in vivo to a diabetic milieu in mice also mimicked the microvascular changes found in patients with diabetes. DLL4 and NOTCH3 (<a href="/entry/600276">600276</a>) were identified as key drivers of diabetic vasculopathy in human blood vessels. <a href="#17" class="mim-tip-reference" title="Wimmer, R. A., Leopoldi, A., Aichinger, M., Wick, N., Hantusch, B., Novatchkova, M., Taubenschmid, J., Hammerle, M., Esk, C., Bagley, J. A., Lindenhofer, D., Chen, G., Boehm, M., Agu, C. A., Yang, F., Fu, B., Zuber, J., Knoblich, J. A., Kerjaschki, D., Penninger, J. M. <strong>Human blood vessel organoids as a model of diabetic vasculopathy.</strong> Nature 565: 505-510, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30651639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30651639</a>] [<a href="https://doi.org/10.1038/s41586-018-0858-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30651639">Wimmer et al. (2019)</a> concluded that organoids derived from human stem cells faithfully recapitulate the structure and function of human blood vessels and are amenable systems for modeling and identifying the regulators of diabetic vasculopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30651639" 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><a href="#11" class="mim-tip-reference" title="Meester, J. A. N., Southgate, L., Stittrich, A.-B., Venselaar, H., Beekmans, S. J. A., den Hollander, N., Bijlsma, E., Helderman-van den Enden, A., Verheij, J. B. G. M., Glusman, G., Roach, J. C., Lehman, A., and 12 others. <strong>Heterozygous loss-of-function mutations in DLL4 cause Adams-Oliver syndrome.</strong> Am. J. Hum. Genet. 97: 475-482, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26299364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26299364</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26299364[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2015.07.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26299364">Meester et al. (2015)</a> screened 91 families with Adams-Oliver syndrome (see AOS6, <a href="/entry/616589">616589</a>) for mutations in the candidate gene DLL4 and identified heterozygous nonsense and missense mutations in 9 families (see, e.g., <a href="#0001">605185.0001</a>-<a href="#0006">605185.0006</a>). Incomplete penetrance as well as marked intrafamilial variability in phenotypic expression was observed; the authors suggested that other genetic, epigenetic, or environmental factors might be involved in the clinical expression of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26299364" 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>Vascular development depends on the highly coordinated actions of a variety of angiogenic regulators, most of which apparently act downstream of vascular endothelial growth factor (VEGF; <a href="/entry/192240">192240</a>). One potential such regulator is Dll4, a partner for Notch receptors. <a href="#3" class="mim-tip-reference" title="Gale, N. W., Dominguez, M. G., Noguera, I., Pan, L., Hughes, V., Valenzuela, D. M., Murphy, A. J., Adams, N. C., Lin, H. C., Holash, J., Thurston, G., Yancopoulos, G. D. <strong>Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development.</strong> Proc. Nat. Acad. Sci. 101: 15949-15954, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15520367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15520367</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15520367[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.0407290101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15520367">Gale et al. (2004)</a> generated mice in which the Dll4 gene was replaced with a reporter gene and found that Dll4 expression was initially restricted to large arteries in the embryo, whereas in adult mice and tumor models, D114 was specifically expressed in smaller arteries and microvessels, with a striking break in expression just as capillaries merge into venules. Consistent with these arterial-specific expression patterns, heterozygous deletion of Dll4 resulted in prominent, albeit variable, defects in arterial development (reminiscent of those in Notch knockouts), including abnormal stenosis and atresia of the aorta, defective arterial branching from the aorta, and even arterial regression, with occasional extension of the defects to the venous circulation; also noted was gross enlargement of the pericardial sac and failure to remodel the yolk sac vasculature. These striking phenotypes resulting from heterozygous deletion of Dll4 indicated that vascular development may be as sensitive to subtle changes in DLL4 dosage as it is to subtle changes in VEGF dosage, because VEGF accounts for the only other example of haploinsufficiency, resulting in obvious vascular abnormalities. <a href="#3" class="mim-tip-reference" title="Gale, N. W., Dominguez, M. G., Noguera, I., Pan, L., Hughes, V., Valenzuela, D. M., Murphy, A. J., Adams, N. C., Lin, H. C., Holash, J., Thurston, G., Yancopoulos, G. D. <strong>Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development.</strong> Proc. Nat. Acad. Sci. 101: 15949-15954, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15520367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15520367</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15520367[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.0407290101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15520367">Gale et al. (2004)</a> concluded that DLL4 appeared to be a major trigger of Notch receptor activities previously implicated in arterial and vascular development. <a href="#8" class="mim-tip-reference" title="Krebs, L. T., Shutter, J. R., Tanigaki, K., Honjo, T., Stark, K. L., Gridley, T. <strong>Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants.</strong> Genes Dev. 18: 2469-2473, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15466160/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15466160</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15466160[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.1239204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15466160">Krebs et al. (2004)</a> and <a href="#2" class="mim-tip-reference" title="Duarte, A., Hirashima, M., Benedito, R., Trindade, A., Diniz, P., Bekman, E., Costa, L., Henrique, D., Rossant, J. <strong>Dosage-sensitive requirement for mouse Dll4 in artery development.</strong> Genes Dev. 18: 2474-2478, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15466159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15466159</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15466159[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.1239004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15466159">Duarte et al. (2004)</a> reported similar findings. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15466159+15466160+15520367" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Lobov, I. B., Renard, R. A., Papadopoulos, N., Gale, N. W., Thurston, G., Yancopoulos, G. D., Wiegand, S. J. <strong>Delta-like ligand 4 (DII4) is induced by VEGF as a negative regulator of angiogenic sprouting.</strong> Proc. Nat. Acad. Sci. 104: 3219-3224, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17296940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17296940</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17296940[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.0611206104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17296940">Lobov et al. (2007)</a> found that Dll4 was most prominently expressed at the leading front of actively growing vessels in postnatal mouse retina, and its expression was dynamically regulated by Vegf. Deletion of a single Dll4 allele or pharmacologic inhibition of Dll4/Notch signaling produced characteristic abnormalities in the developing retinal vasculature, most notably enhanced angiogenic sprouting and increased endothelial cell proliferation, resulting in formation of a denser and more highly interconnected superficial capillary plexus. In a model of ischemic retinopathy, Dll4 blockade enhanced angiogenic sprouting and regrowth of lost retinal vessels while suppressing ectopic pathologic neovascularization. <a href="#9" class="mim-tip-reference" title="Lobov, I. B., Renard, R. A., Papadopoulos, N., Gale, N. W., Thurston, G., Yancopoulos, G. D., Wiegand, S. J. <strong>Delta-like ligand 4 (DII4) is induced by VEGF as a negative regulator of angiogenic sprouting.</strong> Proc. Nat. Acad. Sci. 104: 3219-3224, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17296940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17296940</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17296940[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.0611206104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17296940">Lobov et al. (2007)</a> concluded that DLL4 is induced by VEGF as a negative feedback regulator and prevents overexuberant angiogenic sprouting, promoting formation of a well differentiated vasculature. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17296940" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Suchting, S., Freitas, C., le Noble, F., Benedito, R., Breant, C., Duarte, A., Eichmann, A. <strong>The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching.</strong> Proc. Nat. Acad. Sci. 104: 3225-3230, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17296941/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17296941</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17296941[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.0611177104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17296941">Suchting et al. (2007)</a> found that, although Vegf expression was not significantly altered in Dll4 +/- mouse retinas, Dll4 +/- vessels showed increased expression of Vegf receptor-2 (VEGFR2, or KDR; <a href="/entry/191306">191306</a>) and decreased expression of Vegfr1 (FLT1; <a href="/entry/165070">165070</a>) compared with wildtype, suggesting they could be more responsive to Vegf stimulation. Expression of Dll4 in wildtype tip cells was itself decreased when Vegf signaling was blocked, suggesting that Dll4 may act downstream of Vegf to counter Vegf-mediated angiogenic sprouting. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17296941" 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="Hozumi, K., Mailhos, C., Negishi, N., Hirano, K., Yahata, T., Ando, K., Zuklys, S., Hollander, G. A., Shima, D. T., Habu, S. <strong>Delta-like 4 is indispensable in thymic environment specific for T cell development.</strong> J. Exp. Med. 205: 2507-2513, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18824583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18824583</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18824583[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/10.1084/jem.20080134" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18824583">Hozumi et al. (2008)</a> found that mice lacking Dll4 expression in thymic epithelial cells (TECs) exhibited a marked reduction of Notch1 in hematopoietic cells and a lack of Cd4 and Cd8 double- or single-positive T cells in thymus. The double-negative cell fraction also showed an absence of T-cell progenitors and an aberrant accumulation of B-lineage cells. Enforced expression of the intracellular fragment of Notch1 restored thymic T-cell differentiation. <a href="#5" class="mim-tip-reference" title="Hozumi, K., Mailhos, C., Negishi, N., Hirano, K., Yahata, T., Ando, K., Zuklys, S., Hollander, G. A., Shima, D. T., Habu, S. <strong>Delta-like 4 is indispensable in thymic environment specific for T cell development.</strong> J. Exp. Med. 205: 2507-2513, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18824583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18824583</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18824583[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/10.1084/jem.20080134" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18824583">Hozumi et al. (2008)</a> concluded that the thymus-specific environment for T-cell fate determination requires DLL4 expression to induce NOTCH signaling in cells immigrating into thymus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18824583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using immunohistochemical analysis, <a href="#7" class="mim-tip-reference" title="Koch, U., Fiorini, E., Benedito, R., Besseyrias, V., Schuster-Gossler, K., Pierres, M., Manley, N. R., Duarte, A., MacDonald, H. R., Radtke, F. <strong>Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment.</strong> J. Exp. Med. 205: 2515-2523, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18824585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18824585</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18824585[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/10.1084/jem.20080829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18824585">Koch et al. (2008)</a> demonstrated expression of Dll4, but not Dll1 (<a href="/entry/606582">606582</a>), on TECs in mice. Inactivation of Dll4 in TECs or hematopoietic progenitors in mice resulted in loss of T-cell development with no loss of thymus development, as well as ectopic appearance of immature B cells in thymus. These immature B cells were phenotypically indistinguishable from those developing in the thymus of conditional Notch1-deficient mice. <a href="#7" class="mim-tip-reference" title="Koch, U., Fiorini, E., Benedito, R., Besseyrias, V., Schuster-Gossler, K., Pierres, M., Manley, N. R., Duarte, A., MacDonald, H. R., Radtke, F. <strong>Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment.</strong> J. Exp. Med. 205: 2515-2523, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18824585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18824585</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18824585[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/10.1084/jem.20080829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18824585">Koch et al. (2008)</a> concluded that DLL4 is the essential and nonredundant Notch1 ligand responsible for T-cell fate specification. They proposed that NOTCH1-expressing thymic progenitors interact with DLL4-expressing TECs to suppress B-lineage potential and to induce the first steps of intrathymic T-cell development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18824585" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="allelicVariants" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<span href="#mimAllelicVariantsFold" id="mimAllelicVariantsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimAllelicVariantsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
|
|
</span>
|
|
<strong>6 Selected Examples</a>):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div id="mimAllelicVariantsFold" class="collapse in mimTextToggleFold">
|
|
<div>
|
|
<a href="/allelicVariants/605185" class="btn btn-default" role="button"> Table View </a>
|
|
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=605185[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 ADAMS-OLIVER SYNDROME 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
DLL4, GLN554TER (<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000240088" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000240088</a>)
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs796065344 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs796065344;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs796065344" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs796065344" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000190434 OR RCV000195286" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000190434, RCV000195286" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000190434...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sisters and their mother (family 1) with Adams-Oliver syndrome (AOS6; <a href="/entry/616589">616589</a>), <a href="#11" class="mim-tip-reference" title="Meester, J. A. N., Southgate, L., Stittrich, A.-B., Venselaar, H., Beekmans, S. J. A., den Hollander, N., Bijlsma, E., Helderman-van den Enden, A., Verheij, J. B. G. M., Glusman, G., Roach, J. C., Lehman, A., and 12 others. <strong>Heterozygous loss-of-function mutations in DLL4 cause Adams-Oliver syndrome.</strong> Am. J. Hum. Genet. 97: 475-482, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26299364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26299364</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26299364[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2015.07.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26299364">Meester et al. (2015)</a> identified heterozygosity for a c.1660C-T transition (<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000240088" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000240088</a>) in exon 9 of the DLL4 gene, resulting in a gln554-to-ter (Q554X) substitution within the intracellular domain. The mutation was not found in an unaffected sister or the unaffected maternal grandmother, but was also not detected in the apparently affected maternal grandfather. Failing to demonstrate somatic mosaicism in his blood, <a href="#11" class="mim-tip-reference" title="Meester, J. A. N., Southgate, L., Stittrich, A.-B., Venselaar, H., Beekmans, S. J. A., den Hollander, N., Bijlsma, E., Helderman-van den Enden, A., Verheij, J. B. G. M., Glusman, G., Roach, J. C., Lehman, A., and 12 others. <strong>Heterozygous loss-of-function mutations in DLL4 cause Adams-Oliver syndrome.</strong> Am. J. Hum. Genet. 97: 475-482, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26299364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26299364</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26299364[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2015.07.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26299364">Meester et al. (2015)</a> suggested that somatic mosaicism not affecting hematopoietic tissue remained a possible explanation. The severity of clinical features in this family varied widely: the proband had aplasia cutis congenita (ACC), brachysyndactyly of the second and third toes of her right foot, tricuspid insufficiency, and ventricular septal defect. Her sister exhibited only ACC, and their mother had only short distal phalanges. The maternal grandfather had left brachydactyly of the third and fourth toes confirmed by x-ray. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26299364" 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 ADAMS-OLIVER SYNDROME 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
DLL4, ARG558TER (<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000240089" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000240089</a>)
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs61750844 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61750844;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs61750844" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs61750844" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000190435 OR RCV000195290" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000190435, RCV000195290" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000190435...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sisters (family 2) with Adams-Oliver syndrome (AOS6; <a href="/entry/616589">616589</a>), <a href="#11" class="mim-tip-reference" title="Meester, J. A. N., Southgate, L., Stittrich, A.-B., Venselaar, H., Beekmans, S. J. A., den Hollander, N., Bijlsma, E., Helderman-van den Enden, A., Verheij, J. B. G. M., Glusman, G., Roach, J. C., Lehman, A., and 12 others. <strong>Heterozygous loss-of-function mutations in DLL4 cause Adams-Oliver syndrome.</strong> Am. J. Hum. Genet. 97: 475-482, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26299364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26299364</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26299364[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2015.07.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26299364">Meester et al. (2015)</a> identified heterozygosity for a c.1672C-T transition (<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000240089" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000240089</a>) in exon 9 of the DLL4 gene, resulting in an arg558-to-ter (R558X) substitution within the intracellular domain. The mutation was also present in their unaffected father, indicating incomplete penetrance. Both sisters had aplasia cutis congenita with an underlying skull defect. In addition, 1 sister had brachydactyly of the left foot and missing toes on the right foot, whereas the other sister had bilateral brachysyndactyly of the feet, more severe on the left than right, and also exhibited small kidneys and mild hypertension. Both had normal echocardiograms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26299364" 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 ADAMS-OLIVER SYNDROME 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
DLL4, CYS390ARG (<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000240092" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000240092</a>)
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs796065347 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs796065347;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs796065347" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs796065347" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000190438 OR RCV000195284" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000190438, RCV000195284" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000190438...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a large 4-generation family (family 5) segregating autosomal dominant Adams-Oliver syndrome (AOS6; <a href="/entry/616589">616589</a>), <a href="#11" class="mim-tip-reference" title="Meester, J. A. N., Southgate, L., Stittrich, A.-B., Venselaar, H., Beekmans, S. J. A., den Hollander, N., Bijlsma, E., Helderman-van den Enden, A., Verheij, J. B. G. M., Glusman, G., Roach, J. C., Lehman, A., and 12 others. <strong>Heterozygous loss-of-function mutations in DLL4 cause Adams-Oliver syndrome.</strong> Am. J. Hum. Genet. 97: 475-482, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26299364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26299364</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26299364[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2015.07.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26299364">Meester et al. (2015)</a> identified heterozygosity for a c.1168T-C transition (<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000240092" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000240092</a>) in exon 8 of the DLL4 gene, resulting in a cys390-to-arg (C390R) substitution at a highly conserved residue involved in formation of a disulfide bond within the fifth EGF-like domain. Three-dimensional modeling indicated that an arginine would be too bulky to fit in this domain, suggesting that it would likely disrupt the structure. Affected family members exhibited highly variable clinical expression, with mildly affected parents having severely affected offspring. Scalp abnormalities ranged from a bald area in 4 affected individuals to aplasia cutis congenita (ACC) with underlying skull defect in 1 patient. Two family members exhibited cutis marmorata, and 1 individual with ACC also had congenital splenomegaly, hepatic fibrosis, portal hypertension, and esophageal varices. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26299364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0004" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 ADAMS-OLIVER SYNDROME 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
DLL4, CYS390TYR (<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000240091" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000240091</a>)
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs796065346 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs796065346;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs796065346" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs796065346" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000190437 OR RCV000195288" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000190437, RCV000195288" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000190437...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female patient (family 4) with isolated aplasia cutis congenita (AOS6; <a href="/entry/616589">616589</a>), <a href="#11" class="mim-tip-reference" title="Meester, J. A. N., Southgate, L., Stittrich, A.-B., Venselaar, H., Beekmans, S. J. A., den Hollander, N., Bijlsma, E., Helderman-van den Enden, A., Verheij, J. B. G. M., Glusman, G., Roach, J. C., Lehman, A., and 12 others. <strong>Heterozygous loss-of-function mutations in DLL4 cause Adams-Oliver syndrome.</strong> Am. J. Hum. Genet. 97: 475-482, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26299364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26299364</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26299364[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2015.07.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26299364">Meester et al. (2015)</a> identified heterozygosity for a c.1169G-A transition (<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000240091" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000240091</a>) in exon 8 of the DLL4 gene, resulting in a cys390-to-tyr (C390Y) substitution at a highly conserved residue involved in formation of a disulfide bond within the fifth EGF-like domain. Three-dimensional modeling indicated that a tyrosine would be too bulky to fit in this domain, suggesting that it would likely disrupt the structure. Family members were unavailable for screening. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26299364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0005" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 ADAMS-OLIVER SYNDROME 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
DLL4, ALA121PRO (<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000240095" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000240095</a>)
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs796065350 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs796065350;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs796065350" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs796065350" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000190441 OR RCV000195289" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000190441, RCV000195289" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000190441...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female patient (family 8) with aplasia cutis congenita, symbrachydactyly of both feet, truncus arteriosus, and ventricular septal defect (AOS6; <a href="/entry/616589">616589</a>), <a href="#11" class="mim-tip-reference" title="Meester, J. A. N., Southgate, L., Stittrich, A.-B., Venselaar, H., Beekmans, S. J. A., den Hollander, N., Bijlsma, E., Helderman-van den Enden, A., Verheij, J. B. G. M., Glusman, G., Roach, J. C., Lehman, A., and 12 others. <strong>Heterozygous loss-of-function mutations in DLL4 cause Adams-Oliver syndrome.</strong> Am. J. Hum. Genet. 97: 475-482, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26299364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26299364</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26299364[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2015.07.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26299364">Meester et al. (2015)</a> identified heterozygosity for a c.361G-C transversion (<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000240095" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000240095</a>) in exon 3 of the DLL4 gene, resulting in an ala121-to-pro (A121P) substitution at a highly conserved residue within a beta-strand on the inside of the MNNL domain. The authors noted that the MNNL domain is involved in NOTCH-receptor (see <a href="/entry/190198">190198</a>) binding and predicted that the change would disrupt local structure and function. The mutation was not found in her unaffected parents, indicating that the alteration arose de novo in the proband. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26299364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0006" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 ADAMS-OLIVER SYNDROME 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
DLL4, ARG186CYS (<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000240093" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000240093</a>)
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs796065348 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs796065348;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs796065348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs796065348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000190439 OR RCV000195285 OR RCV004730899" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000190439, RCV000195285, RCV004730899" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000190439...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a father and son (family 6) with isolated aplasia cutis congenita (AOS6; <a href="/entry/616589">616589</a>), <a href="#11" class="mim-tip-reference" title="Meester, J. A. N., Southgate, L., Stittrich, A.-B., Venselaar, H., Beekmans, S. J. A., den Hollander, N., Bijlsma, E., Helderman-van den Enden, A., Verheij, J. B. G. M., Glusman, G., Roach, J. C., Lehman, A., and 12 others. <strong>Heterozygous loss-of-function mutations in DLL4 cause Adams-Oliver syndrome.</strong> Am. J. Hum. Genet. 97: 475-482, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26299364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26299364</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26299364[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2015.07.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26299364">Meester et al. (2015)</a> identified heterozygosity for a c.556C-T transition (<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000240093" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000240093</a>) in exon 4 of the DLL4 gene, resulting in an arg186-to-cys (R186C) substitution at a conserved residue within the surface loop of the ligand-binding DSL domain. The change was predicted to reduce the binding affinity of DLL4 to NOTCH1 (<a href="/entry/190198">190198</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26299364" 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="Benedito2012" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Benedito, R., Rocha, S. F., Woeste, M., Zamykal, M., Radtke, F., Casanovas, O., Duarte, A., Pytowski, B., Adams, R. H.
|
|
<strong>Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling.</strong>
|
|
Nature 484: 110-114, 2012.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22426001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22426001</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22426001" 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/nature10908" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="2" class="mim-anchor"></a>
|
|
<a id="Duarte2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Duarte, A., Hirashima, M., Benedito, R., Trindade, A., Diniz, P., Bekman, E., Costa, L., Henrique, D., Rossant, J.
|
|
<strong>Dosage-sensitive requirement for mouse Dll4 in artery development.</strong>
|
|
Genes Dev. 18: 2474-2478, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15466159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15466159</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15466159[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=15466159" 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.1239004" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="3" class="mim-anchor"></a>
|
|
<a id="Gale2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Gale, N. W., Dominguez, M. G., Noguera, I., Pan, L., Hughes, V., Valenzuela, D. M., Murphy, A. J., Adams, N. C., Lin, H. C., Holash, J., Thurston, G., Yancopoulos, G. D.
|
|
<strong>Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development.</strong>
|
|
Proc. Nat. Acad. Sci. 101: 15949-15954, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15520367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15520367</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15520367[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=15520367" 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.0407290101" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="4" class="mim-anchor"></a>
|
|
<a id="Hellstrom2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Hellstrom, M., Phng, L.-K., Hofmann, J. J., Wallgard, E., Coultas, L., Lindblom, P., Alva, J., Nilsson, A.-K., Karlsson, L., Gaiano, N., Yoon, K., Rossant, J., Iruela-Arispe, M. L., Kalen, M., Gerhardt, H., Betsholtz, C.
|
|
<strong>Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis.</strong>
|
|
Nature 445: 776-780, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17259973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17259973</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17259973" 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/nature05571" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="5" class="mim-anchor"></a>
|
|
<a id="Hozumi2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Hozumi, K., Mailhos, C., Negishi, N., Hirano, K., Yahata, T., Ando, K., Zuklys, S., Hollander, G. A., Shima, D. T., Habu, S.
|
|
<strong>Delta-like 4 is indispensable in thymic environment specific for T cell development.</strong>
|
|
J. Exp. Med. 205: 2507-2513, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18824583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18824583</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18824583[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=18824583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1084/jem.20080134" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="6" class="mim-anchor"></a>
|
|
<a id="Ito2009" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Ito, T., Schaller, M., Hogaboam, C. M., Standiford, T. J., Sandor, M., Lukacs, N. W., Chensue, S. W., Kunkel, S. L.
|
|
<strong>TLR9 regulates the mycobacteria-elicited pulmonary granulomatous immune response in mice through DC-derived Notch ligand delta-like 4.</strong>
|
|
J. Clin. Invest. 119: 33-46, 2009.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19075396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19075396</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19075396[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=19075396" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1172/JCI35647" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="7" class="mim-anchor"></a>
|
|
<a id="Koch2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Koch, U., Fiorini, E., Benedito, R., Besseyrias, V., Schuster-Gossler, K., Pierres, M., Manley, N. R., Duarte, A., MacDonald, H. R., Radtke, F.
|
|
<strong>Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment.</strong>
|
|
J. Exp. Med. 205: 2515-2523, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18824585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18824585</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18824585[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=18824585" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1084/jem.20080829" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="8" class="mim-anchor"></a>
|
|
<a id="Krebs2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Krebs, L. T., Shutter, J. R., Tanigaki, K., Honjo, T., Stark, K. L., Gridley, T.
|
|
<strong>Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants.</strong>
|
|
Genes Dev. 18: 2469-2473, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15466160/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15466160</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15466160[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=15466160" 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.1239204" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="9" class="mim-anchor"></a>
|
|
<a id="Lobov2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Lobov, I. B., Renard, R. A., Papadopoulos, N., Gale, N. W., Thurston, G., Yancopoulos, G. D., Wiegand, S. J.
|
|
<strong>Delta-like ligand 4 (DII4) is induced by VEGF as a negative regulator of angiogenic sprouting.</strong>
|
|
Proc. Nat. Acad. Sci. 104: 3219-3224, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17296940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17296940</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17296940[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=17296940" 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.0611206104" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="10" class="mim-anchor"></a>
|
|
<a id="Luca2015" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Luca, V. C., Jude, K. M., Pierce, N. W., Nachury, M. V., Fischer, S., Garcia, K. C.
|
|
<strong>Structural basis for Notch1 engagement of delta-like 4.</strong>
|
|
Science 347: 847-853, 2015.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25700513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25700513</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25700513[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=25700513" 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.1261093" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="11" class="mim-anchor"></a>
|
|
<a id="Meester2015" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Meester, J. A. N., Southgate, L., Stittrich, A.-B., Venselaar, H., Beekmans, S. J. A., den Hollander, N., Bijlsma, E., Helderman-van den Enden, A., Verheij, J. B. G. M., Glusman, G., Roach, J. C., Lehman, A., and 12 others.
|
|
<strong>Heterozygous loss-of-function mutations in DLL4 cause Adams-Oliver syndrome.</strong>
|
|
Am. J. Hum. Genet. 97: 475-482, 2015.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26299364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26299364</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26299364[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=26299364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/j.ajhg.2015.07.015" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="12" class="mim-anchor"></a>
|
|
<a id="Noguera-Troise2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Noguera-Troise, I., Daly, C., Papadopoulos, N. J., Coetzee, S., Boland, P., Gale, N. W., Lin, H. C., Yancopoulos, G. D., Thurston, G.
|
|
<strong>Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis.</strong>
|
|
Nature 444: 1032-1037, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17183313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17183313</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17183313" 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/nature05355" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="13" class="mim-anchor"></a>
|
|
<a id="Ridgway2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Ridgway, J., Zhang, G., Wu, Y., Stawicki, S., Liang, W.-C., Chanthery, Y., Kowalski, J., Watts, R. J., Callahan, C., Kasman, I., Singh, M., Chien, M., Tan, C., Hongo, J.-A. S., de Sauvage, F., Plowman, G., Yan, M.
|
|
<strong>Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis.</strong>
|
|
Nature 444: 1083-1087, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17183323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17183323</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17183323" 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/nature05313" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="14" class="mim-anchor"></a>
|
|
<a id="Shutter2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Shutter, J. R., Scully, S., Fan, W., Richards, W. G., Kitajewski, J., Deblandre, G. A., Kintner, C. R., Stark, K. L.
|
|
<strong>Dll4, a novel Notch ligand expressed in arterial endothelium.</strong>
|
|
Genes Dev. 14: 1313-1318, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10837024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10837024</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10837024[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=10837024" 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="15" class="mim-anchor"></a>
|
|
<a id="Stumpf2020" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Stumpf, A. M.
|
|
<strong>Personal Communication.</strong>
|
|
Baltimore, Md. 03/16/2020.
|
|
|
|
|
|
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="16" class="mim-anchor"></a>
|
|
<a id="Suchting2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Suchting, S., Freitas, C., le Noble, F., Benedito, R., Breant, C., Duarte, A., Eichmann, A.
|
|
<strong>The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching.</strong>
|
|
Proc. Nat. Acad. Sci. 104: 3225-3230, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17296941/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17296941</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17296941[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=17296941" 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.0611177104" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="17" class="mim-anchor"></a>
|
|
<a id="Wimmer2019" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Wimmer, R. A., Leopoldi, A., Aichinger, M., Wick, N., Hantusch, B., Novatchkova, M., Taubenschmid, J., Hammerle, M., Esk, C., Bagley, J. A., Lindenhofer, D., Chen, G., Boehm, M., Agu, C. A., Yang, F., Fu, B., Zuber, J., Knoblich, J. A., Kerjaschki, D., Penninger, J. M.
|
|
<strong>Human blood vessel organoids as a model of diabetic vasculopathy.</strong>
|
|
Nature 565: 505-510, 2019.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30651639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30651639</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30651639" 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/s41586-018-0858-8" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
</ol>
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="contributors" class="mim-anchor"></a>
|
|
|
|
<div class="row">
|
|
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
|
<span class="mim-text-font">
|
|
<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Anne M. Stumpf - updated : 03/16/2020
|
|
</span>
|
|
</div>
|
|
</div>
|
|
<div class="row collapse" id="mimCollapseContributors">
|
|
<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Ada Hamosh - updated : 06/06/2019<br>Marla J. F. O'Neill - updated : 10/6/2015<br>Ada Hamosh - updated : 3/11/2015<br>Paul J. Converse - updated : 7/16/2012<br>Matthew B. Gross - updated : 10/9/2009<br>Paul J. Converse - updated : 10/8/2009<br>Ada Hamosh - updated : 6/26/2007<br>Ada Hamosh - updated : 4/20/2007<br>Patricia A. Hartz - updated : 4/13/2007<br>Patricia A. Hartz - updated : 3/1/2007<br>Victor A. McKusick - updated : 12/17/2004
|
|
</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">
|
|
Patti M. Sherman : 7/31/2000
|
|
</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">
|
|
alopez : 03/16/2020
|
|
</span>
|
|
</div>
|
|
</div>
|
|
<div class="row collapse" id="mimCollapseEditHistory">
|
|
<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
carol : 08/08/2019<br>alopez : 06/06/2019<br>alopez : 02/13/2018<br>carol : 04/21/2016<br>carol : 10/15/2015<br>carol : 10/14/2015<br>carol : 10/6/2015<br>alopez : 3/11/2015<br>mgross : 7/20/2012<br>terry : 7/16/2012<br>alopez : 4/25/2012<br>mgross : 10/9/2009<br>mgross : 10/9/2009<br>terry : 10/8/2009<br>alopez : 7/2/2007<br>terry : 6/26/2007<br>alopez : 4/24/2007<br>terry : 4/20/2007<br>mgross : 4/17/2007<br>terry : 4/13/2007<br>mgross : 3/1/2007<br>tkritzer : 1/11/2005<br>terry : 12/17/2004<br>mcapotos : 8/7/2000<br>psherman : 8/1/2000
|
|
</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> 605185
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
DELTA-LIKE CANONICAL NOTCH LIGAND 4; DLL4
|
|
|
|
</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">
|
|
DELTA-LIKE 4
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: DLL4</em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 15q15.1
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 15:40,929,340-40,939,073 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
15q15.1
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Adams-Oliver syndrome 6
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
616589
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Notch (see 190198) signaling controls cell fate specification in a variety of cell contexts during embryonic and postnatal development. DLL4 is a transmembrane ligand for Notch receptors that shows restricted expression to endothelial cells (ECs), in particular to arteries and capillaries, and is involved in vascular development (Suchting et al., 2007). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Shutter et al. (2000) identified Dll4 as a mouse EST encoding a polypeptide with homology to the DSL family of Notch ligands. By searching a DNA sequence database with the mouse Dll4 sequence, they identified a partial human brain DLL4 cDNA. Using this partial DLL4 cDNA, Shutter et al. (2000) isolated a full-length human DLL4 coding sequence. The predicted 685-amino acid DLL4 protein exhibits all of the hallmarks of the Delta family of Notch ligands. It has an extracellular region containing 8 EGF-like repeats and a DSL domain involved in Notch binding, as well as a transmembrane domain and a cytoplasmic tail that lacks catalytic motifs. Human DLL4 shares 87% amino acid sequence identity with mouse Dll4. Northern blot analysis of mouse tissues detected highest Dll4 expression in lung, followed by heart, kidney, skeletal muscle, and brain; Dll4 expression was barely detectable in spleen and testis. Northern blot analysis of whole mouse embryos demonstrated increased expression of Dll4 from embryonic day 7 through 17. Analysis by RT-PCR revealed a low level of Dll4 expression in all tissues examined, with higher levels in lung, brown and white adipose, and adrenal. In situ hybridization of mouse tissues showed a strikingly specific expression pattern. In both embryonic and adult tissues, the predominant site of Dll4 expression was the vascular endothelium. Shutter et al. (2000) found a similar expression pattern for human DLL4 by in situ analysis. They suggested that DLL4 is involved in the regulation of vascular biology. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Biochemical Features</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Crystal Structure</em></strong></p><p>
|
|
Luca et al. (2015) determined the crystal structure of the interacting regions of the NOTCH1-DLL4 complex at 2.3-angstrom resolution. The complex reveals a 2-site, antiparallel binding orientation assisted by NOTCH1 O-linked glycosylation. NOTCH1 EGF-like repeats 11 and 12 interact with the DLL4 Delta/Serrate/Lag2 (DSL) domain and module at the N terminus of Notch ligand (MNNL) domains, respectively. Threonine and serine residues on NOTCH1 are functionalized with O-fucose and O-glucose, which act as surrogate amino acids by making specific and essential contacts to residues on DLL4. The elucidation of a direct chemical role for O-glycans in NOTCH1 ligand engagement demonstrates how, by relying on posttranslational modifications of their ligand binding sites, Notch proteins have linked their functional capacity to developmentally regulated biosynthetic pathways. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>By radiation hybrid mapping, Shutter et al. (2000) mapped the DLL4 gene to 15q21.1. By FISH, they mapped the mouse Dll4 gene to 2E3, a region sharing homology of synteny with human 15q. </p><p>Stumpf (2020) mapped the DLL4 gene to chromosome 15q15.1 based on an alignment of the DLL4 sequence (GenBank AF253468) with the genomic sequence (GRCh38).</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Shutter et al. (2000) demonstrated that mouse Dll4 could activate mouse Notch1 (190198) and mouse Notch4 (164951). </p><p>Noguera-Troise et al. (2006) reported that VEGF (192240) dynamically regulates tumor endothelial expression of DLL4, which had been shown to be absolutely required for normal embryonic vascular development (Duarte et al., 2004; Gale et al., 2004; Krebs et al., 2004). To define Dll4 function in tumor angiogenesis, Noguera-Troise et al. (2006) manipulated this pathway in murine tumor models using several approaches. They showed that blockade resulted in markedly increased tumor vascularity, associated with enhanced angiogenic sprouting and branching. Paradoxically, this increased vascularity was nonproductive--as shown by poor perfusion and increased hypoxia, and most importantly, by decreased tumor growth--even for tumors resistant to anti-VEGF therapy. Thus, Noguera-Troise et al. (2006) concluded that VEGF-induced Dll4 acts as a negative regulator of tumor angiogenesis; its blockade results in the striking uncoupling of tumor growth from vessel density, presenting a novel therapeutic approach even for tumors resistant to anti-VEGF therapies. </p><p>Ridgway et al. (2006) showed that DLL4-mediated Notch signaling has a unique role in regulating endothelial cell proliferation and differentiation. Neutralizing DLL4 with a DLL4-selective antibody rendered endothelial cells hyperproliferative, and caused defective cell fate specification or differentiation both in vitro and in vivo. In addition, blocking DLL4 inhibited tumor growth in several tumor models. Remarkably, antibodies against DLL4 and antibodies against VEGF had paradoxically distinct effects on tumor vasculature. Ridgway et al. (2006) stated that their data also indicated that DLL4-mediated Notch signaling is crucial during active vascularization, but less important for normal vessel maintenance. Furthermore, unlike blocking Notch signaling globally, neutralizing DLL4 had no discernible impact on intestinal goblet cell differentiation, supporting the idea that DLL4-mediated Notch signaling is largely restricted to the vascular compartment. </p><p>Hellstrom et al. (2007) presented evidence that Dll4-Notch1 signaling regulates the formation of appropriate numbers of tip cells to control vessel sprouting and branching in mouse retina. They showed that inhibition of Notch signaling using gamma-secretase inhibitors, genetic inactivation of 1 allele of the endothelial Notch ligand Dll4, or endothelial-specific genetic deletion of Notch1 all promoted increased numbers of tip cells. Conversely, activation of Notch by a soluble jagged1 (601920) peptide led to fewer tip cells and vessel branches. Dll4 and reporters of Notch signaling are distributed in a mosaic pattern among endothelial cells of actively sprouting retinal vessels. At this location, Notch1-deleted endothelial cells preferentially assumed tip cell characteristics. Hellstrom et al. (2007) concluded that Dll4-Notch1 signaling between the endothelial cells within the angiogenic sprout restricts tip cell formation in response to VEGF, thereby establishing the adequate ratio between tip and stalk cells required for correct sprouting and branching patterns. The authors further concluded that their model offered an explanation for the dose dependency and haploinsufficiency of the DLL4 gene, and indicated that modulators of DLL4 or Notch signaling, such as gamma-secretase inhibitors developed for Alzheimer disease (104300), might find usage as pharmacologic regulators of angiogenesis. </p><p>Ito et al. (2009) observed altered T helper-17 (Th17; see 603149) cytokine phenotypes in Tlr9 (605474) -/- mice during Mycobacterium antigen-elicited pulmonary granuloma formulation, as well as decreased accumulation of granuloma-associated myeloid dendritic cells (DCs) and profoundly impaired Dll4 expression. DCs, but not macrophages, from wildtype mice promoted differentiation of Th17 cells from mycobacteria-challenged lung Cd4 (186940)-positive T cells. Treating wildtype mice with anti-Dll4 during granuloma formation resulted in larger granulomas and lower levels of Th17 cytokines. Ito et al. (2009) concluded that DLL4 plays an important role in promoting Th17 effector activity during mycobacterial challenge. They suggested that TLR9 may be required for optimal DLL4 expression and regulation of granuloma formation in response to mycobacterial antigen. </p><p>Benedito et al. (2012) used inducible loss-of-function genetics in combination with inhibitors in vivo to demonstrate that DLL4 protein expression in retinal tip cells is only weakly modulated by VEGFR2 (191306) signaling. Surprisingly, Notch inhibition also had no significant impact on VEGFR2 expression and induced deregulated endothelial sprouting and proliferation even in the absence of VEGFR2, which is the most important VEGFA receptor and is considered to be indispensable for these processes. By contrast, VEGFR3 (136352), the main receptor for VEGFC (601528), was strongly modulated by Notch. VEGFR3 kinase activity inhibitors but not ligand-blocking antibodies suppressed the sprouting of endothelial cells that had low Notch signaling activity. Benedito et al. (2012) concluded that their results established that VEGFR2 and VEGFR3 are regulated in a highly differential manner by Notch. They proposed that successful antiangiogenic targeting of these receptors and their ligands will strongly depend on the status of endothelial Notch signaling. </p><p>Wimmer et al. (2019) reported the development of self-organizing 3-dimensional human blood vessel organoids from pluripotent stem cells. These human blood vessel organoids contain endothelial cells and pericytes that self-assemble into capillary networks that are enveloped by a basement membrane. Human blood vessel organoids transplanted into mice formed a stable, perfused vascular tree, including arteries, arterioles, and venules. Exposure of blood vessel organoids to hyperglycemia and inflammatory cytokines in vitro induced thickening of the vascular basement membrane. Human blood vessels exposed in vivo to a diabetic milieu in mice also mimicked the microvascular changes found in patients with diabetes. DLL4 and NOTCH3 (600276) were identified as key drivers of diabetic vasculopathy in human blood vessels. Wimmer et al. (2019) concluded that organoids derived from human stem cells faithfully recapitulate the structure and function of human blood vessels and are amenable systems for modeling and identifying the regulators of diabetic vasculopathy. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Meester et al. (2015) screened 91 families with Adams-Oliver syndrome (see AOS6, 616589) for mutations in the candidate gene DLL4 and identified heterozygous nonsense and missense mutations in 9 families (see, e.g., 605185.0001-605185.0006). Incomplete penetrance as well as marked intrafamilial variability in phenotypic expression was observed; the authors suggested that other genetic, epigenetic, or environmental factors might be involved in the clinical expression of the disease. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Vascular development depends on the highly coordinated actions of a variety of angiogenic regulators, most of which apparently act downstream of vascular endothelial growth factor (VEGF; 192240). One potential such regulator is Dll4, a partner for Notch receptors. Gale et al. (2004) generated mice in which the Dll4 gene was replaced with a reporter gene and found that Dll4 expression was initially restricted to large arteries in the embryo, whereas in adult mice and tumor models, D114 was specifically expressed in smaller arteries and microvessels, with a striking break in expression just as capillaries merge into venules. Consistent with these arterial-specific expression patterns, heterozygous deletion of Dll4 resulted in prominent, albeit variable, defects in arterial development (reminiscent of those in Notch knockouts), including abnormal stenosis and atresia of the aorta, defective arterial branching from the aorta, and even arterial regression, with occasional extension of the defects to the venous circulation; also noted was gross enlargement of the pericardial sac and failure to remodel the yolk sac vasculature. These striking phenotypes resulting from heterozygous deletion of Dll4 indicated that vascular development may be as sensitive to subtle changes in DLL4 dosage as it is to subtle changes in VEGF dosage, because VEGF accounts for the only other example of haploinsufficiency, resulting in obvious vascular abnormalities. Gale et al. (2004) concluded that DLL4 appeared to be a major trigger of Notch receptor activities previously implicated in arterial and vascular development. Krebs et al. (2004) and Duarte et al. (2004) reported similar findings. </p><p>Lobov et al. (2007) found that Dll4 was most prominently expressed at the leading front of actively growing vessels in postnatal mouse retina, and its expression was dynamically regulated by Vegf. Deletion of a single Dll4 allele or pharmacologic inhibition of Dll4/Notch signaling produced characteristic abnormalities in the developing retinal vasculature, most notably enhanced angiogenic sprouting and increased endothelial cell proliferation, resulting in formation of a denser and more highly interconnected superficial capillary plexus. In a model of ischemic retinopathy, Dll4 blockade enhanced angiogenic sprouting and regrowth of lost retinal vessels while suppressing ectopic pathologic neovascularization. Lobov et al. (2007) concluded that DLL4 is induced by VEGF as a negative feedback regulator and prevents overexuberant angiogenic sprouting, promoting formation of a well differentiated vasculature. </p><p>Suchting et al. (2007) found that, although Vegf expression was not significantly altered in Dll4 +/- mouse retinas, Dll4 +/- vessels showed increased expression of Vegf receptor-2 (VEGFR2, or KDR; 191306) and decreased expression of Vegfr1 (FLT1; 165070) compared with wildtype, suggesting they could be more responsive to Vegf stimulation. Expression of Dll4 in wildtype tip cells was itself decreased when Vegf signaling was blocked, suggesting that Dll4 may act downstream of Vegf to counter Vegf-mediated angiogenic sprouting. </p><p>Hozumi et al. (2008) found that mice lacking Dll4 expression in thymic epithelial cells (TECs) exhibited a marked reduction of Notch1 in hematopoietic cells and a lack of Cd4 and Cd8 double- or single-positive T cells in thymus. The double-negative cell fraction also showed an absence of T-cell progenitors and an aberrant accumulation of B-lineage cells. Enforced expression of the intracellular fragment of Notch1 restored thymic T-cell differentiation. Hozumi et al. (2008) concluded that the thymus-specific environment for T-cell fate determination requires DLL4 expression to induce NOTCH signaling in cells immigrating into thymus. </p><p>Using immunohistochemical analysis, Koch et al. (2008) demonstrated expression of Dll4, but not Dll1 (606582), on TECs in mice. Inactivation of Dll4 in TECs or hematopoietic progenitors in mice resulted in loss of T-cell development with no loss of thymus development, as well as ectopic appearance of immature B cells in thymus. These immature B cells were phenotypically indistinguishable from those developing in the thymus of conditional Notch1-deficient mice. Koch et al. (2008) concluded that DLL4 is the essential and nonredundant Notch1 ligand responsible for T-cell fate specification. They proposed that NOTCH1-expressing thymic progenitors interact with DLL4-expressing TECs to suppress B-lineage potential and to induce the first steps of intrathymic T-cell development. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>6 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 ADAMS-OLIVER SYNDROME 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
DLL4, GLN554TER ({dbSNP SCV000240088})
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs796065344,
|
|
|
|
|
|
|
|
ClinVar: RCV000190434, RCV000195286
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sisters and their mother (family 1) with Adams-Oliver syndrome (AOS6; 616589), Meester et al. (2015) identified heterozygosity for a c.1660C-T transition (SCV000240088) in exon 9 of the DLL4 gene, resulting in a gln554-to-ter (Q554X) substitution within the intracellular domain. The mutation was not found in an unaffected sister or the unaffected maternal grandmother, but was also not detected in the apparently affected maternal grandfather. Failing to demonstrate somatic mosaicism in his blood, Meester et al. (2015) suggested that somatic mosaicism not affecting hematopoietic tissue remained a possible explanation. The severity of clinical features in this family varied widely: the proband had aplasia cutis congenita (ACC), brachysyndactyly of the second and third toes of her right foot, tricuspid insufficiency, and ventricular septal defect. Her sister exhibited only ACC, and their mother had only short distal phalanges. The maternal grandfather had left brachydactyly of the third and fourth toes confirmed by x-ray. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 ADAMS-OLIVER SYNDROME 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
DLL4, ARG558TER ({dbSNP SCV000240089})
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs61750844,
|
|
|
|
|
|
|
|
ClinVar: RCV000190435, RCV000195290
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sisters (family 2) with Adams-Oliver syndrome (AOS6; 616589), Meester et al. (2015) identified heterozygosity for a c.1672C-T transition (SCV000240089) in exon 9 of the DLL4 gene, resulting in an arg558-to-ter (R558X) substitution within the intracellular domain. The mutation was also present in their unaffected father, indicating incomplete penetrance. Both sisters had aplasia cutis congenita with an underlying skull defect. In addition, 1 sister had brachydactyly of the left foot and missing toes on the right foot, whereas the other sister had bilateral brachysyndactyly of the feet, more severe on the left than right, and also exhibited small kidneys and mild hypertension. Both had normal echocardiograms. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 ADAMS-OLIVER SYNDROME 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
DLL4, CYS390ARG ({dbSNP SCV000240092})
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs796065347,
|
|
|
|
|
|
|
|
ClinVar: RCV000190438, RCV000195284
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a large 4-generation family (family 5) segregating autosomal dominant Adams-Oliver syndrome (AOS6; 616589), Meester et al. (2015) identified heterozygosity for a c.1168T-C transition (SCV000240092) in exon 8 of the DLL4 gene, resulting in a cys390-to-arg (C390R) substitution at a highly conserved residue involved in formation of a disulfide bond within the fifth EGF-like domain. Three-dimensional modeling indicated that an arginine would be too bulky to fit in this domain, suggesting that it would likely disrupt the structure. Affected family members exhibited highly variable clinical expression, with mildly affected parents having severely affected offspring. Scalp abnormalities ranged from a bald area in 4 affected individuals to aplasia cutis congenita (ACC) with underlying skull defect in 1 patient. Two family members exhibited cutis marmorata, and 1 individual with ACC also had congenital splenomegaly, hepatic fibrosis, portal hypertension, and esophageal varices. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 ADAMS-OLIVER SYNDROME 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
DLL4, CYS390TYR ({dbSNP SCV000240091})
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs796065346,
|
|
|
|
|
|
|
|
ClinVar: RCV000190437, RCV000195288
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female patient (family 4) with isolated aplasia cutis congenita (AOS6; 616589), Meester et al. (2015) identified heterozygosity for a c.1169G-A transition (SCV000240091) in exon 8 of the DLL4 gene, resulting in a cys390-to-tyr (C390Y) substitution at a highly conserved residue involved in formation of a disulfide bond within the fifth EGF-like domain. Three-dimensional modeling indicated that a tyrosine would be too bulky to fit in this domain, suggesting that it would likely disrupt the structure. Family members were unavailable for screening. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 ADAMS-OLIVER SYNDROME 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
DLL4, ALA121PRO ({dbSNP SCV000240095})
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs796065350,
|
|
|
|
|
|
|
|
ClinVar: RCV000190441, RCV000195289
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female patient (family 8) with aplasia cutis congenita, symbrachydactyly of both feet, truncus arteriosus, and ventricular septal defect (AOS6; 616589), Meester et al. (2015) identified heterozygosity for a c.361G-C transversion (SCV000240095) in exon 3 of the DLL4 gene, resulting in an ala121-to-pro (A121P) substitution at a highly conserved residue within a beta-strand on the inside of the MNNL domain. The authors noted that the MNNL domain is involved in NOTCH-receptor (see 190198) binding and predicted that the change would disrupt local structure and function. The mutation was not found in her unaffected parents, indicating that the alteration arose de novo in the proband. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 ADAMS-OLIVER SYNDROME 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
DLL4, ARG186CYS ({dbSNP SCV000240093})
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs796065348,
|
|
|
|
|
|
|
|
ClinVar: RCV000190439, RCV000195285, RCV004730899
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a father and son (family 6) with isolated aplasia cutis congenita (AOS6; 616589), Meester et al. (2015) identified heterozygosity for a c.556C-T transition (SCV000240093) in exon 4 of the DLL4 gene, resulting in an arg186-to-cys (R186C) substitution at a conserved residue within the surface loop of the ligand-binding DSL domain. The change was predicted to reduce the binding affinity of DLL4 to NOTCH1 (190198). </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">
|
|
Benedito, R., Rocha, S. F., Woeste, M., Zamykal, M., Radtke, F., Casanovas, O., Duarte, A., Pytowski, B., Adams, R. H.
|
|
<strong>Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling.</strong>
|
|
Nature 484: 110-114, 2012.
|
|
|
|
|
|
[PubMed: 22426001]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature10908]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Duarte, A., Hirashima, M., Benedito, R., Trindade, A., Diniz, P., Bekman, E., Costa, L., Henrique, D., Rossant, J.
|
|
<strong>Dosage-sensitive requirement for mouse Dll4 in artery development.</strong>
|
|
Genes Dev. 18: 2474-2478, 2004.
|
|
|
|
|
|
[PubMed: 15466159]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1101/gad.1239004]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gale, N. W., Dominguez, M. G., Noguera, I., Pan, L., Hughes, V., Valenzuela, D. M., Murphy, A. J., Adams, N. C., Lin, H. C., Holash, J., Thurston, G., Yancopoulos, G. D.
|
|
<strong>Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development.</strong>
|
|
Proc. Nat. Acad. Sci. 101: 15949-15954, 2004.
|
|
|
|
|
|
[PubMed: 15520367]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.0407290101]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hellstrom, M., Phng, L.-K., Hofmann, J. J., Wallgard, E., Coultas, L., Lindblom, P., Alva, J., Nilsson, A.-K., Karlsson, L., Gaiano, N., Yoon, K., Rossant, J., Iruela-Arispe, M. L., Kalen, M., Gerhardt, H., Betsholtz, C.
|
|
<strong>Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis.</strong>
|
|
Nature 445: 776-780, 2007.
|
|
|
|
|
|
[PubMed: 17259973]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature05571]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hozumi, K., Mailhos, C., Negishi, N., Hirano, K., Yahata, T., Ando, K., Zuklys, S., Hollander, G. A., Shima, D. T., Habu, S.
|
|
<strong>Delta-like 4 is indispensable in thymic environment specific for T cell development.</strong>
|
|
J. Exp. Med. 205: 2507-2513, 2008.
|
|
|
|
|
|
[PubMed: 18824583]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1084/jem.20080134]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ito, T., Schaller, M., Hogaboam, C. M., Standiford, T. J., Sandor, M., Lukacs, N. W., Chensue, S. W., Kunkel, S. L.
|
|
<strong>TLR9 regulates the mycobacteria-elicited pulmonary granulomatous immune response in mice through DC-derived Notch ligand delta-like 4.</strong>
|
|
J. Clin. Invest. 119: 33-46, 2009.
|
|
|
|
|
|
[PubMed: 19075396]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1172/JCI35647]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Koch, U., Fiorini, E., Benedito, R., Besseyrias, V., Schuster-Gossler, K., Pierres, M., Manley, N. R., Duarte, A., MacDonald, H. R., Radtke, F.
|
|
<strong>Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment.</strong>
|
|
J. Exp. Med. 205: 2515-2523, 2008.
|
|
|
|
|
|
[PubMed: 18824585]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1084/jem.20080829]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Krebs, L. T., Shutter, J. R., Tanigaki, K., Honjo, T., Stark, K. L., Gridley, T.
|
|
<strong>Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants.</strong>
|
|
Genes Dev. 18: 2469-2473, 2004.
|
|
|
|
|
|
[PubMed: 15466160]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1101/gad.1239204]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lobov, I. B., Renard, R. A., Papadopoulos, N., Gale, N. W., Thurston, G., Yancopoulos, G. D., Wiegand, S. J.
|
|
<strong>Delta-like ligand 4 (DII4) is induced by VEGF as a negative regulator of angiogenic sprouting.</strong>
|
|
Proc. Nat. Acad. Sci. 104: 3219-3224, 2007.
|
|
|
|
|
|
[PubMed: 17296940]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.0611206104]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Luca, V. C., Jude, K. M., Pierce, N. W., Nachury, M. V., Fischer, S., Garcia, K. C.
|
|
<strong>Structural basis for Notch1 engagement of delta-like 4.</strong>
|
|
Science 347: 847-853, 2015.
|
|
|
|
|
|
[PubMed: 25700513]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1261093]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Meester, J. A. N., Southgate, L., Stittrich, A.-B., Venselaar, H., Beekmans, S. J. A., den Hollander, N., Bijlsma, E., Helderman-van den Enden, A., Verheij, J. B. G. M., Glusman, G., Roach, J. C., Lehman, A., and 12 others.
|
|
<strong>Heterozygous loss-of-function mutations in DLL4 cause Adams-Oliver syndrome.</strong>
|
|
Am. J. Hum. Genet. 97: 475-482, 2015.
|
|
|
|
|
|
[PubMed: 26299364]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.ajhg.2015.07.015]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Noguera-Troise, I., Daly, C., Papadopoulos, N. J., Coetzee, S., Boland, P., Gale, N. W., Lin, H. C., Yancopoulos, G. D., Thurston, G.
|
|
<strong>Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis.</strong>
|
|
Nature 444: 1032-1037, 2006.
|
|
|
|
|
|
[PubMed: 17183313]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature05355]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ridgway, J., Zhang, G., Wu, Y., Stawicki, S., Liang, W.-C., Chanthery, Y., Kowalski, J., Watts, R. J., Callahan, C., Kasman, I., Singh, M., Chien, M., Tan, C., Hongo, J.-A. S., de Sauvage, F., Plowman, G., Yan, M.
|
|
<strong>Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis.</strong>
|
|
Nature 444: 1083-1087, 2006.
|
|
|
|
|
|
[PubMed: 17183323]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature05313]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Shutter, J. R., Scully, S., Fan, W., Richards, W. G., Kitajewski, J., Deblandre, G. A., Kintner, C. R., Stark, K. L.
|
|
<strong>Dll4, a novel Notch ligand expressed in arterial endothelium.</strong>
|
|
Genes Dev. 14: 1313-1318, 2000.
|
|
|
|
|
|
[PubMed: 10837024]
|
|
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Stumpf, A. M.
|
|
<strong>Personal Communication.</strong>
|
|
Baltimore, Md. 03/16/2020.
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Suchting, S., Freitas, C., le Noble, F., Benedito, R., Breant, C., Duarte, A., Eichmann, A.
|
|
<strong>The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching.</strong>
|
|
Proc. Nat. Acad. Sci. 104: 3225-3230, 2007.
|
|
|
|
|
|
[PubMed: 17296941]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.0611177104]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Wimmer, R. A., Leopoldi, A., Aichinger, M., Wick, N., Hantusch, B., Novatchkova, M., Taubenschmid, J., Hammerle, M., Esk, C., Bagley, J. A., Lindenhofer, D., Chen, G., Boehm, M., Agu, C. A., Yang, F., Fu, B., Zuber, J., Knoblich, J. A., Kerjaschki, D., Penninger, J. M.
|
|
<strong>Human blood vessel organoids as a model of diabetic vasculopathy.</strong>
|
|
Nature 565: 505-510, 2019.
|
|
|
|
|
|
[PubMed: 30651639]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/s41586-018-0858-8]
|
|
|
|
|
|
</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">
|
|
Anne M. Stumpf - updated : 03/16/2020<br>Ada Hamosh - updated : 06/06/2019<br>Marla J. F. O'Neill - updated : 10/6/2015<br>Ada Hamosh - updated : 3/11/2015<br>Paul J. Converse - updated : 7/16/2012<br>Matthew B. Gross - updated : 10/9/2009<br>Paul J. Converse - updated : 10/8/2009<br>Ada Hamosh - updated : 6/26/2007<br>Ada Hamosh - updated : 4/20/2007<br>Patricia A. Hartz - updated : 4/13/2007<br>Patricia A. Hartz - updated : 3/1/2007<br>Victor A. McKusick - updated : 12/17/2004
|
|
</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">
|
|
Patti M. Sherman : 7/31/2000
|
|
</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">
|
|
alopez : 03/16/2020<br>carol : 08/08/2019<br>alopez : 06/06/2019<br>alopez : 02/13/2018<br>carol : 04/21/2016<br>carol : 10/15/2015<br>carol : 10/14/2015<br>carol : 10/6/2015<br>alopez : 3/11/2015<br>mgross : 7/20/2012<br>terry : 7/16/2012<br>alopez : 4/25/2012<br>mgross : 10/9/2009<br>mgross : 10/9/2009<br>terry : 10/8/2009<br>alopez : 7/2/2007<br>terry : 6/26/2007<br>alopez : 4/24/2007<br>terry : 4/20/2007<br>mgross : 4/17/2007<br>terry : 4/13/2007<br>mgross : 3/1/2007<br>tkritzer : 1/11/2005<br>terry : 12/17/2004<br>mcapotos : 8/7/2000<br>psherman : 8/1/2000
|
|
</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 13, 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>
|
|
|
|
|