5490 lines
502 KiB
Text
5490 lines
502 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
|
|
|
|
- *170280 - PERFORIN 1; PRF1
|
|
|
|
|
|
- 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=170280"><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">*170280</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="#cloning">Cloning and Expression</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#mapping">Mapping</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="#molecularGenetics">Molecular Genetics</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation" style="margin-left: 1em">
|
|
<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</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/170280">Table View</a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#seeAlso"><strong>See Also</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#references"><strong>References</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#contributors"><strong>Contributors</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#creationDate"><strong>Creation Date</strong></a>
|
|
</li>
|
|
|
|
|
|
|
|
<li role="presentation">
|
|
<a href="#editHistory"><strong>Edit History</strong></a>
|
|
</li>
|
|
|
|
</ul>
|
|
|
|
</nav>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimFloatingLinksMenu">
|
|
|
|
<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
|
|
<h4 class="panel-title">
|
|
<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
|
|
<div style="display: table-row">
|
|
<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
|
|
|
|
<div style="display: table-cell;">External Links</div>
|
|
</div>
|
|
</a>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
|
|
<div id="mimExternalLinksFold" class="collapse in">
|
|
|
|
<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000180644;t=ENST00000441259" 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=5551" 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=170280" 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=ENSG00000180644;t=ENST00000441259" 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_001083116,NM_005041" 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_001083116" 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=170280" 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=01362&isoform_id=01362_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/PRF1" 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/35386,129819,189847,190340,705360,38649195,40254808,62088788,119574792,127798593,133908621,189053455,255661250,527461813,527461815,567319611,567319613,1707062224" 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/P14222" 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=5551" 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=ENSG00000180644;t=ENST00000441259" 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=PRF1" 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=PRF1" 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+5551" 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/PRF1" 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:5551" 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/5551" 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=chr10&hgg_gene=ENST00000441259.2&hgg_start=70597348&hgg_end=70602741&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
|
|
|
<div style="display: table-cell;">Clinical Resources</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
|
|
|
|
<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:9360" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://medlineplus.gov/genetics/gene/prf1" 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=170280[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=170280[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000180644" 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=PRF1" 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=PRF1" 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=PRF1" 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="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
|
|
<div id="mimLocusSpecificDBsFold" class="collapse">
|
|
<div style="margin-left: 0.5em;"><a href="http://structure.bmc.lu.se/idbase/PRF1base/" title="PRF1base: Mutation registry for Familiar haemophagocytic lymphohistiocytosis, type II (FHL2)" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">PRF1base: Mutation registr…</a></div><div style="margin-left: 0.5em;"><a href="http://www.LOVD.nl/PRF1" title="CCHMC Molecular Genetics Laboratory Mutation Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">CCHMC Molecular Genetics L…</a></div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=PRF1&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/PA33732" 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:9360" 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://www.mousephenotype.org/data/genes/MGI:97551" 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/PRF1#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:97551" 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/5551/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=5551" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
|
|
|
<div style="display: table-cell;">Cellular Pathways</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
|
</span>
|
|
</div>
|
|
<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
|
<div class="panel-body small mim-panel-body">
|
|
|
|
|
|
|
|
|
|
<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:5551" 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=PRF1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
|
|
|
|
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
<span>
|
|
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
|
|
|
|
</span>
|
|
</span>
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
|
|
|
|
<div>
|
|
|
|
<a id="title" class="mim-anchor"></a>
|
|
|
|
<div>
|
|
<a id="number" class="mim-anchor"></a>
|
|
<div class="text-right">
|
|
|
|
|
|
|
|
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
|
|
|
|
<strong>SNOMEDCT:</strong> 304132006, 306058006<br />
|
|
|
|
|
|
<strong>ICD10CM:</strong> D61.9<br />
|
|
|
|
|
|
<strong>ICD9CM:</strong> 284.9<br />
|
|
|
|
|
|
|
|
|
|
">ICD+</a>
|
|
|
|
</div>
|
|
<div>
|
|
<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
170280
|
|
</span>
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
<div>
|
|
<a id="preferredTitle" class="mim-anchor"></a>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
PERFORIN 1; PRF1
|
|
|
|
</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">
|
|
PFN1<br />
|
|
PORE-FORMING PROTEIN; PFP
|
|
</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=PRF1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PRF1</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/10/274?start=-3&limit=10&highlight=274">10q22.1</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr10:70597348-70602741&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'})">10:70,597,348-70,602,741</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=609135,603553,605027" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/10/274?start=-3&limit=10&highlight=274">
|
|
10q22.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Aplastic anemia
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/609135"> 609135 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hemophagocytic lymphohistiocytosis, familial, 2
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/603553"> 603553 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Lymphoma, non-Hodgkin
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/605027"> 605027 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</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/170280" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/170280" 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="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>Perforin-1 (PRF1) is one of the major cytolytic proteins of cytolytic granules. One of the main pathways of lymphocyte-mediated cytolysis entails the secretion onto target membranes of cytolytic granules contained in cytolytic effector lymphocytes of T-cell or NK-cell type. Perforin has a molecular mass of 70 to 75 kD and shows extensive similarity in structure to complement component C9 (<a href="/entry/120940">120940</a>). PRF1 is a pore-forming protein with a mechanism of transmembrane channel formation similar to C9. <a href="#20" class="mim-tip-reference" title="Podack, E. R., Lowrey, D. M., Lichtenheld, M., Olsen, K. J., Aebischer, T., Binder, D., Rupp, F., Hengartner, H. <strong>Structure, function and expression of murine and human perforin 1 (P1).</strong> Immun. Rev. 103: 203-211, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3292394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3292394</a>] [<a href="https://doi.org/10.1111/j.1600-065x.1988.tb00756.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3292394">Podack et al. (1988)</a> reviewed information on the structure and expression of PRF1 obtained through the analysis of cDNA clones. <a href="#23" class="mim-tip-reference" title="Shinkai, Y., Takio, K., Okumura, K. <strong>Homology of perforin to the ninth component of complement (C9).</strong> Nature 334: 525-527, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3261391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3261391</a>] [<a href="https://doi.org/10.1038/334525a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3261391">Shinkai et al. (1988)</a> demonstrated homology of perforin with C9 at their respective functionally conserved regions. They also found that perforin is expressed only in killer cell lines and not in helper T lymphocytes or other tumor cells tested. <a href="#15" class="mim-tip-reference" title="Lichtenheld, M. G., Olsen, K. J., Lu, P., Lowrey, D. M., Hameed, A., Hengartner, H., Podack, E. R. <strong>Structure and function of human perforin.</strong> Nature 335: 448-451, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3419519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3419519</a>] [<a href="https://doi.org/10.1038/335448a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3419519">Lichtenheld et al. (1988)</a> determined the primary structure of human perforin. In the mouse, <a href="#29" class="mim-tip-reference" title="Trapani, J. A., Kwon, B. S., Kozak, C. A., Chintamaneni, C., Young, J. D.-E., Dupont, B. <strong>Genomic organization of the mouse pore-forming protein (perforin) gene and localization to chromosome 10: similarities to and differences from C9.</strong> J. Exp. Med. 171: 545-557, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2303785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2303785</a>] [<a href="https://doi.org/10.1084/jem.171.2.545" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2303785">Trapani et al. (1990)</a> found that the perforin gene has a simplified structure compared to C9. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3419519+3292394+3261391+2303785" 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>Using a panel of somatic cell hybrid cell lines, <a href="#29" class="mim-tip-reference" title="Trapani, J. A., Kwon, B. S., Kozak, C. A., Chintamaneni, C., Young, J. D.-E., Dupont, B. <strong>Genomic organization of the mouse pore-forming protein (perforin) gene and localization to chromosome 10: similarities to and differences from C9.</strong> J. Exp. Med. 171: 545-557, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2303785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2303785</a>] [<a href="https://doi.org/10.1084/jem.171.2.545" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2303785">Trapani et al. (1990)</a> mapped the Pfp gene to mouse chromosome 10. By in situ hybridization with a human perforin cDNA probe, <a href="#24" class="mim-tip-reference" title="Shinkai, Y., Yoshida, M. C., Maeda, K., Kobata, T., Maruyama, K., Yodoi, J., Yagita, H., Okumura, K. <strong>Molecular cloning and chromosomal assignment of a human perforin (PFP) gene.</strong> Immunogenetics 30: 452-457, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2592021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2592021</a>] [<a href="https://doi.org/10.1007/BF02421177" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2592021">Shinkai et al. (1989)</a> assigned the PFP gene to 17q11-q21. <a href="#11" class="mim-tip-reference" title="Fink, T. M., Zimmer, M., Weitz, S., Tschopp, J., Jenne, D. E., Lichter, P. <strong>Human perforin (PRF1) maps to 10q22, a region that is syntenic with mouse chromosome 10.</strong> Genomics 13: 1300-1302, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1505959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1505959</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90050-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1505959">Fink et al. (1992)</a> was prompted to reexamine the mapping of PRF1 in the human because the gene was undetectable in a human chromosome 17 reference library in which clones for vitronectin, which maps to the region where PRF1 was supposed to lie, and because of the lack of any known homology between human chromosome 17 and mouse chromosome 10. Using the cosmid DNA containing the PRF1 gene as a probe for fluorescence in situ hybridization, they mapped the gene to human 10q22, a region that is syntenic with mouse chromosome 10. Thus, the perforin locus is not linked to that of any of the genes of the terminal complement system with which it shows partial homology of sequence. Lymphocyte-mediated cytotoxicity is thought to consist of the polarized secretion of granule-stored perforin leading to target-cell lysis. Nevertheless, perforin-independent pathways were postulated to explain the cytolytic activity of lymphocytes that apparently lacked perforin and the DNA degradation found in dying target cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2592021+2303785+1505959" 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="#13" class="mim-tip-reference" title="Law, R. H. P., Lukoyanova, N., Voskoboinik, I., Caradoc-Davies, T. T., Baran, K., Dunstone, M. A., D'Angelo, M. E., Orlova, E. V., Coulibaly, F., Verschoor, S., Browne, K. A., Ciccone, A., Kuiper, M. J., Bird, P. I., Trapani, J. A., Saibil, H. R., Whisstock, J. C. <strong>The structural basis for membrane binding and pore formation by lymphocyte perforin.</strong> Nature 468: 447-451, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21037563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21037563</a>] [<a href="https://doi.org/10.1038/nature09518" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21037563">Law et al. (2010)</a> elucidated the mechanism of perforin pore formation by determining the x-ray crystal structure of monomeric murine perforin, together with a cryoelectron microscopy reconstruction of the entire perforin pore. Perforin is a thin key-shaped molecule, comprising an amino-terminal membrane attack complex perforin-like (MACPF)/cholesterol-dependent cytolysin (CDC) domain followed by an epidermal growth factor (EGF) domain that, together with the extreme carboxy-terminal sequence, forms a central shelf-like structure. A C-terminal C2 domain mediates initial, calcium ion-dependent membrane binding. Most unexpectedly, however, electron microscopy revealed that the orientation of the perforin MACPF domain in the pore is inside-out relative to the subunit arrangement in CDCs. <a href="#13" class="mim-tip-reference" title="Law, R. H. P., Lukoyanova, N., Voskoboinik, I., Caradoc-Davies, T. T., Baran, K., Dunstone, M. A., D'Angelo, M. E., Orlova, E. V., Coulibaly, F., Verschoor, S., Browne, K. A., Ciccone, A., Kuiper, M. J., Bird, P. I., Trapani, J. A., Saibil, H. R., Whisstock, J. C. <strong>The structural basis for membrane binding and pore formation by lymphocyte perforin.</strong> Nature 468: 447-451, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21037563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21037563</a>] [<a href="https://doi.org/10.1038/nature09518" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21037563">Law et al. (2010)</a> concluded that their data revealed remarkable flexibility in the mechanism of action of the conserved MACPF/CDC fold and provided new insights into how related immune defense molecules such as complement proteins assemble into pores. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21037563" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="molecularGenetics" class="mim-anchor"></a>
|
|
<h4 href="#mimMolecularGeneticsFold" id="mimMolecularGeneticsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimMolecularGeneticsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimMolecularGeneticsFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Familial Hemophagocytic Lymphohistiocytosis</em></strong></p><p>
|
|
<a href="#28" class="mim-tip-reference" title="Stepp, S. E., Dufourcq-Lagelouse, R., Le Deist, F., Bhawan, S., Certain, S., Mathew, P. A., Henter, J.-I., Bennett, M., Fischer, A., de Saint Basile, G., Kumar, V. <strong>Perforin gene defects in familial hemophagocytic lymphohistiocytosis.</strong> Science 286: 1957-1959, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10583959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10583959</a>] [<a href="https://doi.org/10.1126/science.286.5446.1957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10583959">Stepp et al. (1999)</a> identified mutations in homozygosity and compound heterozygosity in patients with familial hemophagocytic lymphohistiocytosis (FHL2; <a href="/entry/603553">603553</a>). Four patients had missense mutations and 4 patients had homozygous nonsense mutations. <a href="#28" class="mim-tip-reference" title="Stepp, S. E., Dufourcq-Lagelouse, R., Le Deist, F., Bhawan, S., Certain, S., Mathew, P. A., Henter, J.-I., Bennett, M., Fischer, A., de Saint Basile, G., Kumar, V. <strong>Perforin gene defects in familial hemophagocytic lymphohistiocytosis.</strong> Science 286: 1957-1959, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10583959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10583959</a>] [<a href="https://doi.org/10.1126/science.286.5446.1957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10583959">Stepp et al. (1999)</a> generated cytotoxic cells by culturing previously frozen cells from 4 FHL patients and controls in phytohemagglutinin and interleukin-2 (<a href="/entry/147680">147680</a>). CD3 (see <a href="/entry/186740">186740</a>)-dependent cytolytic activity was measured in a 4-hour assay. Cells from all patients had greatly reduced cytolytic activity compared with cells from normal controls. Cells from a patient with a premature stop codon displayed no cytotoxicity, and cells from 3 patients with missense mutations showed greatly reduced lysis of the target cells. <a href="#28" class="mim-tip-reference" title="Stepp, S. E., Dufourcq-Lagelouse, R., Le Deist, F., Bhawan, S., Certain, S., Mathew, P. A., Henter, J.-I., Bennett, M., Fischer, A., de Saint Basile, G., Kumar, V. <strong>Perforin gene defects in familial hemophagocytic lymphohistiocytosis.</strong> Science 286: 1957-1959, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10583959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10583959</a>] [<a href="https://doi.org/10.1126/science.286.5446.1957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10583959">Stepp et al. (1999)</a> concluded that perforin-mediated cytotoxic activity of CD8+ T cells is defective in FHL patients. No perforin protein was detectable in patient cells using immunostaining. Two patients with low-level cytotoxic activity had a small amount of detectable perforin staining. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10583959" 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="Goransdotter Ericson, K., Fadeel, B., Nilsson-Ardnor, S., Soderhall, C., Samuelsson, A., Janka, G., Schneider, M., Gurgey, A., Yalman, N., Revesz, T., Egeler, R. M., Jahnukainen, K., Storm-Mathiesen, I., Haraldsson, A., Poole, J., de Saint Basile, G., Nordenskjold, M., Henter, J.-I. <strong>Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis.</strong> Am. J. Hum. Genet. 68: 590-597, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11179007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11179007</a>] [<a href="https://doi.org/10.1086/318796" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11179007">Goransdotter Ericson et al. (2001)</a> reported a comprehensive survey of 34 patients with FHL for mutations in the coding region of the perforin gene and the relative frequency of perforin mutations in FHL. Perforin mutations were identified in 7 of the 34 families investigated. Six children were homozygous for the mutation, and 1 patient was a compound heterozygote. In 4 families, a previously reported mutation in codon 374 (W374X; <a href="#0002">170280.0002</a>), causing a premature stop codon, was identified, making this the most common perforin mutation identified in FHL patients. They found perforin mutations in 20% (7 of 34) of all FHL patients investigated, with a somewhat higher prevalence, approximately 30% (6 of 20), in children whose parents originated from Turkey. They concluded that perforin mutations account for 20 to 40% of FHL cases, that the locus on chromosome 9 (FHL1; <a href="/entry/267700">267700</a>) accounts for approximately 10%, and that most FHL cases are caused by mutations in as yet unidentified genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11179007" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 25 (58%) of 43 unrelated North American families with children diagnosed with primary hemophagocytic lymphohistiocytosis, <a href="#19" class="mim-tip-reference" title="Molleran Lee, S., Villanueva, J., Sumegi, J., Zhang, K., Kogawa, K., Davis, J., Filipovich, A. H. <strong>Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis.</strong> J. Med. Genet. 41: 137-144, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14757862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14757862</a>] [<a href="https://doi.org/10.1136/jmg.2003.011528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14757862">Molleran Lee et al. (2004)</a> identified mutations in the PRF1 gene. There was no significant difference in median age at diagnosis when comparing patients with or without perforin mutations (6 months vs 7 months, respectively); however, comparing patients with PRF1 mutations who expressed low levels of perforin to those with no detectable perforin, the median age at onset was 54 months versus 3 months, respectively (p less than 0.001). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14757862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Role in Lymphoma</em></strong></p><p>
|
|
<a href="#7" class="mim-tip-reference" title="Clementi, R., Emmi, L., Maccario, R., Liotta, F., Moretta, L., Danesino, C., Arico, M. <strong>Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. (Letter)</strong> Blood 100: 2266-2267, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12229880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12229880</a>] [<a href="https://doi.org/10.1182/blood-2002-04-1030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12229880">Clementi et al. (2002)</a> reported 2 sibs with adult-onset FHL in whom they identified compound heterozygosity for a W374X mutation and an A91V (<a href="#0011">170280.0011</a>) substitution. At age 21 years, the sister presented with fever, weight loss, weakness, hepatosplenomegaly, and pancytopenia. Repeat bone marrow biopsies showed a T-cell infiltration with no evidence for clonal proliferation. She was diagnosed with a T-cell lymphoblastic lymphoma (<a href="/entry/605027">605027</a>) and underwent autologous bone marrow transplantation. Her brother presented 2 years later at age 22 years with decreased liver function, fever, lymphadenopathy, pancytopenia, and neurologic symptoms consistent with FHL. Both patients had complete absence of NK cell activity and perforin expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12229880" 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="Clementi, R., Dagna, L., Dianzani, U., Dupre, L., Dianzani, I., Ponzoni, M., Cometa, A., Chiocchetti, A., Sabbadini, M. G., Rugarli, C., Ciceri, F., Maccario, R., Locatelli, F., Danesino, C., Ferrarini, M., Bregni, M. <strong>Inherited perforin and Fas mutations in a patient with autoimmune lymphoproliferative syndrome and lymphoma.</strong> New Eng. J. Med. 351: 1419-1424, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15459303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15459303</a>] [<a href="https://doi.org/10.1056/NEJMoa041432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15459303">Clementi et al. (2004)</a> reported a 27-year-old man with autoimmune lymphoproliferative syndrome (ALPS; <a href="/entry/601859">601859</a>) who later developed a large B-cell lymphoma. Genetic analysis identified heterozygous mutations in the FAS gene (<a href="/entry/134637">134637</a>), which has been known to be associated with ALPS, and the perforin gene (N252S; <a href="#0009">170280.0009</a>). The FAS mutation was inherited from his healthy father and was also carried by his healthy brother, whereas the PRF1 mutation was inherited from his healthy mother. The authors concluded that the combined effect of the 2 mutant genes contributed to the development of APLS and lymphoma in this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15459303" 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="Clementi, R., Locatelli, F., Dupre, L., Garaventa, A., Emmi, L., Bregni, M., Cefalo, G., Moretta, A., Danesino, C., Comis, M., Pession, A., Ramenghi, U., Maccario, R., Arico, M., Roncarolo, M. G. <strong>A proportion of patients with lymphoma may harbor mutations of the perforin gene.</strong> Blood 105: 4424-4428, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15728124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15728124</a>] [<a href="https://doi.org/10.1182/blood-2004-04-1477" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15728124">Clementi et al. (2005)</a> reported 3 additional patients with lymphoma who were compound heterozygous for mutations in the PRF1 gene. A 7-year-old boy had Epstein-Barr virus-positive Hodgkin lymphoma, which was successfully treated, and developed a large B-cell non-Hodgkin lymphoma 3 years later. During treatment for the second disease, he developed severe hemophagocytosis. Hematopoietic stem cell transplantation was successful. An unrelated 7-year-old girl developed a subcutaneous T-cell lymphoma associated with hemophagocytosis on bone marrow biopsy. An 18-year-old girl developed peripheral T-cell lymphoma with marrow infiltration and evidence of hemophagocytosis, and underwent successful bone marrow transplantation. <a href="#9" class="mim-tip-reference" title="Clementi, R., Locatelli, F., Dupre, L., Garaventa, A., Emmi, L., Bregni, M., Cefalo, G., Moretta, A., Danesino, C., Comis, M., Pession, A., Ramenghi, U., Maccario, R., Arico, M., Roncarolo, M. G. <strong>A proportion of patients with lymphoma may harbor mutations of the perforin gene.</strong> Blood 105: 4424-4428, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15728124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15728124</a>] [<a href="https://doi.org/10.1182/blood-2004-04-1477" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15728124">Clementi et al. (2005)</a> reported another 3 patients, with lymphoma, B-cell, T-cell and Hodgkin disease, respectively, who all had the same heterozygous A91V substitution (<a href="#0011">170280.0011</a>) in the PRF1 gene. <a href="#9" class="mim-tip-reference" title="Clementi, R., Locatelli, F., Dupre, L., Garaventa, A., Emmi, L., Bregni, M., Cefalo, G., Moretta, A., Danesino, C., Comis, M., Pession, A., Ramenghi, U., Maccario, R., Arico, M., Roncarolo, M. G. <strong>A proportion of patients with lymphoma may harbor mutations of the perforin gene.</strong> Blood 105: 4424-4428, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15728124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15728124</a>] [<a href="https://doi.org/10.1182/blood-2004-04-1477" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15728124">Clementi et al. (2005)</a> noted that all of the patients they reported with lymphoma and mutations in the PRF1 gene were young, between the ages of 7 and 29 years. The findings suggested a more complex dysregulation of the immune system in the absence of perforin, with some patients developing FHL and some developing other lymphoproliferative disorders, including various forms of lymphoma. The authors postulated that heterozygous mutations in the PRF1 gene may increase susceptibility to the development of lymphoma, perhaps acting as a synergistic factor with other genetic mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15728124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Aplastic Anemia</em></strong></p><p>
|
|
<a href="#26" class="mim-tip-reference" title="Solomou, E. E., Gibellini, F., Stewart, B., Malide, D., Berg, M., Visconte, V., Green, S., Childs, R., Chanock, S. J., Young, N. S. <strong>Perforin gene mutations in patients with acquired aplastic anemia.</strong> Blood 109: 5234-5237, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17311987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17311987</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17311987[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/10.1182/blood-2006-12-063495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17311987">Solomou et al. (2007)</a> identified mutations in the PRF1 gene (<a href="#0011">170280.0011</a>-<a href="#0013">170280.0013</a>) in 5 unrelated patients with adult-onset aplastic anemia (<a href="/entry/609135">609135</a>). Four of the 5 patients showed hemophagocytosis on bone marrow biopsy, but none had clinical manifestations of the hemophagocytosis syndrome. Perforin protein levels in these patients were very low or absent, perforin granules were absent, and natural killer cell cytotoxicity was significantly decreased. <a href="#26" class="mim-tip-reference" title="Solomou, E. E., Gibellini, F., Stewart, B., Malide, D., Berg, M., Visconte, V., Green, S., Childs, R., Chanock, S. J., Young, N. S. <strong>Perforin gene mutations in patients with acquired aplastic anemia.</strong> Blood 109: 5234-5237, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17311987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17311987</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17311987[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/10.1182/blood-2006-12-063495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17311987">Solomou et al. (2007)</a> concluded that PRF1 gene alterations may explain aberrant proliferation and activation of cytotoxic T cells in aplastic anemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17311987" 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="genotypePhenotypeCorrelations" class="mim-anchor"></a>
|
|
<h4 href="#mimGenotypePhenotypeCorrelationsFold" id="mimGenotypePhenotypeCorrelationsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimGenotypePhenotypeCorrelationsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Genotype/Phenotype Correlations</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<div id="mimGenotypePhenotypeCorrelationsFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<p><a href="#22" class="mim-tip-reference" title="Risma, K. A., Frayer, R. W., Filipovich, A. H., Sumegi, J. <strong>Aberrant maturation of mutant perforin underlies the clinical diversity of hemophagocytic lymphohistiocytosis.</strong> J. Clin. Invest. 116: 182-192, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16374518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16374518</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16374518[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/JCI26217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16374518">Risma et al. (2006)</a> classified 21 human PRF1 disease-associated missense mutations into 3 broad classes based on expression in rat basophilic leukemia (RBL-1) cells. Class 1 mutations (see, e.g., A91V, <a href="#0011">170280.0011</a>, G429E, <a href="#0005">170280.0005</a>) resulted in partial maturation of perforin; class 2 mutations (see, e.g., R225W, <a href="#0004">170280.0004</a>) resulted in no apparent proteolytic maturation of the perforin protein; and class 3 mutations resulted in no recognizable forms of perforin due to protein misfolding and protein degradation. Class 1 mutations exhibited lytic function and were associated with residual protein detection and variable cytotoxic function. Patients with class 1 mutations had later disease onset compared to those with class 2 or 3 mutations. By contrast, class 3 mutations caused severely diminished protein detection and cytotoxicity, and patients with class 3 mutations had disease onset before 1 year of age and absent NK function. Patients with class 2 mutations had an intermediate phenotype. <a href="#22" class="mim-tip-reference" title="Risma, K. A., Frayer, R. W., Filipovich, A. H., Sumegi, J. <strong>Aberrant maturation of mutant perforin underlies the clinical diversity of hemophagocytic lymphohistiocytosis.</strong> J. Clin. Invest. 116: 182-192, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16374518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16374518</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16374518[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/JCI26217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16374518">Risma et al. (2006)</a> concluded that the pathogenic mechanism of perforin missense mutations may involve a protein dosage effect of the mature protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16374518" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Trizzino, A., zur Stadt, U., Ueda, I., Risma, K., Janka, G., Ishii, E., Beutel, K., Sumegi, J., Cannella, S., Pende, D., Mian, A., Henter, J.-I., Griffiths, G., Santoro, A., Filipovich, A., Arico, M. <strong>Genotype-phenotype study of familial haemophagocytic lymphohistiocytosis due to perforin mutations.</strong> J. Med. Genet. 45: 15-21, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17873118/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17873118</a>] [<a href="https://doi.org/10.1136/jmg.2007.052670" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17873118">Trizzino et al. (2008)</a> analyzed data from 124 FHL patients, who had 63 different mutations in the PRF1 gene, including 11 nonsense, 10 frameshift, 38 missense, and 4 in-frame deletions. The W374X mutation was present in 32 patients and was associated with Turkish origin; 50delT (<a href="#0001">170280.0001</a>) was found in 21 patients and was associated with African American origin; and 1090delCT (<a href="#0014">170280.0014</a>) was found in 7 Japanese patients. Flow cytometry showed that perforin expression was absent in 40 patients, reduced in 6, and normal in 4. Later onset and residual cytotoxic function were observed in patients with at least 1 missense mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17873118" 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>To evaluate the role of perforin, <a href="#16" class="mim-tip-reference" title="Lowin, B., Beermann, F., Schmidt, A., Tschopp, J. <strong>A null mutation in the perforin gene impairs cytolytic T lymphocyte- and natural killer cell-mediated cytotoxicity.</strong> Proc. Nat. Acad. Sci. 91: 11571-11575, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7972104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7972104</a>] [<a href="https://doi.org/10.1073/pnas.91.24.11571" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7972104">Lowin et al. (1994)</a> used gene targeting in embryonic stem cells to produce mice lacking perforin. Mice homozygous for the disrupted gene had no perforin mRNA. The mice were healthy, however, and activation and granzyme A secretion of perforin-free cytolytic T cells were unaltered. The killing activity of cytolytic T cells as well as of natural killer (NT) cells was impaired but not abolished. <a href="#16" class="mim-tip-reference" title="Lowin, B., Beermann, F., Schmidt, A., Tschopp, J. <strong>A null mutation in the perforin gene impairs cytolytic T lymphocyte- and natural killer cell-mediated cytotoxicity.</strong> Proc. Nat. Acad. Sci. 91: 11571-11575, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7972104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7972104</a>] [<a href="https://doi.org/10.1073/pnas.91.24.11571" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7972104">Lowin et al. (1994)</a> concluded that perforin is a crucial effector molecule in T cell- and NK cell-mediated cytolysis; however, alternative perforin-independent lytic mechanisms also exist. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7972104" 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>When perforin-deficient mice were infected with lymphocytic choriomeningitis virus, CD8+ T cell-, interferon gamma- (IFNG; <a href="/entry/147570">147570</a>), and TNF-alpha (<a href="/entry/191160">191160</a>)-dependent immunopathology and mortality similar to that in humans with FHL was seen (<a href="#17" class="mim-tip-reference" title="Matloubian, M., Suresh, M., Glass, A., Galvan, M., Chow, K., Whitmire, J. K., Walsh, C. M., Clark, W. R., Ahmed, R. <strong>A role for perforin in downregulating T-cell responses during chronic viral infection.</strong> J. Virol. 73: 2527-2536, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9971838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9971838</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9971838[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/10.1128/JVI.73.3.2527-2536.1999" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9971838">Matloubian et al., 1999</a> and <a href="#2" class="mim-tip-reference" title="Binder, D., van den Broek, M. F., Kagi, D., Bluethmann, H., Fehr, J., Hengartner, H., Zinkernagel, R. M. <strong>Aplastic anemia rescued by exhaustion of cytokine-secreting CD8+ T cells in persistent infection with lymphocytic choriomeningitis virus.</strong> J. Exp. Med. 187: 1903-1920, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9607930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9607930</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9607930[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.187.11.1903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9607930">Binder et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9607930+9971838" 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="Badovinac, V. P., Tvinnereim, A. R., Harty, J. T. <strong>Regulation of antigen-specific CD8(+) T cell homeostasis by perforin and interferon-gamma.</strong> Science 290: 1354-1357, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11082062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11082062</a>] [<a href="https://doi.org/10.1126/science.290.5495.1354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11082062">Badovinac et al. (2000)</a> showed that Prf1 knockout mice eliminated Listeria monocytogenes as well as wildtype mice did but had a higher number of antigen-specific cytotoxic CD8 cells; the ratio of cells responding to immunodominant antigens was the same, as measured by intracellular cytokine or MHC class I tetramer staining. Likewise, the rate of CD8-positive T-cell death after clearance of infection was indistinguishable from wildtype mice. In mice that also had disruption of the Ifng gene, there was a much greater expansion of cytotoxic T cells, an equivalence of cells responding to dominant antigens, and an attenuated rate of T-cell death compared to wildtype. In contrast to Ifng knockout mice, <a href="#1" class="mim-tip-reference" title="Badovinac, V. P., Tvinnereim, A. R., Harty, J. T. <strong>Regulation of antigen-specific CD8(+) T cell homeostasis by perforin and interferon-gamma.</strong> Science 290: 1354-1357, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11082062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11082062</a>] [<a href="https://doi.org/10.1126/science.290.5495.1354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11082062">Badovinac et al. (2000)</a> found the Prf1 knockout mice failed to clear lymphocytic choriomeningitis virus and died. The authors proposed that their findings may suggest strategies for enhancing T-cell memory in response to vaccination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11082062" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Smyth, M. J., Thia, K. Y. T., Street, S. E. A., MacGregor, D., Godfrey, D. I., Trapani, J. A. <strong>Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma.</strong> J. Exp. Med. 192: 755-760, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10974040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10974040</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10974040[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.192.5.755" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10974040">Smyth et al. (2000)</a> found that Pfp1-null mice had a high incidence of spontaneous lymphoma of distinct cell lineages, including T cells, B cells, and natural killer cells, compared to wildtype mice. The susceptibility to lymphoma was accentuated in mice who also lacked the tumor suppressor gene p53 (<a href="/entry/191170">191170</a>). Pfp1-null mice were at least 1,000-fold more susceptible to these lymphomas when transplanted with the malignant cells, compared to immunocompetent mice in which tumor rejection was controlled by CD8+ T lymphocytes. The findings implicated direct cytotoxicity by lymphocytes in regulating lymphomagenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10974040" 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>16 Selected Examples</a>):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div id="mimAllelicVariantsFold" class="collapse in mimTextToggleFold">
|
|
<div>
|
|
<a href="/allelicVariants/170280" class="btn btn-default" role="button"> Table View </a>
|
|
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=170280[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 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PRF1, 1-BP DEL, 50T
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs147035858 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs147035858;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs147035858?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs147035858" 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=rs147035858" 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=RCV000541899 OR RCV000627438 OR RCV001201274 OR RCV002261110 OR RCV002506353 OR RCV003419965 OR RCV003476293" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000541899, RCV000627438, RCV001201274, RCV002261110, RCV002506353, RCV003419965, RCV003476293" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000541899...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with familial hemophagocytic lymphohistiocytosis (FHL2; <a href="/entry/603553">603553</a>) from a consanguineous union, <a href="#28" class="mim-tip-reference" title="Stepp, S. E., Dufourcq-Lagelouse, R., Le Deist, F., Bhawan, S., Certain, S., Mathew, P. A., Henter, J.-I., Bennett, M., Fischer, A., de Saint Basile, G., Kumar, V. <strong>Perforin gene defects in familial hemophagocytic lymphohistiocytosis.</strong> Science 286: 1957-1959, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10583959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10583959</a>] [<a href="https://doi.org/10.1126/science.286.5446.1957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10583959">Stepp et al. (1999)</a> found homozygosity for deletion of a T at nucleotide 50 of the PRF1 gene, resulting in a frameshift and stop in exon 2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10583959" 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 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PRF1, TRP374TER
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs104894176 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894176;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs104894176?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104894176" 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=rs104894176" 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=RCV000014708 OR RCV000760450 OR RCV002260963 OR RCV002513052 OR RCV003473101 OR RCV005042053" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014708, RCV000760450, RCV002260963, RCV002513052, RCV003473101, RCV005042053" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014708...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 patients with familial hemophagocytic lymphohistiocytosis (FHL2; <a href="/entry/603553">603553</a>) from unrelated consanguineous families, <a href="#28" class="mim-tip-reference" title="Stepp, S. E., Dufourcq-Lagelouse, R., Le Deist, F., Bhawan, S., Certain, S., Mathew, P. A., Henter, J.-I., Bennett, M., Fischer, A., de Saint Basile, G., Kumar, V. <strong>Perforin gene defects in familial hemophagocytic lymphohistiocytosis.</strong> Science 286: 1957-1959, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10583959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10583959</a>] [<a href="https://doi.org/10.1126/science.286.5446.1957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10583959">Stepp et al. (1999)</a> identified a homozygous G-to-A transition at nucleotide 1122 of the PRF1 gene, resulting in a trp374-to-ter (W374X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10583959" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 sibs with adult-onset hemophagocytic lymphohistiocytosis, diagnosed at ages 22 and 21 years, respectively, <a href="#7" class="mim-tip-reference" title="Clementi, R., Emmi, L., Maccario, R., Liotta, F., Moretta, L., Danesino, C., Arico, M. <strong>Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. (Letter)</strong> Blood 100: 2266-2267, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12229880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12229880</a>] [<a href="https://doi.org/10.1182/blood-2002-04-1030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12229880">Clementi et al. (2002)</a> identified compound heterozygosity for the W374X mutation and an A91V substitution (<a href="#0011">170280.0011</a>). The unrelated parents from southern Italy were each heterozygous for 1 of the substitutions. The patients had an atypical presentation and an unusually mild course of the disease. <a href="#9" class="mim-tip-reference" title="Clementi, R., Locatelli, F., Dupre, L., Garaventa, A., Emmi, L., Bregni, M., Cefalo, G., Moretta, A., Danesino, C., Comis, M., Pession, A., Ramenghi, U., Maccario, R., Arico, M., Roncarolo, M. G. <strong>A proportion of patients with lymphoma may harbor mutations of the perforin gene.</strong> Blood 105: 4424-4428, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15728124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15728124</a>] [<a href="https://doi.org/10.1182/blood-2004-04-1477" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15728124">Clementi et al. (2005)</a> later reported that 1 of the sibs had a non-Hodgkin lymphoma (<a href="/entry/605027">605027</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15728124+12229880" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Zur Stadt, U., Beutel, K., Kolberg, S., Schneppenheim, R., Kabisch, H., Janka, G., Hennies, H. C. <strong>Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A.</strong> Hum. Mutat. 27: 62-68, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16278825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16278825</a>] [<a href="https://doi.org/10.1002/humu.20274" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16278825">Zur Stadt et al. (2006)</a> found the W374X mutation in PRF1 in 12 of 32 patients from Turkey and noted that it was associated with very early onset of the disease (below the age of 3 months) in all cases. In contrast, they found the W374X mutation in only 3 of 23 patients from Germany. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16278825" 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 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PRF1, GLN64TER
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs104894180 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894180;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs104894180?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104894180" 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=rs104894180" 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=RCV000014710 OR RCV003460476" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014710, RCV003460476" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014710...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with familial hemophagocytic lymphohistiocytosis (FHL2; <a href="/entry/603553">603553</a>) from a consanguineous family, <a href="#28" class="mim-tip-reference" title="Stepp, S. E., Dufourcq-Lagelouse, R., Le Deist, F., Bhawan, S., Certain, S., Mathew, P. A., Henter, J.-I., Bennett, M., Fischer, A., de Saint Basile, G., Kumar, V. <strong>Perforin gene defects in familial hemophagocytic lymphohistiocytosis.</strong> Science 286: 1957-1959, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10583959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10583959</a>] [<a href="https://doi.org/10.1126/science.286.5446.1957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10583959">Stepp et al. (1999)</a> found homozygosity for a 190C-T transition in the PRF1 gene, resulting in a glu64-to-ter (Q64X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10583959" 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="Goransdotter Ericson, K., Fadeel, B., Nilsson-Ardnor, S., Soderhall, C., Samuelsson, A., Janka, G., Schneider, M., Gurgey, A., Yalman, N., Revesz, T., Egeler, R. M., Jahnukainen, K., Storm-Mathiesen, I., Haraldsson, A., Poole, J., de Saint Basile, G., Nordenskjold, M., Henter, J.-I. <strong>Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis.</strong> Am. J. Hum. Genet. 68: 590-597, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11179007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11179007</a>] [<a href="https://doi.org/10.1086/318796" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11179007">Goransdotter Ericson et al. (2001)</a> found the Q64X mutation in 4 families and pointed out that it was the most common perforin mutation identified in FHL patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11179007" 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 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PRF1, ARG225TRP
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28933973 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28933973;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs28933973?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28933973" 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=rs28933973" 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=RCV000014711 OR RCV002260964 OR RCV002281706 OR RCV002513053 OR RCV003473102 OR RCV004814906" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014711, RCV002260964, RCV002281706, RCV002513053, RCV003473102, RCV004814906" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014711...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with familial hemophagocytic lymphohistiocytosis (FHL2; <a href="/entry/603553">603553</a>), <a href="#28" class="mim-tip-reference" title="Stepp, S. E., Dufourcq-Lagelouse, R., Le Deist, F., Bhawan, S., Certain, S., Mathew, P. A., Henter, J.-I., Bennett, M., Fischer, A., de Saint Basile, G., Kumar, V. <strong>Perforin gene defects in familial hemophagocytic lymphohistiocytosis.</strong> Science 286: 1957-1959, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10583959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10583959</a>] [<a href="https://doi.org/10.1126/science.286.5446.1957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10583959">Stepp et al. (1999)</a> identified compound heterozygosity for mutations in the PRF1 gene: a 673C-T transition, resulting in an arg225-to-trp (R225W) substitution, and a 1286G-A transition, resulting in a gly429-to-glu mutation (G429E; <a href="#0005">170280.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10583959" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Voskoboinik, I., Thia, M.-C., De Bono, A., Browne, K., Cretney, E., Jackson, J. T., Darcy, P. K., Jane, S. M., Smyth, M. J., Trapani, J. A. <strong>The functional basis for hemophagocytic lymphohistiocytosis in a patient with co-inherited missense mutations in the perforin (PFN1) gene.</strong> J. Exp. Med. 200: 811-816, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15365097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15365097</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15365097[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.20040776" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15365097">Voskoboinik et al. (2004)</a> developed a robust expression system in rat basophil leukemia (RBL) cells in order to define the basis of perforin dysfunction associated with the R225W and G429E mutations inherited by a compound heterozygote FHL patient. RBL cells expressing the 67-kD wildtype perforin efficiently killed human Jurkat T-cell lines. Mutation of the rodent protein at residues comparable to R225W resulted in a truncated 45-kD protein and a complete loss of cytotoxicity. Immunohistochemical analysis showed that wildtype perforin, but not R225W perforin, was packaged in secretory granules. In contrast, the rodent equivalent of the G429E mutation was correctly processed, stored, and released, but it possessed reduced cytotoxic capacity. <a href="#33" class="mim-tip-reference" title="Voskoboinik, I., Thia, M.-C., De Bono, A., Browne, K., Cretney, E., Jackson, J. T., Darcy, P. K., Jane, S. M., Smyth, M. J., Trapani, J. A. <strong>The functional basis for hemophagocytic lymphohistiocytosis in a patient with co-inherited missense mutations in the perforin (PFN1) gene.</strong> J. Exp. Med. 200: 811-816, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15365097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15365097</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15365097[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.20040776" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15365097">Voskoboinik et al. (2004)</a> concluded that the cellular basis for perforin mutation dysfunction in FHL patients involving other mutations can be studied using the RBL expression system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15365097" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Molleran Lee, S., Villanueva, J., Sumegi, J., Zhang, K., Kogawa, K., Davis, J., Filipovich, A. H. <strong>Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis.</strong> J. Med. Genet. 41: 137-144, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14757862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14757862</a>] [<a href="https://doi.org/10.1136/jmg.2003.011528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14757862">Molleran Lee et al. (2004)</a> identified a homozygous R225W mutation in 2 unrelated patients with FHL2. One was a 2-year-old Filipino boy and the other was a 5-year-old Caucasian girl. The patients were ascertained from a large cohort of 50 unrelated patients with a clinical diagnosis of FHL. No specific clinical details were available, but laboratory studies showed decreased NK function with variably decreased perforin-expressing NK cells (91% and 53%, respectively). These changes were not as severe as seen in patients with other PRF1 mutations. <a href="#19" class="mim-tip-reference" title="Molleran Lee, S., Villanueva, J., Sumegi, J., Zhang, K., Kogawa, K., Davis, J., Filipovich, A. H. <strong>Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis.</strong> J. Med. Genet. 41: 137-144, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14757862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14757862</a>] [<a href="https://doi.org/10.1136/jmg.2003.011528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14757862">Molleran Lee et al. (2004)</a> noted the relatively later age at onset of these patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14757862" 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="Chiapparini, L., Uziel, G., Vallinoto, C., Bruzzone, M. G., Rovelli, A., Tricomi, G., Bizzi, A., Nardocci, N., Rizzari, C., Savoiardo, M. <strong>Hemophagocytic lymphohistiocytosis with neurological presentation: MRI findings and a nearly miss (sic) diagnosis.</strong> Neurol. Sci. 32: 473-477, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21234777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21234777</a>] [<a href="https://doi.org/10.1007/s10072-010-0467-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21234777">Chiapparini et al. (2011)</a> reported a 13-year-old girl with FHL2 who presented with ataxia, headache, double vision, vomiting, and a progressive increase in intracranial pressure. She had papilledema and brain MRI showed a swollen cerebellum with tonsillar herniation and signal abnormalities; some T2 hyperintensities were also present in supratentorial areas. CSF showed protein, IgG, and IgM levels consistent with blood-brain barrier damage. She was treated with steroids, but developed fever, worsening ataxia, and decreased sensation in the lower limbs after interruption of steroids. She also had organomegaly. Laboratory studies showed increased triglycerides and ferritin, anemia, elevated liver enzymes, and decreased NK activity. Bone marrow biopsy showed hypoplasia of the myeloid line with adequate erythropoiesis and an infiltration of lymphocytes and histiomonocytoid cells; hemophagocytosis was rare. She underwent bone marrow biopsy and was in good condition after 18 months. Genetic analysis identified a homozygous R225W mutation. <a href="#4" class="mim-tip-reference" title="Chiapparini, L., Uziel, G., Vallinoto, C., Bruzzone, M. G., Rovelli, A., Tricomi, G., Bizzi, A., Nardocci, N., Rizzari, C., Savoiardo, M. <strong>Hemophagocytic lymphohistiocytosis with neurological presentation: MRI findings and a nearly miss (sic) diagnosis.</strong> Neurol. Sci. 32: 473-477, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21234777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21234777</a>] [<a href="https://doi.org/10.1007/s10072-010-0467-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21234777">Chiapparini et al. (2011)</a> noted the unusual but prominent neurologic presentation in this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21234777" 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="#10" class="mim-tip-reference" title="Dias, C., McDonald, A., Sincan, M., Rupps, R., Markello, T., Salvarinova, R., Santos, R. F., Menghrajani, K., Ahaghotu, C., Sutherland, D. P., Fortuno, E. S., III, Kollmann, T. R., Demos, M., Friedman, J. M., Speert, D. P., Gahl, W. A., Boerkoel, C. F. <strong>Recurrent subacute post-viral onset of ataxia associated with a PRF1 mutation.</strong> Europ. J. Hum. Genet. 21: 1232-1239, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23443029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23443029</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23443029[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2013.20" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23443029">Dias et al. (2013)</a> reported 2 sisters, born of consanguineous Lebanese parents, who were found by exome sequencing to carry a heterozygous R225W mutation. The phenotype was not entirely consistent with FHL2, but there were some similar features. One child presented with ataxia, abnormal eye movements, dysarthria, and white matter changes on brain MRI after an episode of gastroenteritis. She had partial resolution, but then showed further white matter changes on MRI and developed splenomegaly, lymphadenopathy, mild pancytopenia, elevated liver enzymes, and hypertrophic cardiomyopathy. Bone marrow biopsy was normal except for iron depletion. Immunologic studies showed normal numbers of T, B, and NK cells. She then developed seizures and loss of vision and cognitive and motor skills. There was intermittent fever and neck rigidity during this time; she died at age 61 months. Laboratory studies showed decreased production of IL1B (<a href="/entry/147720">147720</a>) and a broad decrease in inflammatory cytokines. The older sister had mild developmental delay and hearing loss. At age 75.5 months, she developed seizures, fever, and deterioration of mental status associated with varicella meningitis. She recovered transiently, but then developed ataxia and diffuse white matter changes on brain MRI. She died at age 91 months. The brain imaging in these patients showed cerebellar atrophy with T2-weighted hyperintense lesions in the cerebellum and cerebral white matter with later involvement of the gray matter. One girl also had signal changes in the periventricular and deep white matter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23443029" 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 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PRF1, GLY429GLU
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs104894181 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894181;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs104894181?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104894181" 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=rs104894181" 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=RCV000014712" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014712" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014712</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the gly429-to-glu (G429E) mutation in the PRF1 gene that was found in compound heterozygous state in a patient with familial hemophagocytic lymphohistiocytosis (FHL2; <a href="/entry/603553">603553</a>) by <a href="#28" class="mim-tip-reference" title="Stepp, S. E., Dufourcq-Lagelouse, R., Le Deist, F., Bhawan, S., Certain, S., Mathew, P. A., Henter, J.-I., Bennett, M., Fischer, A., de Saint Basile, G., Kumar, V. <strong>Perforin gene defects in familial hemophagocytic lymphohistiocytosis.</strong> Science 286: 1957-1959, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10583959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10583959</a>] [<a href="https://doi.org/10.1126/science.286.5446.1957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10583959">Stepp et al. (1999)</a>, see <a href="#0004">170280.0004</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10583959" 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 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PRF1, PRO345LEU
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28933374 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28933374;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs28933374?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28933374" 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=rs28933374" 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=RCV000014713 OR RCV002281707" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014713, RCV002281707" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014713...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with familial hemophagocytic lymphohistiocytosis (FHL2; <a href="/entry/603553">603553</a>) from a consanguineous family, <a href="#28" class="mim-tip-reference" title="Stepp, S. E., Dufourcq-Lagelouse, R., Le Deist, F., Bhawan, S., Certain, S., Mathew, P. A., Henter, J.-I., Bennett, M., Fischer, A., de Saint Basile, G., Kumar, V. <strong>Perforin gene defects in familial hemophagocytic lymphohistiocytosis.</strong> Science 286: 1957-1959, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10583959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10583959</a>] [<a href="https://doi.org/10.1126/science.286.5446.1957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10583959">Stepp et al. (1999)</a> identified a homozygous 1034C-T transition in the PRF1 gene, resulting in a pro345-to-leu (P345L) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10583959" 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="0007" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PRF1, CYS279TYR
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs104894182 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894182;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs104894182?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104894182" 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=rs104894182" 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=RCV000014714 OR RCV003466860" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014714, RCV003466860" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014714...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with familial hemophagocytic lymphohistiocytosis (FHL2; <a href="/entry/603553">603553</a>), <a href="#28" class="mim-tip-reference" title="Stepp, S. E., Dufourcq-Lagelouse, R., Le Deist, F., Bhawan, S., Certain, S., Mathew, P. A., Henter, J.-I., Bennett, M., Fischer, A., de Saint Basile, G., Kumar, V. <strong>Perforin gene defects in familial hemophagocytic lymphohistiocytosis.</strong> Science 286: 1957-1959, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10583959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10583959</a>] [<a href="https://doi.org/10.1126/science.286.5446.1957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10583959">Stepp et al. (1999)</a> identified compound heterozygosity for mutations in the PRF1 gene: an 836C-A transversion, resulting in a cys279-to-tyr (C279Y) substitution, and a 548T-G transversion, resulting in a val183-to-gly (V183G; <a href="#0008">170280.0008</a>) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10583959" 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="0008" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PRF1, VAL183GLY
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894183 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894183;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=rs104894183" 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=rs104894183" 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=RCV000014715" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014715" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014715</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the val183-to-gly (V183G) mutation in the PRF1 gene that was found in compound heterozygous state in a patient with familial hemophagocytic lymphohistiocytosis (FHL2; <a href="/entry/603553">603553</a>) by <a href="#28" class="mim-tip-reference" title="Stepp, S. E., Dufourcq-Lagelouse, R., Le Deist, F., Bhawan, S., Certain, S., Mathew, P. A., Henter, J.-I., Bennett, M., Fischer, A., de Saint Basile, G., Kumar, V. <strong>Perforin gene defects in familial hemophagocytic lymphohistiocytosis.</strong> Science 286: 1957-1959, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10583959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10583959</a>] [<a href="https://doi.org/10.1126/science.286.5446.1957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10583959">Stepp et al. (1999)</a>, see <a href="#0007">170280.0007</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10583959" 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="0009" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PRF1, ASN252SER
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28933375 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28933375;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs28933375?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28933375" 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=rs28933375" 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=RCV000014716 OR RCV000246747 OR RCV000767055 OR RCV002260965" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014716, RCV000246747, RCV000767055, RCV002260965" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014716...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant, formerly designated HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2, with the 'included' title of LYMPHOMA, NON-HODGKIN, has been reclassified based on the report by <a href="#8" class="mim-tip-reference" title="Clementi, R., Ferrarini, M., Bregni, M. <strong>Autoimmune lymphoproliferative syndrome and perforin. (Letter)</strong> New Eng. J. Med. 352: 306-307, 2005."None>Clementi et al. (2005)</a>.</p><p>In a patient with familial hemophagocytic lymphohistiocytosis (FHL2; <a href="/entry/603553">603553</a>), <a href="#28" class="mim-tip-reference" title="Stepp, S. E., Dufourcq-Lagelouse, R., Le Deist, F., Bhawan, S., Certain, S., Mathew, P. A., Henter, J.-I., Bennett, M., Fischer, A., de Saint Basile, G., Kumar, V. <strong>Perforin gene defects in familial hemophagocytic lymphohistiocytosis.</strong> Science 286: 1957-1959, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10583959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10583959</a>] [<a href="https://doi.org/10.1126/science.286.5446.1957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10583959">Stepp et al. (1999)</a> identified a 755A-G transition in the PRF1 gene, resulting in an asn252-to-ser (N252S) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10583959" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 27-year-old man with autoimmune lymphoproliferative syndrome (<a href="/entry/601859">601859</a>) who later developed a T-cell-rich, histiocyte-rich, diffuse large B-cell lymphoma (<a href="/entry/605027">605027</a>), <a href="#6" class="mim-tip-reference" title="Clementi, R., Dagna, L., Dianzani, U., Dupre, L., Dianzani, I., Ponzoni, M., Cometa, A., Chiocchetti, A., Sabbadini, M. G., Rugarli, C., Ciceri, F., Maccario, R., Locatelli, F., Danesino, C., Ferrarini, M., Bregni, M. <strong>Inherited perforin and Fas mutations in a patient with autoimmune lymphoproliferative syndrome and lymphoma.</strong> New Eng. J. Med. 351: 1419-1424, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15459303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15459303</a>] [<a href="https://doi.org/10.1056/NEJMoa041432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15459303">Clementi et al. (2004)</a> identified a heterozygous N252S mutation in the PRF1 gene and a heterozygous mutation in the FAS gene (<a href="/entry/134637">134637</a>). The FAS mutation was inherited from his healthy father and was also carried by his healthy brother, whereas the PRF1 mutation was inherited from his healthy mother. <a href="#6" class="mim-tip-reference" title="Clementi, R., Dagna, L., Dianzani, U., Dupre, L., Dianzani, I., Ponzoni, M., Cometa, A., Chiocchetti, A., Sabbadini, M. G., Rugarli, C., Ciceri, F., Maccario, R., Locatelli, F., Danesino, C., Ferrarini, M., Bregni, M. <strong>Inherited perforin and Fas mutations in a patient with autoimmune lymphoproliferative syndrome and lymphoma.</strong> New Eng. J. Med. 351: 1419-1424, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15459303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15459303</a>] [<a href="https://doi.org/10.1056/NEJMoa041432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15459303">Clementi et al. (2004)</a> noted that the N252S substitution occurs within the membrane attack complex of the perforin protein, a region involved in the pore-forming activity of the molecule. However, both the patient and his mother had normal levels of perforin and normal NK cell activity. The authors suggested that the combined effect of the 2 mutant genes contributed to the development of ALPS and lymphoma in this patient. <a href="#21" class="mim-tip-reference" title="Rieux-Laucat, F., Le Deist, F., De Saint Basile, G. <strong>Autoimmune lymphoproliferative syndrome and perforin. (Letter)</strong> New Eng. J. Med. 352: 306 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15659737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15659737</a>] [<a href="https://doi.org/10.1056/NEJM200501203520319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15659737">Rieux-Laucat et al. (2005)</a> cast doubt on the pathogenicity of the N252S mutation, and the primary authors provided a rebuttal (<a href="#8" class="mim-tip-reference" title="Clementi, R., Ferrarini, M., Bregni, M. <strong>Autoimmune lymphoproliferative syndrome and perforin. (Letter)</strong> New Eng. J. Med. 352: 306-307, 2005."None>Clementi et al., 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15459303+15659737" 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="Clementi, R., Locatelli, F., Dupre, L., Garaventa, A., Emmi, L., Bregni, M., Cefalo, G., Moretta, A., Danesino, C., Comis, M., Pession, A., Ramenghi, U., Maccario, R., Arico, M., Roncarolo, M. G. <strong>A proportion of patients with lymphoma may harbor mutations of the perforin gene.</strong> Blood 105: 4424-4428, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15728124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15728124</a>] [<a href="https://doi.org/10.1182/blood-2004-04-1477" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15728124">Clementi et al. (2005)</a> identified the N252S mutation in 1 of 660 (0.02%) control alleles, suggesting that it is a benign polymorphism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15728124" 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="0010" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PRF1, THR435MET
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28933376 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28933376;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs28933376?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28933376" 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=rs28933376" 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=RCV000014718 OR RCV002260966 OR RCV003473103" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014718, RCV002260966, RCV003473103" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014718...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p><a href="#35" class="mim-tip-reference" title="Wagner, R., Morgan, G., Strobel, S. <strong>A prospective study of CD45 isoform expression in haemophagocytic lymphohistiocytosis; an abnormal inherited immunophenotype in one family.</strong> Clin. Exp. Immun. 99: 216-220, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7851014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7851014</a>] [<a href="https://doi.org/10.1111/j.1365-2249.1995.tb05535.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7851014">Wagner et al. (1995)</a> described a patient with familial hemophagocytic lymphohistiocytosis (FHL2; <a href="/entry/603553">603553</a>) with a defect in splicing of CD45 (<a href="/entry/151460">151460</a>). <a href="#18" class="mim-tip-reference" title="McCormick, J., Flower, D. R., Strobel, S., Wallace, D. L., Beverley, P. C. L., Tchilian, E. Z. <strong>Novel perforin mutation in a patient with hemophagocytic lymphohistiocytosis and CD45 abnormal splicing.</strong> Am. J. Med. Genet. 117A: 255-260, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12599189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12599189</a>] [<a href="https://doi.org/10.1002/ajmg.a.10010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12599189">McCormick et al. (2003)</a> analyzed the perforin status in this patient and identified a novel 1304C-T transition in exon 3 of the PRF1 gene, resulting in a thr435-to-met (T435M) mutation. Threonine-435 is conserved between human, mouse, and rat, and is located in the highly conserved Ca(2+)-binding domain of perforin. Molecular modeling predicted that the T435M mutation would affect the calcium binding of the molecule and therefore impair perforin function. The abnormal CD45 splicing was caused by a 77C-G polymorphism in exon A of the CD45 gene, which cosegregated with the T435M mutation in the family. <a href="#18" class="mim-tip-reference" title="McCormick, J., Flower, D. R., Strobel, S., Wallace, D. L., Beverley, P. C. L., Tchilian, E. Z. <strong>Novel perforin mutation in a patient with hemophagocytic lymphohistiocytosis and CD45 abnormal splicing.</strong> Am. J. Med. Genet. 117A: 255-260, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12599189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12599189</a>] [<a href="https://doi.org/10.1002/ajmg.a.10010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12599189">McCormick et al. (2003)</a> postulated that both mutations were involved in the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12599189+7851014" 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="0011" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PRF1, ALA91VAL
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs35947132 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs35947132;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs35947132?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs35947132" 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=rs35947132" 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=RCV000014719 OR RCV000224458 OR RCV000456018 OR RCV000547554 OR RCV002260967 OR RCV003398509" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014719, RCV000224458, RCV000456018, RCV000547554, RCV002260967, RCV003398509" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014719...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant, formerly designated HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2, SUSCEPTIBILITY TO, with 2 'included' designations, LYMPHOMA, NON-HODGKIN, SUSCEPTIBILITY TO and APLASTIC ANEMIA, SUSCEPTIBILITY TO, has been reclassified based on the reports by <a href="#19" class="mim-tip-reference" title="Molleran Lee, S., Villanueva, J., Sumegi, J., Zhang, K., Kogawa, K., Davis, J., Filipovich, A. H. <strong>Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis.</strong> J. Med. Genet. 41: 137-144, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14757862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14757862</a>] [<a href="https://doi.org/10.1136/jmg.2003.011528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14757862">Molleran Lee et al. (2004)</a>, <a href="#37" class="mim-tip-reference" title="zur Stadt, U., Beutel, K., Weber, B., Kabisch, H., Schneppenheim, R., Janka, G. <strong>A91V is a polymorphism in the perforin gene not causative of an FHLH phenotype. (Letter)</strong> Blood 104: 1909 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15342365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15342365</a>] [<a href="https://doi.org/10.1182/blood-2004-02-0733" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15342365">zur Stadt et al. (2004)</a>, and <a href="#14" class="mim-tip-reference" title="Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O'Donnell-Luria, A. H., Ware, J. S., Hill, A. J., Cummings, B. B., Tukiainen, T., Birnbaum, D. P., and 68 others. <strong>Analysis of protein-coding genetic variation in 60,706 humans.</strong> Nature 536: 285-291, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27535533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27535533</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27535533[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature19057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27535533">Lek et al. (2016)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14757862+15342365+27535533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 sibs with adult onset and atypical presentation of hemophagocytic lymphohistiocytosis (FHL2; <a href="/entry/603553">603553</a>), <a href="#7" class="mim-tip-reference" title="Clementi, R., Emmi, L., Maccario, R., Liotta, F., Moretta, L., Danesino, C., Arico, M. <strong>Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. (Letter)</strong> Blood 100: 2266-2267, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12229880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12229880</a>] [<a href="https://doi.org/10.1182/blood-2002-04-1030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12229880">Clementi et al. (2002)</a> identified compound heterozygosity of a 272C-T transition in exon 2 of the PRF1 gene, resulting in an ala91-to-val (A91V) substitution, and a trp374-to-ter (W374X; <a href="#0002">170280.0002</a>) mutation in the PRF1 gene. <a href="#9" class="mim-tip-reference" title="Clementi, R., Locatelli, F., Dupre, L., Garaventa, A., Emmi, L., Bregni, M., Cefalo, G., Moretta, A., Danesino, C., Comis, M., Pession, A., Ramenghi, U., Maccario, R., Arico, M., Roncarolo, M. G. <strong>A proportion of patients with lymphoma may harbor mutations of the perforin gene.</strong> Blood 105: 4424-4428, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15728124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15728124</a>] [<a href="https://doi.org/10.1182/blood-2004-04-1477" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15728124">Clementi et al. (2005)</a> reported that 1 of the sibs had a non-Hodgkin lymphoma (<a href="/entry/605027">605027</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15728124+12229880" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Busiello, R., Adriani, M., Locatelli, F., Galgani, M., Fimiani, G., Clementi, R., Ursini, M. V., Racioppi, L., Pignata, C. <strong>Atypical features of familial hemophagocytic lymphohistiocytosis. (Letter)</strong> Blood 103: 4610-4612, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14739222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14739222</a>] [<a href="https://doi.org/10.1182/blood-2003-10-3551" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14739222">Busiello et al. (2004)</a> reported a family in which fraternal twins were both homozygous for the A91V substitution but showed markedly different phenotypic expression. The proband presented at age 13 years with persistent fever, hepatosplenomegaly, cytopenia, and lymph node enlargement. Signs of hemophagocytosis in a liver biopsy specimen led to the diagnosis of FHL. The patient died after a rapidly progressive disease course. All the remaining family members, including the homozygous twin, were considered normal. Natural killer activity was severely impaired in the patient but normal in the asymptomatic twin. Both twins and the father carried a second PRF1 mutation in heterozygous state: 695G-A transition resulting in an R231H amino acid change. The report highlighted the long disease-free interval during which biochemical or immunologic alterations may not be evident and the suggestion that factors other than mutation in the perforin gene may be involved. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14739222" 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="Clementi, R., Chiocchetti, A., Cappellano, G., Cerutti, E., Ferretti, M., Orilieri, E., Dianzani, I., Ferrarini, M., Bregni, M., Danesino, C., Bozzi, V., Putti, M. C., Cerutti, F., Cometa, A., Locatelli, F., Maccario, R., Ramenghi, U., Dianzani, U. <strong>Variations of the perforin gene in patients with autoimmunity/lymphoproliferation and defective Fas function.</strong> Blood 108: 3079-3084, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16720836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16720836</a>] [<a href="https://doi.org/10.1182/blood-2006-02-001412" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16720836">Clementi et al. (2006)</a> identified the A91V substitution of PRF1 in 6 of 28 patients with Dianzani autoimmune lymphoproliferative disease (DALD; <a href="/entry/605233">605233</a>), a disorder that resembles autoimmune lymphoproliferative syndrome (ALPS; <a href="/entry/601859">601859</a>) but lacks expansion of double-negative T cells. Presence of A91V conferred an odds ratio of 3 for DALD, and the odds ratio increased to 17 if variations in the osteopontin (SPP1; <a href="/entry/166490">166490</a>) gene associated with increased osteopontin production were also present. However, A91V was relatively frequent (4.6%) in controls. <a href="#5" class="mim-tip-reference" title="Clementi, R., Chiocchetti, A., Cappellano, G., Cerutti, E., Ferretti, M., Orilieri, E., Dianzani, I., Ferrarini, M., Bregni, M., Danesino, C., Bozzi, V., Putti, M. C., Cerutti, F., Cometa, A., Locatelli, F., Maccario, R., Ramenghi, U., Dianzani, U. <strong>Variations of the perforin gene in patients with autoimmunity/lymphoproliferation and defective Fas function.</strong> Blood 108: 3079-3084, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16720836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16720836</a>] [<a href="https://doi.org/10.1182/blood-2006-02-001412" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16720836">Clementi et al. (2006)</a> suggested that A91V may be a susceptibility factor for DALD in patients with defective FAS (TNFRSF6; <a href="/entry/134637">134637</a>) function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16720836" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Solomou, E. E., Gibellini, F., Stewart, B., Malide, D., Berg, M., Visconte, V., Green, S., Childs, R., Chanock, S. J., Young, N. S. <strong>Perforin gene mutations in patients with acquired aplastic anemia.</strong> Blood 109: 5234-5237, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17311987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17311987</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17311987[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/10.1182/blood-2006-12-063495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17311987">Solomou et al. (2007)</a> identified a heterozygous A91V substitution in 3 unrelated adults who developed aplastic anemia (<a href="/entry/609135">609135</a>) at ages 31, 77, and 78, respectively. Two of these patients had evidence of hemophagocytosis on bone marrow biopsy with no other clinical features of hemophagocytic syndrome. One patient had no response to immunosuppression, and 2 had only partial responses. Perforin protein levels and perforin granules were markedly decreased or absent in CD8(+) T cells. All 3 patients also carried a heterozygous synonymous his300-to-his (H300H) polymorphism in exon 3 of the PRF1 gene. The A91V substitution was identified in 24 (1.0%) of 2,312 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17311987" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Molleran Lee, S., Villanueva, J., Sumegi, J., Zhang, K., Kogawa, K., Davis, J., Filipovich, A. H. <strong>Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis.</strong> J. Med. Genet. 41: 137-144, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14757862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14757862</a>] [<a href="https://doi.org/10.1136/jmg.2003.011528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14757862">Molleran Lee et al. (2004)</a> and <a href="#37" class="mim-tip-reference" title="zur Stadt, U., Beutel, K., Weber, B., Kabisch, H., Schneppenheim, R., Janka, G. <strong>A91V is a polymorphism in the perforin gene not causative of an FHLH phenotype. (Letter)</strong> Blood 104: 1909 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15342365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15342365</a>] [<a href="https://doi.org/10.1182/blood-2004-02-0733" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15342365">zur Stadt et al. (2004)</a> identified the A91V substitution with an allelic frequency of 3% and 9%, respectively, suggesting that it is a polymorphism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14757862+15342365" 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="#14" class="mim-tip-reference" title="Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O'Donnell-Luria, A. H., Ware, J. S., Hill, A. J., Cummings, B. B., Tukiainen, T., Birnbaum, D. P., and 68 others. <strong>Analysis of protein-coding genetic variation in 60,706 humans.</strong> Nature 536: 285-291, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27535533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27535533</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27535533[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature19057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27535533">Lek et al. (2016)</a> noted that the A211V (A91V) variant has a high allele frequency (0.0174) in the South Asian population in the ExAC database, suggesting that it is not pathogenic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27535533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Variant Function</em></strong></p><p>
|
|
In rat basophil leukemia cells, <a href="#34" class="mim-tip-reference" title="Voskoboinik, I., Thia, M.-C., Trapani, J. A. <strong>A functional analysis of the putative polymorphisms A91V and N252S and 22 missense perforin mutations associated with familial hemophagocytic lymphohistiocytosis.</strong> Blood 105: 4700-4706, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15755897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15755897</a>] [<a href="https://doi.org/10.1182/blood-2004-12-4935" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15755897">Voskoboinik et al. (2005)</a> found that the A91V PRF1 protein showed decreased expression, resulting in partial loss of lytic capacity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15755897" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In studies of rat basophil leukemia cells and perforin-deficient mouse cytotoxic T cells, <a href="#32" class="mim-tip-reference" title="Voskoboinik, I., Sutton, V. R., Ciccone, A., House, C. M., Chia, J., Darcy, P. K., Yagita, H., Trapani, J. A. <strong>Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function.</strong> Blood 110: 1184-1190, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17475905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17475905</a>] [<a href="https://doi.org/10.1182/blood-2007-02-072850" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17475905">Voskoboinik et al. (2007)</a> found that human A91V mutant protein had a 10-fold decrease in target cell lysis activity compared to wildtype protein. The mutant protein was also present at lower levels. Further studies suggested that the mutant protein undergoes abnormal folding. <a href="#32" class="mim-tip-reference" title="Voskoboinik, I., Sutton, V. R., Ciccone, A., House, C. M., Chia, J., Darcy, P. K., Yagita, H., Trapani, J. A. <strong>Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function.</strong> Blood 110: 1184-1190, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17475905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17475905</a>] [<a href="https://doi.org/10.1182/blood-2007-02-072850" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17475905">Voskoboinik et al. (2007)</a> suggested that the diminished lytic activity of the A91V protein may be partly rescued by other granule toxins, thus resulting in a less dramatic clinical effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17475905" 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="0012" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 APLASTIC ANEMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PRF1, SER388ILE
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs193302875 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs193302875;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=rs193302875" 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=rs193302875" 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=RCV000014722 OR RCV004700235" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014722, RCV004700235" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014722...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 33-year-old Hispanic patient with aplastic anemia (<a href="/entry/609135">609135</a>), <a href="#26" class="mim-tip-reference" title="Solomou, E. E., Gibellini, F., Stewart, B., Malide, D., Berg, M., Visconte, V., Green, S., Childs, R., Chanock, S. J., Young, N. S. <strong>Perforin gene mutations in patients with acquired aplastic anemia.</strong> Blood 109: 5234-5237, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17311987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17311987</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17311987[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/10.1182/blood-2006-12-063495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17311987">Solomou et al. (2007)</a> identified a heterozygous G-to-T transversion in exon 3 of the PRF1 gene, resulting in a ser388-to-ile (S388I) substitution. The patient was also heterozygous for a synonymous ala274-to-ala (A274A) polymorphism in the PRF1 gene. Bone marrow biopsy showed hemophagocytosis, but the patient had no other clinical features of hemophagocytic syndrome. Perforin granules were absent in CD8(+) T cells. There was no clinical response to immunosuppression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17311987" 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="0013" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 APLASTIC ANEMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PRF1, ARG4HIS
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs35418374 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs35418374;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs35418374?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs35418374" 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=rs35418374" 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=RCV000014723 OR RCV000242526 OR RCV000425105 OR RCV000545742 OR RCV002260968" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014723, RCV000242526, RCV000425105, RCV000545742, RCV002260968" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014723...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 21-year-old African American patient with aplastic anemia (<a href="/entry/609135">609135</a>), <a href="#26" class="mim-tip-reference" title="Solomou, E. E., Gibellini, F., Stewart, B., Malide, D., Berg, M., Visconte, V., Green, S., Childs, R., Chanock, S. J., Young, N. S. <strong>Perforin gene mutations in patients with acquired aplastic anemia.</strong> Blood 109: 5234-5237, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17311987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17311987</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17311987[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/10.1182/blood-2006-12-063495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17311987">Solomou et al. (2007)</a> identified a heterozygous G-to-A transition in exon 2 of the PRF1 gene, resulting in an arg4-to-his (R4H) substitution. Bone marrow biopsy showed features of hemophagocytosis, but the patient had no other clinical manifestations of the hemophagocytosis syndrome. There was no clinical response to immunosuppression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17311987" 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="0014" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PRF1, 2-BP DEL, 1090CT
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs771552960 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs771552960;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs771552960?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs771552960" 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=rs771552960" 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=RCV000014724 OR RCV003473104 OR RCV004700236 OR RCV005049338" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014724, RCV003473104, RCV004700236, RCV005049338" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014724...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese patient with familial hemophagocytic lymphohistiocytosis (FHL2; <a href="/entry/603553">603553</a>), <a href="#31" class="mim-tip-reference" title="Ueda, I., Morimoto, A., Inaba, T., Yagi, T., Hibi, S., Sugimoto, T., Sako, M., Yanai, F., Fukushima, T., Nakayama, M., Ishii, E., Imashuku, S. <strong>Characteristic perforin gene mutations of haemophagocytic lymphohistiocytosis patients in Japan.</strong> Brit. J. Haemat. 121: 503-510, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12716377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12716377</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2003.04298.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12716377">Ueda et al. (2003)</a> identified homozygosity for a 2-bp deletion (1090delCT) in exon 3 of the PRF1 gene, resulting in a frameshift and premature termination after 456 amino acids. Two additional Japanese FHL2 patients were found to be compound heterozygous 1090delCT and a 1-bp deletion (207delC; <a href="#0015">170280.0015</a>) in exon 2, resulting in frameshift and premature termination after 106 amino acids. A fourth Japanese patient was compound heterozygous for 1090delCT and a 1246C-T transition in exon 3 of the PRF1 gene, resulting in a gln416-to-ter (Q416X; <a href="#0016">170280.0016</a>) substitution. <a href="#31" class="mim-tip-reference" title="Ueda, I., Morimoto, A., Inaba, T., Yagi, T., Hibi, S., Sugimoto, T., Sako, M., Yanai, F., Fukushima, T., Nakayama, M., Ishii, E., Imashuku, S. <strong>Characteristic perforin gene mutations of haemophagocytic lymphohistiocytosis patients in Japan.</strong> Brit. J. Haemat. 121: 503-510, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12716377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12716377</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2003.04298.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12716377">Ueda et al. (2003)</a> noted that although none of these patients were directly related, they all had ancestors who originated from the southwestern part of Japan. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12716377" 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="0015" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PRF1, 1-BP DEL, 207C
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs786205093 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205093;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs786205093?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs786205093" 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=rs786205093" 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=RCV000014725 OR RCV003460477" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014725, RCV003460477" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014725...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 1-bp deletion in the PRF1 gene (207delC) that was found in compound heterozygous state in patients with familial hemophagocytic lymphohistiocytosis (FHL2; <a href="/entry/603553">603553</a>) by <a href="#31" class="mim-tip-reference" title="Ueda, I., Morimoto, A., Inaba, T., Yagi, T., Hibi, S., Sugimoto, T., Sako, M., Yanai, F., Fukushima, T., Nakayama, M., Ishii, E., Imashuku, S. <strong>Characteristic perforin gene mutations of haemophagocytic lymphohistiocytosis patients in Japan.</strong> Brit. J. Haemat. 121: 503-510, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12716377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12716377</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2003.04298.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12716377">Ueda et al. (2003)</a>, see <a href="#0014">170280.0014</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12716377" 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="0016" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
PRF1, GLN416TER
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs193302876 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs193302876;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs193302876?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs193302876" 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=rs193302876" 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=RCV000014726 OR RCV003460478" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014726, RCV003460478" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014726...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the gln416-to-ter (Q416X) mutation in the PRF1 gene that was found in compound heterozygous state in a patient with familial hemophagocytic lymphohistiocytosis (FHL2; <a href="/entry/603553">603553</a>) by <a href="#31" class="mim-tip-reference" title="Ueda, I., Morimoto, A., Inaba, T., Yagi, T., Hibi, S., Sugimoto, T., Sako, M., Yanai, F., Fukushima, T., Nakayama, M., Ishii, E., Imashuku, S. <strong>Characteristic perforin gene mutations of haemophagocytic lymphohistiocytosis patients in Japan.</strong> Brit. J. Haemat. 121: 503-510, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12716377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12716377</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2003.04298.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12716377">Ueda et al. (2003)</a>, see <a href="#0014">170280.0014</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12716377" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="seeAlso" class="mim-anchor"></a>
|
|
<h4 href="#mimSeeAlsoFold" id="mimSeeAlsoToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span class="mim-font">
|
|
<span id="mimSeeAlsoToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<div id="mimSeeAlsoFold" class="collapse in mimTextToggleFold">
|
|
<span class="mim-text-font">
|
|
<a href="#Stanley1988" class="mim-tip-reference" title="Stanley, K., Luzio, P. <strong>A family of killer proteins.</strong> Nature 334: 475-476, 1988.">Stanley and Luzio (1988)</a>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="references"class="mim-anchor"></a>
|
|
<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span class="mim-font">
|
|
<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div id="mimReferencesFold" class="collapse in mimTextToggleFold">
|
|
<ol>
|
|
|
|
<li>
|
|
<a id="1" class="mim-anchor"></a>
|
|
<a id="Badovinac2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Badovinac, V. P., Tvinnereim, A. R., Harty, J. T.
|
|
<strong>Regulation of antigen-specific CD8(+) T cell homeostasis by perforin and interferon-gamma.</strong>
|
|
Science 290: 1354-1357, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11082062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11082062</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11082062" 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.290.5495.1354" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="2" class="mim-anchor"></a>
|
|
<a id="Binder1998" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Binder, D., van den Broek, M. F., Kagi, D., Bluethmann, H., Fehr, J., Hengartner, H., Zinkernagel, R. M.
|
|
<strong>Aplastic anemia rescued by exhaustion of cytokine-secreting CD8+ T cells in persistent infection with lymphocytic choriomeningitis virus.</strong>
|
|
J. Exp. Med. 187: 1903-1920, 1998.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9607930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9607930</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9607930[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=9607930" 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.187.11.1903" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="3" class="mim-anchor"></a>
|
|
<a id="Busiello2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Busiello, R., Adriani, M., Locatelli, F., Galgani, M., Fimiani, G., Clementi, R., Ursini, M. V., Racioppi, L., Pignata, C.
|
|
<strong>Atypical features of familial hemophagocytic lymphohistiocytosis. (Letter)</strong>
|
|
Blood 103: 4610-4612, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14739222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14739222</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14739222" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1182/blood-2003-10-3551" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="4" class="mim-anchor"></a>
|
|
<a id="Chiapparini2011" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Chiapparini, L., Uziel, G., Vallinoto, C., Bruzzone, M. G., Rovelli, A., Tricomi, G., Bizzi, A., Nardocci, N., Rizzari, C., Savoiardo, M.
|
|
<strong>Hemophagocytic lymphohistiocytosis with neurological presentation: MRI findings and a nearly miss (sic) diagnosis.</strong>
|
|
Neurol. Sci. 32: 473-477, 2011.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21234777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21234777</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21234777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1007/s10072-010-0467-2" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="5" class="mim-anchor"></a>
|
|
<a id="Clementi2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Clementi, R., Chiocchetti, A., Cappellano, G., Cerutti, E., Ferretti, M., Orilieri, E., Dianzani, I., Ferrarini, M., Bregni, M., Danesino, C., Bozzi, V., Putti, M. C., Cerutti, F., Cometa, A., Locatelli, F., Maccario, R., Ramenghi, U., Dianzani, U.
|
|
<strong>Variations of the perforin gene in patients with autoimmunity/lymphoproliferation and defective Fas function.</strong>
|
|
Blood 108: 3079-3084, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16720836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16720836</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16720836" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1182/blood-2006-02-001412" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="6" class="mim-anchor"></a>
|
|
<a id="Clementi2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Clementi, R., Dagna, L., Dianzani, U., Dupre, L., Dianzani, I., Ponzoni, M., Cometa, A., Chiocchetti, A., Sabbadini, M. G., Rugarli, C., Ciceri, F., Maccario, R., Locatelli, F., Danesino, C., Ferrarini, M., Bregni, M.
|
|
<strong>Inherited perforin and Fas mutations in a patient with autoimmune lymphoproliferative syndrome and lymphoma.</strong>
|
|
New Eng. J. Med. 351: 1419-1424, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15459303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15459303</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15459303" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1056/NEJMoa041432" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="7" class="mim-anchor"></a>
|
|
<a id="Clementi2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Clementi, R., Emmi, L., Maccario, R., Liotta, F., Moretta, L., Danesino, C., Arico, M.
|
|
<strong>Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. (Letter)</strong>
|
|
Blood 100: 2266-2267, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12229880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12229880</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12229880" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1182/blood-2002-04-1030" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="8" class="mim-anchor"></a>
|
|
<a id="Clementi2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Clementi, R., Ferrarini, M., Bregni, M.
|
|
<strong>Autoimmune lymphoproliferative syndrome and perforin. (Letter)</strong>
|
|
New Eng. J. Med. 352: 306-307, 2005.
|
|
|
|
|
|
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="9" class="mim-anchor"></a>
|
|
<a id="Clementi2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Clementi, R., Locatelli, F., Dupre, L., Garaventa, A., Emmi, L., Bregni, M., Cefalo, G., Moretta, A., Danesino, C., Comis, M., Pession, A., Ramenghi, U., Maccario, R., Arico, M., Roncarolo, M. G.
|
|
<strong>A proportion of patients with lymphoma may harbor mutations of the perforin gene.</strong>
|
|
Blood 105: 4424-4428, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15728124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15728124</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15728124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1182/blood-2004-04-1477" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="10" class="mim-anchor"></a>
|
|
<a id="Dias2013" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Dias, C., McDonald, A., Sincan, M., Rupps, R., Markello, T., Salvarinova, R., Santos, R. F., Menghrajani, K., Ahaghotu, C., Sutherland, D. P., Fortuno, E. S., III, Kollmann, T. R., Demos, M., Friedman, J. M., Speert, D. P., Gahl, W. A., Boerkoel, C. F.
|
|
<strong>Recurrent subacute post-viral onset of ataxia associated with a PRF1 mutation.</strong>
|
|
Europ. J. Hum. Genet. 21: 1232-1239, 2013.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23443029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23443029</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23443029[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=23443029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/ejhg.2013.20" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="11" class="mim-anchor"></a>
|
|
<a id="Fink1992" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Fink, T. M., Zimmer, M., Weitz, S., Tschopp, J., Jenne, D. E., Lichter, P.
|
|
<strong>Human perforin (PRF1) maps to 10q22, a region that is syntenic with mouse chromosome 10.</strong>
|
|
Genomics 13: 1300-1302, 1992.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1505959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1505959</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1505959" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/0888-7543(92)90050-3" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="12" class="mim-anchor"></a>
|
|
<a id="Goransdotter Ericson2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Goransdotter Ericson, K., Fadeel, B., Nilsson-Ardnor, S., Soderhall, C., Samuelsson, A., Janka, G., Schneider, M., Gurgey, A., Yalman, N., Revesz, T., Egeler, R. M., Jahnukainen, K., Storm-Mathiesen, I., Haraldsson, A., Poole, J., de Saint Basile, G., Nordenskjold, M., Henter, J.-I.
|
|
<strong>Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis.</strong>
|
|
Am. J. Hum. Genet. 68: 590-597, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11179007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11179007</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11179007" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1086/318796" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="13" class="mim-anchor"></a>
|
|
<a id="Law2010" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Law, R. H. P., Lukoyanova, N., Voskoboinik, I., Caradoc-Davies, T. T., Baran, K., Dunstone, M. A., D'Angelo, M. E., Orlova, E. V., Coulibaly, F., Verschoor, S., Browne, K. A., Ciccone, A., Kuiper, M. J., Bird, P. I., Trapani, J. A., Saibil, H. R., Whisstock, J. C.
|
|
<strong>The structural basis for membrane binding and pore formation by lymphocyte perforin.</strong>
|
|
Nature 468: 447-451, 2010.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21037563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21037563</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21037563" 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/nature09518" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="14" class="mim-anchor"></a>
|
|
<a id="Lek2016" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O'Donnell-Luria, A. H., Ware, J. S., Hill, A. J., Cummings, B. B., Tukiainen, T., Birnbaum, D. P., and 68 others.
|
|
<strong>Analysis of protein-coding genetic variation in 60,706 humans.</strong>
|
|
Nature 536: 285-291, 2016.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27535533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27535533</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27535533[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=27535533" 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/nature19057" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="15" class="mim-anchor"></a>
|
|
<a id="Lichtenheld1988" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Lichtenheld, M. G., Olsen, K. J., Lu, P., Lowrey, D. M., Hameed, A., Hengartner, H., Podack, E. R.
|
|
<strong>Structure and function of human perforin.</strong>
|
|
Nature 335: 448-451, 1988.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3419519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3419519</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3419519" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/335448a0" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="16" class="mim-anchor"></a>
|
|
<a id="Lowin1994" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Lowin, B., Beermann, F., Schmidt, A., Tschopp, J.
|
|
<strong>A null mutation in the perforin gene impairs cytolytic T lymphocyte- and natural killer cell-mediated cytotoxicity.</strong>
|
|
Proc. Nat. Acad. Sci. 91: 11571-11575, 1994.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7972104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7972104</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7972104" 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.91.24.11571" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="17" class="mim-anchor"></a>
|
|
<a id="Matloubian1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Matloubian, M., Suresh, M., Glass, A., Galvan, M., Chow, K., Whitmire, J. K., Walsh, C. M., Clark, W. R., Ahmed, R.
|
|
<strong>A role for perforin in downregulating T-cell responses during chronic viral infection.</strong>
|
|
J. Virol. 73: 2527-2536, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9971838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9971838</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9971838[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=9971838" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1128/JVI.73.3.2527-2536.1999" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="18" class="mim-anchor"></a>
|
|
<a id="McCormick2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
McCormick, J., Flower, D. R., Strobel, S., Wallace, D. L., Beverley, P. C. L., Tchilian, E. Z.
|
|
<strong>Novel perforin mutation in a patient with hemophagocytic lymphohistiocytosis and CD45 abnormal splicing.</strong>
|
|
Am. J. Med. Genet. 117A: 255-260, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12599189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12599189</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12599189" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/ajmg.a.10010" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="19" class="mim-anchor"></a>
|
|
<a id="Molleran Lee2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Molleran Lee, S., Villanueva, J., Sumegi, J., Zhang, K., Kogawa, K., Davis, J., Filipovich, A. H.
|
|
<strong>Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis.</strong>
|
|
J. Med. Genet. 41: 137-144, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14757862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14757862</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14757862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1136/jmg.2003.011528" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="20" class="mim-anchor"></a>
|
|
<a id="Podack1988" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Podack, E. R., Lowrey, D. M., Lichtenheld, M., Olsen, K. J., Aebischer, T., Binder, D., Rupp, F., Hengartner, H.
|
|
<strong>Structure, function and expression of murine and human perforin 1 (P1).</strong>
|
|
Immun. Rev. 103: 203-211, 1988.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3292394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3292394</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3292394" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1111/j.1600-065x.1988.tb00756.x" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="21" class="mim-anchor"></a>
|
|
<a id="Rieux-Laucat2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Rieux-Laucat, F., Le Deist, F., De Saint Basile, G.
|
|
<strong>Autoimmune lymphoproliferative syndrome and perforin. (Letter)</strong>
|
|
New Eng. J. Med. 352: 306 only, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15659737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15659737</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15659737" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1056/NEJM200501203520319" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="22" class="mim-anchor"></a>
|
|
<a id="Risma2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Risma, K. A., Frayer, R. W., Filipovich, A. H., Sumegi, J.
|
|
<strong>Aberrant maturation of mutant perforin underlies the clinical diversity of hemophagocytic lymphohistiocytosis.</strong>
|
|
J. Clin. Invest. 116: 182-192, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16374518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16374518</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16374518[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=16374518" 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/JCI26217" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="23" class="mim-anchor"></a>
|
|
<a id="Shinkai1988" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Shinkai, Y., Takio, K., Okumura, K.
|
|
<strong>Homology of perforin to the ninth component of complement (C9).</strong>
|
|
Nature 334: 525-527, 1988.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3261391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3261391</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3261391" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/334525a0" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="24" class="mim-anchor"></a>
|
|
<a id="Shinkai1989" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Shinkai, Y., Yoshida, M. C., Maeda, K., Kobata, T., Maruyama, K., Yodoi, J., Yagita, H., Okumura, K.
|
|
<strong>Molecular cloning and chromosomal assignment of a human perforin (PFP) gene.</strong>
|
|
Immunogenetics 30: 452-457, 1989.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2592021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2592021</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2592021" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1007/BF02421177" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="25" class="mim-anchor"></a>
|
|
<a id="Smyth2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Smyth, M. J., Thia, K. Y. T., Street, S. E. A., MacGregor, D., Godfrey, D. I., Trapani, J. A.
|
|
<strong>Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma.</strong>
|
|
J. Exp. Med. 192: 755-760, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10974040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10974040</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10974040[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=10974040" 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.192.5.755" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="26" class="mim-anchor"></a>
|
|
<a id="Solomou2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Solomou, E. E., Gibellini, F., Stewart, B., Malide, D., Berg, M., Visconte, V., Green, S., Childs, R., Chanock, S. J., Young, N. S.
|
|
<strong>Perforin gene mutations in patients with acquired aplastic anemia.</strong>
|
|
Blood 109: 5234-5237, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17311987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17311987</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17311987[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=17311987" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1182/blood-2006-12-063495" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="27" class="mim-anchor"></a>
|
|
<a id="Stanley1988" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Stanley, K., Luzio, P.
|
|
<strong>A family of killer proteins.</strong>
|
|
Nature 334: 475-476, 1988.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3261390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3261390</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3261390" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/334475a0" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="28" class="mim-anchor"></a>
|
|
<a id="Stepp1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Stepp, S. E., Dufourcq-Lagelouse, R., Le Deist, F., Bhawan, S., Certain, S., Mathew, P. A., Henter, J.-I., Bennett, M., Fischer, A., de Saint Basile, G., Kumar, V.
|
|
<strong>Perforin gene defects in familial hemophagocytic lymphohistiocytosis.</strong>
|
|
Science 286: 1957-1959, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10583959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10583959</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10583959" 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.286.5446.1957" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="29" class="mim-anchor"></a>
|
|
<a id="Trapani1990" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Trapani, J. A., Kwon, B. S., Kozak, C. A., Chintamaneni, C., Young, J. D.-E., Dupont, B.
|
|
<strong>Genomic organization of the mouse pore-forming protein (perforin) gene and localization to chromosome 10: similarities to and differences from C9.</strong>
|
|
J. Exp. Med. 171: 545-557, 1990.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2303785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2303785</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2303785" 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.171.2.545" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="30" class="mim-anchor"></a>
|
|
<a id="Trizzino2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Trizzino, A., zur Stadt, U., Ueda, I., Risma, K., Janka, G., Ishii, E., Beutel, K., Sumegi, J., Cannella, S., Pende, D., Mian, A., Henter, J.-I., Griffiths, G., Santoro, A., Filipovich, A., Arico, M.
|
|
<strong>Genotype-phenotype study of familial haemophagocytic lymphohistiocytosis due to perforin mutations.</strong>
|
|
J. Med. Genet. 45: 15-21, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17873118/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17873118</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17873118" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1136/jmg.2007.052670" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="31" class="mim-anchor"></a>
|
|
<a id="Ueda2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Ueda, I., Morimoto, A., Inaba, T., Yagi, T., Hibi, S., Sugimoto, T., Sako, M., Yanai, F., Fukushima, T., Nakayama, M., Ishii, E., Imashuku, S.
|
|
<strong>Characteristic perforin gene mutations of haemophagocytic lymphohistiocytosis patients in Japan.</strong>
|
|
Brit. J. Haemat. 121: 503-510, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12716377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12716377</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12716377" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1046/j.1365-2141.2003.04298.x" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="32" class="mim-anchor"></a>
|
|
<a id="Voskoboinik2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Voskoboinik, I., Sutton, V. R., Ciccone, A., House, C. M., Chia, J., Darcy, P. K., Yagita, H., Trapani, J. A.
|
|
<strong>Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function.</strong>
|
|
Blood 110: 1184-1190, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17475905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17475905</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17475905" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1182/blood-2007-02-072850" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="33" class="mim-anchor"></a>
|
|
<a id="Voskoboinik2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Voskoboinik, I., Thia, M.-C., De Bono, A., Browne, K., Cretney, E., Jackson, J. T., Darcy, P. K., Jane, S. M., Smyth, M. J., Trapani, J. A.
|
|
<strong>The functional basis for hemophagocytic lymphohistiocytosis in a patient with co-inherited missense mutations in the perforin (PFN1) gene.</strong>
|
|
J. Exp. Med. 200: 811-816, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15365097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15365097</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15365097[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=15365097" 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.20040776" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="34" class="mim-anchor"></a>
|
|
<a id="Voskoboinik2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Voskoboinik, I., Thia, M.-C., Trapani, J. A.
|
|
<strong>A functional analysis of the putative polymorphisms A91V and N252S and 22 missense perforin mutations associated with familial hemophagocytic lymphohistiocytosis.</strong>
|
|
Blood 105: 4700-4706, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15755897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15755897</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15755897" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1182/blood-2004-12-4935" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="35" class="mim-anchor"></a>
|
|
<a id="Wagner1995" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Wagner, R., Morgan, G., Strobel, S.
|
|
<strong>A prospective study of CD45 isoform expression in haemophagocytic lymphohistiocytosis; an abnormal inherited immunophenotype in one family.</strong>
|
|
Clin. Exp. Immun. 99: 216-220, 1995.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7851014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7851014</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7851014" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1111/j.1365-2249.1995.tb05535.x" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="36" class="mim-anchor"></a>
|
|
<a id="Zur Stadt2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Zur Stadt, U., Beutel, K., Kolberg, S., Schneppenheim, R., Kabisch, H., Janka, G., Hennies, H. C.
|
|
<strong>Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A.</strong>
|
|
Hum. Mutat. 27: 62-68, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16278825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16278825</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16278825" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/humu.20274" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="37" class="mim-anchor"></a>
|
|
<a id="zur Stadt2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
zur Stadt, U., Beutel, K., Weber, B., Kabisch, H., Schneppenheim, R., Janka, G.
|
|
<strong>A91V is a polymorphism in the perforin gene not causative of an FHLH phenotype. (Letter)</strong>
|
|
Blood 104: 1909 only, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15342365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15342365</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15342365" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1182/blood-2004-02-0733" 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">
|
|
Ada Hamosh - updated : 11/30/2016
|
|
</span>
|
|
</div>
|
|
</div>
|
|
<div class="row collapse" id="mimCollapseContributors">
|
|
<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Cassandra L. Kniffin - updated : 12/4/2013<br>Ada Hamosh - updated : 1/31/2011<br>Marla J. F. O'Neill - updated : 11/6/2008<br>Cassandra L. Kniffin - updated : 10/2/2007<br>Cassandra L. Kniffin - updated : 9/20/2007<br>Paul J. Converse - updated : 4/12/2007<br>Cassandra L. Kniffin - updated : 3/13/2006<br>Victor A. McKusick - updated : 1/20/2006<br>Cassandra L. Kniffin - updated : 10/6/2005<br>Victor A. McKusick - updated : 8/11/2005<br>Victor A. McKusick - updated : 1/31/2005<br>Paul J. Converse - updated : 1/5/2005<br>Victor A. McKusick - updated : 10/22/2004<br>Marla J. F. O'Neill - updated : 9/29/2004<br>Victor A. McKusick - updated : 9/17/2004<br>Victor A. McKusick - updated : 3/21/2003<br>Victor A. McKusick - updated : 3/19/2001<br>Paul J. Converse - updated : 11/30/2000<br>Ada Hamosh - updated : 12/15/1999
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="creationDate" class="mim-anchor"></a>
|
|
<div class="row">
|
|
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
|
<span class="text-nowrap mim-text-font">
|
|
Creation Date:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Victor A. McKusick : 9/15/1988
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="editHistory" class="mim-anchor"></a>
|
|
|
|
<div class="row">
|
|
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
|
<span class="text-nowrap mim-text-font">
|
|
<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
carol : 08/18/2023
|
|
</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 : 08/21/2019<br>carol : 05/31/2018<br>alopez : 04/10/2018<br>carol : 10/20/2017<br>alopez : 12/01/2016<br>carol : 12/01/2016<br>carol : 11/30/2016<br>carol : 05/05/2015<br>alopez : 4/29/2015<br>mcolton : 4/20/2015<br>carol : 11/18/2014<br>carol : 12/6/2013<br>carol : 12/6/2013<br>ckniffin : 12/4/2013<br>carol : 9/5/2013<br>terry : 1/17/2012<br>alopez : 2/4/2011<br>terry : 1/31/2011<br>terry : 11/19/2008<br>wwang : 11/12/2008<br>terry : 11/6/2008<br>wwang : 10/9/2007<br>ckniffin : 10/2/2007<br>terry : 9/26/2007<br>wwang : 9/25/2007<br>ckniffin : 9/20/2007<br>ckniffin : 9/20/2007<br>mgross : 4/13/2007<br>terry : 4/12/2007<br>carol : 1/31/2007<br>carol : 9/8/2006<br>wwang : 3/17/2006<br>ckniffin : 3/13/2006<br>alopez : 3/9/2006<br>alopez : 3/9/2006<br>terry : 1/20/2006<br>ckniffin : 10/17/2005<br>carol : 10/11/2005<br>ckniffin : 10/6/2005<br>wwang : 8/12/2005<br>terry : 8/11/2005<br>tkritzer : 2/4/2005<br>terry : 1/31/2005<br>mgross : 1/5/2005<br>mgross : 1/5/2005<br>carol : 11/17/2004<br>ckniffin : 11/2/2004<br>terry : 10/29/2004<br>terry : 10/22/2004<br>tkritzer : 9/29/2004<br>tkritzer : 9/24/2004<br>tkritzer : 9/21/2004<br>alopez : 9/20/2004<br>terry : 9/17/2004<br>terry : 5/16/2003<br>tkritzer : 4/7/2003<br>tkritzer : 4/3/2003<br>terry : 3/21/2003<br>cwells : 3/29/2001<br>terry : 3/19/2001<br>mgross : 3/2/2001<br>mgross : 11/30/2000<br>mgross : 11/30/2000<br>alopez : 2/10/2000<br>alopez : 12/17/1999<br>alopez : 12/17/1999<br>terry : 12/15/1999<br>carol : 12/19/1994<br>carol : 4/7/1993<br>carol : 8/17/1992<br>carol : 8/14/1992<br>supermim : 3/16/1992<br>carol : 7/2/1990
|
|
</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> 170280
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
PERFORIN 1; PRF1
|
|
|
|
</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">
|
|
PFN1<br />
|
|
PORE-FORMING PROTEIN; PFP
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: PRF1</em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
|
|
<strong>SNOMEDCT:</strong> 304132006, 306058006;
|
|
|
|
|
|
<strong>ICD10CM:</strong> D61.9;
|
|
|
|
|
|
<strong>ICD9CM:</strong> 284.9;
|
|
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 10q22.1
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 10:70,597,348-70,602,741 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
10q22.1
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Aplastic anemia
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
609135
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hemophagocytic lymphohistiocytosis, familial, 2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
603553
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Lymphoma, non-Hodgkin
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
605027
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</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>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Perforin-1 (PRF1) is one of the major cytolytic proteins of cytolytic granules. One of the main pathways of lymphocyte-mediated cytolysis entails the secretion onto target membranes of cytolytic granules contained in cytolytic effector lymphocytes of T-cell or NK-cell type. Perforin has a molecular mass of 70 to 75 kD and shows extensive similarity in structure to complement component C9 (120940). PRF1 is a pore-forming protein with a mechanism of transmembrane channel formation similar to C9. Podack et al. (1988) reviewed information on the structure and expression of PRF1 obtained through the analysis of cDNA clones. Shinkai et al. (1988) demonstrated homology of perforin with C9 at their respective functionally conserved regions. They also found that perforin is expressed only in killer cell lines and not in helper T lymphocytes or other tumor cells tested. Lichtenheld et al. (1988) determined the primary structure of human perforin. In the mouse, Trapani et al. (1990) found that the perforin gene has a simplified structure compared to C9. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Using a panel of somatic cell hybrid cell lines, Trapani et al. (1990) mapped the Pfp gene to mouse chromosome 10. By in situ hybridization with a human perforin cDNA probe, Shinkai et al. (1989) assigned the PFP gene to 17q11-q21. Fink et al. (1992) was prompted to reexamine the mapping of PRF1 in the human because the gene was undetectable in a human chromosome 17 reference library in which clones for vitronectin, which maps to the region where PRF1 was supposed to lie, and because of the lack of any known homology between human chromosome 17 and mouse chromosome 10. Using the cosmid DNA containing the PRF1 gene as a probe for fluorescence in situ hybridization, they mapped the gene to human 10q22, a region that is syntenic with mouse chromosome 10. Thus, the perforin locus is not linked to that of any of the genes of the terminal complement system with which it shows partial homology of sequence. Lymphocyte-mediated cytotoxicity is thought to consist of the polarized secretion of granule-stored perforin leading to target-cell lysis. Nevertheless, perforin-independent pathways were postulated to explain the cytolytic activity of lymphocytes that apparently lacked perforin and the DNA degradation found in dying target cells. </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>
|
|
Law et al. (2010) elucidated the mechanism of perforin pore formation by determining the x-ray crystal structure of monomeric murine perforin, together with a cryoelectron microscopy reconstruction of the entire perforin pore. Perforin is a thin key-shaped molecule, comprising an amino-terminal membrane attack complex perforin-like (MACPF)/cholesterol-dependent cytolysin (CDC) domain followed by an epidermal growth factor (EGF) domain that, together with the extreme carboxy-terminal sequence, forms a central shelf-like structure. A C-terminal C2 domain mediates initial, calcium ion-dependent membrane binding. Most unexpectedly, however, electron microscopy revealed that the orientation of the perforin MACPF domain in the pore is inside-out relative to the subunit arrangement in CDCs. Law et al. (2010) concluded that their data revealed remarkable flexibility in the mechanism of action of the conserved MACPF/CDC fold and provided new insights into how related immune defense molecules such as complement proteins assemble into pores. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Familial Hemophagocytic Lymphohistiocytosis</em></strong></p><p>
|
|
Stepp et al. (1999) identified mutations in homozygosity and compound heterozygosity in patients with familial hemophagocytic lymphohistiocytosis (FHL2; 603553). Four patients had missense mutations and 4 patients had homozygous nonsense mutations. Stepp et al. (1999) generated cytotoxic cells by culturing previously frozen cells from 4 FHL patients and controls in phytohemagglutinin and interleukin-2 (147680). CD3 (see 186740)-dependent cytolytic activity was measured in a 4-hour assay. Cells from all patients had greatly reduced cytolytic activity compared with cells from normal controls. Cells from a patient with a premature stop codon displayed no cytotoxicity, and cells from 3 patients with missense mutations showed greatly reduced lysis of the target cells. Stepp et al. (1999) concluded that perforin-mediated cytotoxic activity of CD8+ T cells is defective in FHL patients. No perforin protein was detectable in patient cells using immunostaining. Two patients with low-level cytotoxic activity had a small amount of detectable perforin staining. </p><p>Goransdotter Ericson et al. (2001) reported a comprehensive survey of 34 patients with FHL for mutations in the coding region of the perforin gene and the relative frequency of perforin mutations in FHL. Perforin mutations were identified in 7 of the 34 families investigated. Six children were homozygous for the mutation, and 1 patient was a compound heterozygote. In 4 families, a previously reported mutation in codon 374 (W374X; 170280.0002), causing a premature stop codon, was identified, making this the most common perforin mutation identified in FHL patients. They found perforin mutations in 20% (7 of 34) of all FHL patients investigated, with a somewhat higher prevalence, approximately 30% (6 of 20), in children whose parents originated from Turkey. They concluded that perforin mutations account for 20 to 40% of FHL cases, that the locus on chromosome 9 (FHL1; 267700) accounts for approximately 10%, and that most FHL cases are caused by mutations in as yet unidentified genes. </p><p>In 25 (58%) of 43 unrelated North American families with children diagnosed with primary hemophagocytic lymphohistiocytosis, Molleran Lee et al. (2004) identified mutations in the PRF1 gene. There was no significant difference in median age at diagnosis when comparing patients with or without perforin mutations (6 months vs 7 months, respectively); however, comparing patients with PRF1 mutations who expressed low levels of perforin to those with no detectable perforin, the median age at onset was 54 months versus 3 months, respectively (p less than 0.001). </p><p><strong><em>Role in Lymphoma</em></strong></p><p>
|
|
Clementi et al. (2002) reported 2 sibs with adult-onset FHL in whom they identified compound heterozygosity for a W374X mutation and an A91V (170280.0011) substitution. At age 21 years, the sister presented with fever, weight loss, weakness, hepatosplenomegaly, and pancytopenia. Repeat bone marrow biopsies showed a T-cell infiltration with no evidence for clonal proliferation. She was diagnosed with a T-cell lymphoblastic lymphoma (605027) and underwent autologous bone marrow transplantation. Her brother presented 2 years later at age 22 years with decreased liver function, fever, lymphadenopathy, pancytopenia, and neurologic symptoms consistent with FHL. Both patients had complete absence of NK cell activity and perforin expression. </p><p>Clementi et al. (2004) reported a 27-year-old man with autoimmune lymphoproliferative syndrome (ALPS; 601859) who later developed a large B-cell lymphoma. Genetic analysis identified heterozygous mutations in the FAS gene (134637), which has been known to be associated with ALPS, and the perforin gene (N252S; 170280.0009). The FAS mutation was inherited from his healthy father and was also carried by his healthy brother, whereas the PRF1 mutation was inherited from his healthy mother. The authors concluded that the combined effect of the 2 mutant genes contributed to the development of APLS and lymphoma in this patient. </p><p>Clementi et al. (2005) reported 3 additional patients with lymphoma who were compound heterozygous for mutations in the PRF1 gene. A 7-year-old boy had Epstein-Barr virus-positive Hodgkin lymphoma, which was successfully treated, and developed a large B-cell non-Hodgkin lymphoma 3 years later. During treatment for the second disease, he developed severe hemophagocytosis. Hematopoietic stem cell transplantation was successful. An unrelated 7-year-old girl developed a subcutaneous T-cell lymphoma associated with hemophagocytosis on bone marrow biopsy. An 18-year-old girl developed peripheral T-cell lymphoma with marrow infiltration and evidence of hemophagocytosis, and underwent successful bone marrow transplantation. Clementi et al. (2005) reported another 3 patients, with lymphoma, B-cell, T-cell and Hodgkin disease, respectively, who all had the same heterozygous A91V substitution (170280.0011) in the PRF1 gene. Clementi et al. (2005) noted that all of the patients they reported with lymphoma and mutations in the PRF1 gene were young, between the ages of 7 and 29 years. The findings suggested a more complex dysregulation of the immune system in the absence of perforin, with some patients developing FHL and some developing other lymphoproliferative disorders, including various forms of lymphoma. The authors postulated that heterozygous mutations in the PRF1 gene may increase susceptibility to the development of lymphoma, perhaps acting as a synergistic factor with other genetic mutations. </p><p><strong><em>Aplastic Anemia</em></strong></p><p>
|
|
Solomou et al. (2007) identified mutations in the PRF1 gene (170280.0011-170280.0013) in 5 unrelated patients with adult-onset aplastic anemia (609135). Four of the 5 patients showed hemophagocytosis on bone marrow biopsy, but none had clinical manifestations of the hemophagocytosis syndrome. Perforin protein levels in these patients were very low or absent, perforin granules were absent, and natural killer cell cytotoxicity was significantly decreased. Solomou et al. (2007) concluded that PRF1 gene alterations may explain aberrant proliferation and activation of cytotoxic T cells in aplastic anemia. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Genotype/Phenotype Correlations</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Risma et al. (2006) classified 21 human PRF1 disease-associated missense mutations into 3 broad classes based on expression in rat basophilic leukemia (RBL-1) cells. Class 1 mutations (see, e.g., A91V, 170280.0011, G429E, 170280.0005) resulted in partial maturation of perforin; class 2 mutations (see, e.g., R225W, 170280.0004) resulted in no apparent proteolytic maturation of the perforin protein; and class 3 mutations resulted in no recognizable forms of perforin due to protein misfolding and protein degradation. Class 1 mutations exhibited lytic function and were associated with residual protein detection and variable cytotoxic function. Patients with class 1 mutations had later disease onset compared to those with class 2 or 3 mutations. By contrast, class 3 mutations caused severely diminished protein detection and cytotoxicity, and patients with class 3 mutations had disease onset before 1 year of age and absent NK function. Patients with class 2 mutations had an intermediate phenotype. Risma et al. (2006) concluded that the pathogenic mechanism of perforin missense mutations may involve a protein dosage effect of the mature protein. </p><p>Trizzino et al. (2008) analyzed data from 124 FHL patients, who had 63 different mutations in the PRF1 gene, including 11 nonsense, 10 frameshift, 38 missense, and 4 in-frame deletions. The W374X mutation was present in 32 patients and was associated with Turkish origin; 50delT (170280.0001) was found in 21 patients and was associated with African American origin; and 1090delCT (170280.0014) was found in 7 Japanese patients. Flow cytometry showed that perforin expression was absent in 40 patients, reduced in 6, and normal in 4. Later onset and residual cytotoxic function were observed in patients with at least 1 missense mutation. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>To evaluate the role of perforin, Lowin et al. (1994) used gene targeting in embryonic stem cells to produce mice lacking perforin. Mice homozygous for the disrupted gene had no perforin mRNA. The mice were healthy, however, and activation and granzyme A secretion of perforin-free cytolytic T cells were unaltered. The killing activity of cytolytic T cells as well as of natural killer (NT) cells was impaired but not abolished. Lowin et al. (1994) concluded that perforin is a crucial effector molecule in T cell- and NK cell-mediated cytolysis; however, alternative perforin-independent lytic mechanisms also exist. </p><p>When perforin-deficient mice were infected with lymphocytic choriomeningitis virus, CD8+ T cell-, interferon gamma- (IFNG; 147570), and TNF-alpha (191160)-dependent immunopathology and mortality similar to that in humans with FHL was seen (Matloubian et al., 1999 and Binder et al., 1998). </p><p>Badovinac et al. (2000) showed that Prf1 knockout mice eliminated Listeria monocytogenes as well as wildtype mice did but had a higher number of antigen-specific cytotoxic CD8 cells; the ratio of cells responding to immunodominant antigens was the same, as measured by intracellular cytokine or MHC class I tetramer staining. Likewise, the rate of CD8-positive T-cell death after clearance of infection was indistinguishable from wildtype mice. In mice that also had disruption of the Ifng gene, there was a much greater expansion of cytotoxic T cells, an equivalence of cells responding to dominant antigens, and an attenuated rate of T-cell death compared to wildtype. In contrast to Ifng knockout mice, Badovinac et al. (2000) found the Prf1 knockout mice failed to clear lymphocytic choriomeningitis virus and died. The authors proposed that their findings may suggest strategies for enhancing T-cell memory in response to vaccination. </p><p>Smyth et al. (2000) found that Pfp1-null mice had a high incidence of spontaneous lymphoma of distinct cell lineages, including T cells, B cells, and natural killer cells, compared to wildtype mice. The susceptibility to lymphoma was accentuated in mice who also lacked the tumor suppressor gene p53 (191170). Pfp1-null mice were at least 1,000-fold more susceptible to these lymphomas when transplanted with the malignant cells, compared to immunocompetent mice in which tumor rejection was controlled by CD8+ T lymphocytes. The findings implicated direct cytotoxicity by lymphocytes in regulating lymphomagenesis. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>16 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRF1, 1-BP DEL, 50T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs147035858,
|
|
|
|
|
|
gnomAD: rs147035858,
|
|
|
|
|
|
ClinVar: RCV000541899, RCV000627438, RCV001201274, RCV002261110, RCV002506353, RCV003419965, RCV003476293
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553) from a consanguineous union, Stepp et al. (1999) found homozygosity for deletion of a T at nucleotide 50 of the PRF1 gene, resulting in a frameshift and stop in exon 2. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRF1, TRP374TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894176,
|
|
|
|
|
|
gnomAD: rs104894176,
|
|
|
|
|
|
ClinVar: RCV000014708, RCV000760450, RCV002260963, RCV002513052, RCV003473101, RCV005042053
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 patients with familial hemophagocytic lymphohistiocytosis (FHL2; 603553) from unrelated consanguineous families, Stepp et al. (1999) identified a homozygous G-to-A transition at nucleotide 1122 of the PRF1 gene, resulting in a trp374-to-ter (W374X) substitution. </p><p>In 2 sibs with adult-onset hemophagocytic lymphohistiocytosis, diagnosed at ages 22 and 21 years, respectively, Clementi et al. (2002) identified compound heterozygosity for the W374X mutation and an A91V substitution (170280.0011). The unrelated parents from southern Italy were each heterozygous for 1 of the substitutions. The patients had an atypical presentation and an unusually mild course of the disease. Clementi et al. (2005) later reported that 1 of the sibs had a non-Hodgkin lymphoma (605027). </p><p>Zur Stadt et al. (2006) found the W374X mutation in PRF1 in 12 of 32 patients from Turkey and noted that it was associated with very early onset of the disease (below the age of 3 months) in all cases. In contrast, they found the W374X mutation in only 3 of 23 patients from Germany. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRF1, GLN64TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894180,
|
|
|
|
|
|
gnomAD: rs104894180,
|
|
|
|
|
|
ClinVar: RCV000014710, RCV003460476
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553) from a consanguineous family, Stepp et al. (1999) found homozygosity for a 190C-T transition in the PRF1 gene, resulting in a glu64-to-ter (Q64X) substitution. </p><p>Goransdotter Ericson et al. (2001) found the Q64X mutation in 4 families and pointed out that it was the most common perforin mutation identified in FHL patients. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRF1, ARG225TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28933973,
|
|
|
|
|
|
gnomAD: rs28933973,
|
|
|
|
|
|
ClinVar: RCV000014711, RCV002260964, RCV002281706, RCV002513053, RCV003473102, RCV004814906
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553), Stepp et al. (1999) identified compound heterozygosity for mutations in the PRF1 gene: a 673C-T transition, resulting in an arg225-to-trp (R225W) substitution, and a 1286G-A transition, resulting in a gly429-to-glu mutation (G429E; 170280.0005). </p><p>Voskoboinik et al. (2004) developed a robust expression system in rat basophil leukemia (RBL) cells in order to define the basis of perforin dysfunction associated with the R225W and G429E mutations inherited by a compound heterozygote FHL patient. RBL cells expressing the 67-kD wildtype perforin efficiently killed human Jurkat T-cell lines. Mutation of the rodent protein at residues comparable to R225W resulted in a truncated 45-kD protein and a complete loss of cytotoxicity. Immunohistochemical analysis showed that wildtype perforin, but not R225W perforin, was packaged in secretory granules. In contrast, the rodent equivalent of the G429E mutation was correctly processed, stored, and released, but it possessed reduced cytotoxic capacity. Voskoboinik et al. (2004) concluded that the cellular basis for perforin mutation dysfunction in FHL patients involving other mutations can be studied using the RBL expression system. </p><p>Molleran Lee et al. (2004) identified a homozygous R225W mutation in 2 unrelated patients with FHL2. One was a 2-year-old Filipino boy and the other was a 5-year-old Caucasian girl. The patients were ascertained from a large cohort of 50 unrelated patients with a clinical diagnosis of FHL. No specific clinical details were available, but laboratory studies showed decreased NK function with variably decreased perforin-expressing NK cells (91% and 53%, respectively). These changes were not as severe as seen in patients with other PRF1 mutations. Molleran Lee et al. (2004) noted the relatively later age at onset of these patients. </p><p>Chiapparini et al. (2011) reported a 13-year-old girl with FHL2 who presented with ataxia, headache, double vision, vomiting, and a progressive increase in intracranial pressure. She had papilledema and brain MRI showed a swollen cerebellum with tonsillar herniation and signal abnormalities; some T2 hyperintensities were also present in supratentorial areas. CSF showed protein, IgG, and IgM levels consistent with blood-brain barrier damage. She was treated with steroids, but developed fever, worsening ataxia, and decreased sensation in the lower limbs after interruption of steroids. She also had organomegaly. Laboratory studies showed increased triglycerides and ferritin, anemia, elevated liver enzymes, and decreased NK activity. Bone marrow biopsy showed hypoplasia of the myeloid line with adequate erythropoiesis and an infiltration of lymphocytes and histiomonocytoid cells; hemophagocytosis was rare. She underwent bone marrow biopsy and was in good condition after 18 months. Genetic analysis identified a homozygous R225W mutation. Chiapparini et al. (2011) noted the unusual but prominent neurologic presentation in this patient. </p><p>Dias et al. (2013) reported 2 sisters, born of consanguineous Lebanese parents, who were found by exome sequencing to carry a heterozygous R225W mutation. The phenotype was not entirely consistent with FHL2, but there were some similar features. One child presented with ataxia, abnormal eye movements, dysarthria, and white matter changes on brain MRI after an episode of gastroenteritis. She had partial resolution, but then showed further white matter changes on MRI and developed splenomegaly, lymphadenopathy, mild pancytopenia, elevated liver enzymes, and hypertrophic cardiomyopathy. Bone marrow biopsy was normal except for iron depletion. Immunologic studies showed normal numbers of T, B, and NK cells. She then developed seizures and loss of vision and cognitive and motor skills. There was intermittent fever and neck rigidity during this time; she died at age 61 months. Laboratory studies showed decreased production of IL1B (147720) and a broad decrease in inflammatory cytokines. The older sister had mild developmental delay and hearing loss. At age 75.5 months, she developed seizures, fever, and deterioration of mental status associated with varicella meningitis. She recovered transiently, but then developed ataxia and diffuse white matter changes on brain MRI. She died at age 91 months. The brain imaging in these patients showed cerebellar atrophy with T2-weighted hyperintense lesions in the cerebellum and cerebral white matter with later involvement of the gray matter. One girl also had signal changes in the periventricular and deep white matter. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRF1, GLY429GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894181,
|
|
|
|
|
|
gnomAD: rs104894181,
|
|
|
|
|
|
ClinVar: RCV000014712
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the gly429-to-glu (G429E) mutation in the PRF1 gene that was found in compound heterozygous state in a patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553) by Stepp et al. (1999), see 170280.0004. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRF1, PRO345LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28933374,
|
|
|
|
|
|
gnomAD: rs28933374,
|
|
|
|
|
|
ClinVar: RCV000014713, RCV002281707
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553) from a consanguineous family, Stepp et al. (1999) identified a homozygous 1034C-T transition in the PRF1 gene, resulting in a pro345-to-leu (P345L) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRF1, CYS279TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894182,
|
|
|
|
|
|
gnomAD: rs104894182,
|
|
|
|
|
|
ClinVar: RCV000014714, RCV003466860
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553), Stepp et al. (1999) identified compound heterozygosity for mutations in the PRF1 gene: an 836C-A transversion, resulting in a cys279-to-tyr (C279Y) substitution, and a 548T-G transversion, resulting in a val183-to-gly (V183G; 170280.0008) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRF1, VAL183GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894183,
|
|
|
|
|
|
|
|
ClinVar: RCV000014715
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the val183-to-gly (V183G) mutation in the PRF1 gene that was found in compound heterozygous state in a patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553) by Stepp et al. (1999), see 170280.0007. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRF1, ASN252SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28933375,
|
|
|
|
|
|
gnomAD: rs28933375,
|
|
|
|
|
|
ClinVar: RCV000014716, RCV000246747, RCV000767055, RCV002260965
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant, formerly designated HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2, with the 'included' title of LYMPHOMA, NON-HODGKIN, has been reclassified based on the report by Clementi et al. (2005).</p><p>In a patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553), Stepp et al. (1999) identified a 755A-G transition in the PRF1 gene, resulting in an asn252-to-ser (N252S) substitution. </p><p>In a 27-year-old man with autoimmune lymphoproliferative syndrome (601859) who later developed a T-cell-rich, histiocyte-rich, diffuse large B-cell lymphoma (605027), Clementi et al. (2004) identified a heterozygous N252S mutation in the PRF1 gene and a heterozygous mutation in the FAS gene (134637). The FAS mutation was inherited from his healthy father and was also carried by his healthy brother, whereas the PRF1 mutation was inherited from his healthy mother. Clementi et al. (2004) noted that the N252S substitution occurs within the membrane attack complex of the perforin protein, a region involved in the pore-forming activity of the molecule. However, both the patient and his mother had normal levels of perforin and normal NK cell activity. The authors suggested that the combined effect of the 2 mutant genes contributed to the development of ALPS and lymphoma in this patient. Rieux-Laucat et al. (2005) cast doubt on the pathogenicity of the N252S mutation, and the primary authors provided a rebuttal (Clementi et al., 2005). </p><p>Clementi et al. (2005) identified the N252S mutation in 1 of 660 (0.02%) control alleles, suggesting that it is a benign polymorphism. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRF1, THR435MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28933376,
|
|
|
|
|
|
gnomAD: rs28933376,
|
|
|
|
|
|
ClinVar: RCV000014718, RCV002260966, RCV003473103
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Wagner et al. (1995) described a patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553) with a defect in splicing of CD45 (151460). McCormick et al. (2003) analyzed the perforin status in this patient and identified a novel 1304C-T transition in exon 3 of the PRF1 gene, resulting in a thr435-to-met (T435M) mutation. Threonine-435 is conserved between human, mouse, and rat, and is located in the highly conserved Ca(2+)-binding domain of perforin. Molecular modeling predicted that the T435M mutation would affect the calcium binding of the molecule and therefore impair perforin function. The abnormal CD45 splicing was caused by a 77C-G polymorphism in exon A of the CD45 gene, which cosegregated with the T435M mutation in the family. McCormick et al. (2003) postulated that both mutations were involved in the disorder. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRF1, ALA91VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs35947132,
|
|
|
|
|
|
gnomAD: rs35947132,
|
|
|
|
|
|
ClinVar: RCV000014719, RCV000224458, RCV000456018, RCV000547554, RCV002260967, RCV003398509
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant, formerly designated HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2, SUSCEPTIBILITY TO, with 2 'included' designations, LYMPHOMA, NON-HODGKIN, SUSCEPTIBILITY TO and APLASTIC ANEMIA, SUSCEPTIBILITY TO, has been reclassified based on the reports by Molleran Lee et al. (2004), zur Stadt et al. (2004), and Lek et al. (2016). </p><p>In 2 sibs with adult onset and atypical presentation of hemophagocytic lymphohistiocytosis (FHL2; 603553), Clementi et al. (2002) identified compound heterozygosity of a 272C-T transition in exon 2 of the PRF1 gene, resulting in an ala91-to-val (A91V) substitution, and a trp374-to-ter (W374X; 170280.0002) mutation in the PRF1 gene. Clementi et al. (2005) reported that 1 of the sibs had a non-Hodgkin lymphoma (605027). </p><p>Busiello et al. (2004) reported a family in which fraternal twins were both homozygous for the A91V substitution but showed markedly different phenotypic expression. The proband presented at age 13 years with persistent fever, hepatosplenomegaly, cytopenia, and lymph node enlargement. Signs of hemophagocytosis in a liver biopsy specimen led to the diagnosis of FHL. The patient died after a rapidly progressive disease course. All the remaining family members, including the homozygous twin, were considered normal. Natural killer activity was severely impaired in the patient but normal in the asymptomatic twin. Both twins and the father carried a second PRF1 mutation in heterozygous state: 695G-A transition resulting in an R231H amino acid change. The report highlighted the long disease-free interval during which biochemical or immunologic alterations may not be evident and the suggestion that factors other than mutation in the perforin gene may be involved. </p><p>Clementi et al. (2006) identified the A91V substitution of PRF1 in 6 of 28 patients with Dianzani autoimmune lymphoproliferative disease (DALD; 605233), a disorder that resembles autoimmune lymphoproliferative syndrome (ALPS; 601859) but lacks expansion of double-negative T cells. Presence of A91V conferred an odds ratio of 3 for DALD, and the odds ratio increased to 17 if variations in the osteopontin (SPP1; 166490) gene associated with increased osteopontin production were also present. However, A91V was relatively frequent (4.6%) in controls. Clementi et al. (2006) suggested that A91V may be a susceptibility factor for DALD in patients with defective FAS (TNFRSF6; 134637) function. </p><p>Solomou et al. (2007) identified a heterozygous A91V substitution in 3 unrelated adults who developed aplastic anemia (609135) at ages 31, 77, and 78, respectively. Two of these patients had evidence of hemophagocytosis on bone marrow biopsy with no other clinical features of hemophagocytic syndrome. One patient had no response to immunosuppression, and 2 had only partial responses. Perforin protein levels and perforin granules were markedly decreased or absent in CD8(+) T cells. All 3 patients also carried a heterozygous synonymous his300-to-his (H300H) polymorphism in exon 3 of the PRF1 gene. The A91V substitution was identified in 24 (1.0%) of 2,312 control chromosomes. </p><p>Molleran Lee et al. (2004) and zur Stadt et al. (2004) identified the A91V substitution with an allelic frequency of 3% and 9%, respectively, suggesting that it is a polymorphism. </p><p>Lek et al. (2016) noted that the A211V (A91V) variant has a high allele frequency (0.0174) in the South Asian population in the ExAC database, suggesting that it is not pathogenic. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
In rat basophil leukemia cells, Voskoboinik et al. (2005) found that the A91V PRF1 protein showed decreased expression, resulting in partial loss of lytic capacity. </p><p>In studies of rat basophil leukemia cells and perforin-deficient mouse cytotoxic T cells, Voskoboinik et al. (2007) found that human A91V mutant protein had a 10-fold decrease in target cell lysis activity compared to wildtype protein. The mutant protein was also present at lower levels. Further studies suggested that the mutant protein undergoes abnormal folding. Voskoboinik et al. (2007) suggested that the diminished lytic activity of the A91V protein may be partly rescued by other granule toxins, thus resulting in a less dramatic clinical effect. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 APLASTIC ANEMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRF1, SER388ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs193302875,
|
|
|
|
|
|
|
|
ClinVar: RCV000014722, RCV004700235
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 33-year-old Hispanic patient with aplastic anemia (609135), Solomou et al. (2007) identified a heterozygous G-to-T transversion in exon 3 of the PRF1 gene, resulting in a ser388-to-ile (S388I) substitution. The patient was also heterozygous for a synonymous ala274-to-ala (A274A) polymorphism in the PRF1 gene. Bone marrow biopsy showed hemophagocytosis, but the patient had no other clinical features of hemophagocytic syndrome. Perforin granules were absent in CD8(+) T cells. There was no clinical response to immunosuppression. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 APLASTIC ANEMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRF1, ARG4HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs35418374,
|
|
|
|
|
|
gnomAD: rs35418374,
|
|
|
|
|
|
ClinVar: RCV000014723, RCV000242526, RCV000425105, RCV000545742, RCV002260968
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 21-year-old African American patient with aplastic anemia (609135), Solomou et al. (2007) identified a heterozygous G-to-A transition in exon 2 of the PRF1 gene, resulting in an arg4-to-his (R4H) substitution. Bone marrow biopsy showed features of hemophagocytosis, but the patient had no other clinical manifestations of the hemophagocytosis syndrome. There was no clinical response to immunosuppression. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRF1, 2-BP DEL, 1090CT
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs771552960,
|
|
|
|
|
|
gnomAD: rs771552960,
|
|
|
|
|
|
ClinVar: RCV000014724, RCV003473104, RCV004700236, RCV005049338
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553), Ueda et al. (2003) identified homozygosity for a 2-bp deletion (1090delCT) in exon 3 of the PRF1 gene, resulting in a frameshift and premature termination after 456 amino acids. Two additional Japanese FHL2 patients were found to be compound heterozygous 1090delCT and a 1-bp deletion (207delC; 170280.0015) in exon 2, resulting in frameshift and premature termination after 106 amino acids. A fourth Japanese patient was compound heterozygous for 1090delCT and a 1246C-T transition in exon 3 of the PRF1 gene, resulting in a gln416-to-ter (Q416X; 170280.0016) substitution. Ueda et al. (2003) noted that although none of these patients were directly related, they all had ancestors who originated from the southwestern part of Japan. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRF1, 1-BP DEL, 207C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs786205093,
|
|
|
|
|
|
gnomAD: rs786205093,
|
|
|
|
|
|
ClinVar: RCV000014725, RCV003460477
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 1-bp deletion in the PRF1 gene (207delC) that was found in compound heterozygous state in patients with familial hemophagocytic lymphohistiocytosis (FHL2; 603553) by Ueda et al. (2003), see 170280.0014. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PRF1, GLN416TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs193302876,
|
|
|
|
|
|
gnomAD: rs193302876,
|
|
|
|
|
|
ClinVar: RCV000014726, RCV003460478
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the gln416-to-ter (Q416X) mutation in the PRF1 gene that was found in compound heterozygous state in a patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553) by Ueda et al. (2003), see 170280.0014. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Stanley and Luzio (1988)
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Badovinac, V. P., Tvinnereim, A. R., Harty, J. T.
|
|
<strong>Regulation of antigen-specific CD8(+) T cell homeostasis by perforin and interferon-gamma.</strong>
|
|
Science 290: 1354-1357, 2000.
|
|
|
|
|
|
[PubMed: 11082062]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.290.5495.1354]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Binder, D., van den Broek, M. F., Kagi, D., Bluethmann, H., Fehr, J., Hengartner, H., Zinkernagel, R. M.
|
|
<strong>Aplastic anemia rescued by exhaustion of cytokine-secreting CD8+ T cells in persistent infection with lymphocytic choriomeningitis virus.</strong>
|
|
J. Exp. Med. 187: 1903-1920, 1998.
|
|
|
|
|
|
[PubMed: 9607930]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1084/jem.187.11.1903]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Busiello, R., Adriani, M., Locatelli, F., Galgani, M., Fimiani, G., Clementi, R., Ursini, M. V., Racioppi, L., Pignata, C.
|
|
<strong>Atypical features of familial hemophagocytic lymphohistiocytosis. (Letter)</strong>
|
|
Blood 103: 4610-4612, 2004.
|
|
|
|
|
|
[PubMed: 14739222]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1182/blood-2003-10-3551]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Chiapparini, L., Uziel, G., Vallinoto, C., Bruzzone, M. G., Rovelli, A., Tricomi, G., Bizzi, A., Nardocci, N., Rizzari, C., Savoiardo, M.
|
|
<strong>Hemophagocytic lymphohistiocytosis with neurological presentation: MRI findings and a nearly miss (sic) diagnosis.</strong>
|
|
Neurol. Sci. 32: 473-477, 2011.
|
|
|
|
|
|
[PubMed: 21234777]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s10072-010-0467-2]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Clementi, R., Chiocchetti, A., Cappellano, G., Cerutti, E., Ferretti, M., Orilieri, E., Dianzani, I., Ferrarini, M., Bregni, M., Danesino, C., Bozzi, V., Putti, M. C., Cerutti, F., Cometa, A., Locatelli, F., Maccario, R., Ramenghi, U., Dianzani, U.
|
|
<strong>Variations of the perforin gene in patients with autoimmunity/lymphoproliferation and defective Fas function.</strong>
|
|
Blood 108: 3079-3084, 2006.
|
|
|
|
|
|
[PubMed: 16720836]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1182/blood-2006-02-001412]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Clementi, R., Dagna, L., Dianzani, U., Dupre, L., Dianzani, I., Ponzoni, M., Cometa, A., Chiocchetti, A., Sabbadini, M. G., Rugarli, C., Ciceri, F., Maccario, R., Locatelli, F., Danesino, C., Ferrarini, M., Bregni, M.
|
|
<strong>Inherited perforin and Fas mutations in a patient with autoimmune lymphoproliferative syndrome and lymphoma.</strong>
|
|
New Eng. J. Med. 351: 1419-1424, 2004.
|
|
|
|
|
|
[PubMed: 15459303]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1056/NEJMoa041432]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Clementi, R., Emmi, L., Maccario, R., Liotta, F., Moretta, L., Danesino, C., Arico, M.
|
|
<strong>Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. (Letter)</strong>
|
|
Blood 100: 2266-2267, 2002.
|
|
|
|
|
|
[PubMed: 12229880]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1182/blood-2002-04-1030]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Clementi, R., Ferrarini, M., Bregni, M.
|
|
<strong>Autoimmune lymphoproliferative syndrome and perforin. (Letter)</strong>
|
|
New Eng. J. Med. 352: 306-307, 2005.
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Clementi, R., Locatelli, F., Dupre, L., Garaventa, A., Emmi, L., Bregni, M., Cefalo, G., Moretta, A., Danesino, C., Comis, M., Pession, A., Ramenghi, U., Maccario, R., Arico, M., Roncarolo, M. G.
|
|
<strong>A proportion of patients with lymphoma may harbor mutations of the perforin gene.</strong>
|
|
Blood 105: 4424-4428, 2005.
|
|
|
|
|
|
[PubMed: 15728124]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1182/blood-2004-04-1477]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Dias, C., McDonald, A., Sincan, M., Rupps, R., Markello, T., Salvarinova, R., Santos, R. F., Menghrajani, K., Ahaghotu, C., Sutherland, D. P., Fortuno, E. S., III, Kollmann, T. R., Demos, M., Friedman, J. M., Speert, D. P., Gahl, W. A., Boerkoel, C. F.
|
|
<strong>Recurrent subacute post-viral onset of ataxia associated with a PRF1 mutation.</strong>
|
|
Europ. J. Hum. Genet. 21: 1232-1239, 2013.
|
|
|
|
|
|
[PubMed: 23443029]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ejhg.2013.20]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Fink, T. M., Zimmer, M., Weitz, S., Tschopp, J., Jenne, D. E., Lichter, P.
|
|
<strong>Human perforin (PRF1) maps to 10q22, a region that is syntenic with mouse chromosome 10.</strong>
|
|
Genomics 13: 1300-1302, 1992.
|
|
|
|
|
|
[PubMed: 1505959]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/0888-7543(92)90050-3]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Goransdotter Ericson, K., Fadeel, B., Nilsson-Ardnor, S., Soderhall, C., Samuelsson, A., Janka, G., Schneider, M., Gurgey, A., Yalman, N., Revesz, T., Egeler, R. M., Jahnukainen, K., Storm-Mathiesen, I., Haraldsson, A., Poole, J., de Saint Basile, G., Nordenskjold, M., Henter, J.-I.
|
|
<strong>Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis.</strong>
|
|
Am. J. Hum. Genet. 68: 590-597, 2001.
|
|
|
|
|
|
[PubMed: 11179007]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1086/318796]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Law, R. H. P., Lukoyanova, N., Voskoboinik, I., Caradoc-Davies, T. T., Baran, K., Dunstone, M. A., D'Angelo, M. E., Orlova, E. V., Coulibaly, F., Verschoor, S., Browne, K. A., Ciccone, A., Kuiper, M. J., Bird, P. I., Trapani, J. A., Saibil, H. R., Whisstock, J. C.
|
|
<strong>The structural basis for membrane binding and pore formation by lymphocyte perforin.</strong>
|
|
Nature 468: 447-451, 2010.
|
|
|
|
|
|
[PubMed: 21037563]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature09518]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O'Donnell-Luria, A. H., Ware, J. S., Hill, A. J., Cummings, B. B., Tukiainen, T., Birnbaum, D. P., and 68 others.
|
|
<strong>Analysis of protein-coding genetic variation in 60,706 humans.</strong>
|
|
Nature 536: 285-291, 2016.
|
|
|
|
|
|
[PubMed: 27535533]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature19057]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lichtenheld, M. G., Olsen, K. J., Lu, P., Lowrey, D. M., Hameed, A., Hengartner, H., Podack, E. R.
|
|
<strong>Structure and function of human perforin.</strong>
|
|
Nature 335: 448-451, 1988.
|
|
|
|
|
|
[PubMed: 3419519]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/335448a0]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lowin, B., Beermann, F., Schmidt, A., Tschopp, J.
|
|
<strong>A null mutation in the perforin gene impairs cytolytic T lymphocyte- and natural killer cell-mediated cytotoxicity.</strong>
|
|
Proc. Nat. Acad. Sci. 91: 11571-11575, 1994.
|
|
|
|
|
|
[PubMed: 7972104]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.91.24.11571]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Matloubian, M., Suresh, M., Glass, A., Galvan, M., Chow, K., Whitmire, J. K., Walsh, C. M., Clark, W. R., Ahmed, R.
|
|
<strong>A role for perforin in downregulating T-cell responses during chronic viral infection.</strong>
|
|
J. Virol. 73: 2527-2536, 1999.
|
|
|
|
|
|
[PubMed: 9971838]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1128/JVI.73.3.2527-2536.1999]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
McCormick, J., Flower, D. R., Strobel, S., Wallace, D. L., Beverley, P. C. L., Tchilian, E. Z.
|
|
<strong>Novel perforin mutation in a patient with hemophagocytic lymphohistiocytosis and CD45 abnormal splicing.</strong>
|
|
Am. J. Med. Genet. 117A: 255-260, 2003.
|
|
|
|
|
|
[PubMed: 12599189]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.a.10010]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Molleran Lee, S., Villanueva, J., Sumegi, J., Zhang, K., Kogawa, K., Davis, J., Filipovich, A. H.
|
|
<strong>Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis.</strong>
|
|
J. Med. Genet. 41: 137-144, 2004.
|
|
|
|
|
|
[PubMed: 14757862]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1136/jmg.2003.011528]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Podack, E. R., Lowrey, D. M., Lichtenheld, M., Olsen, K. J., Aebischer, T., Binder, D., Rupp, F., Hengartner, H.
|
|
<strong>Structure, function and expression of murine and human perforin 1 (P1).</strong>
|
|
Immun. Rev. 103: 203-211, 1988.
|
|
|
|
|
|
[PubMed: 3292394]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1111/j.1600-065x.1988.tb00756.x]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Rieux-Laucat, F., Le Deist, F., De Saint Basile, G.
|
|
<strong>Autoimmune lymphoproliferative syndrome and perforin. (Letter)</strong>
|
|
New Eng. J. Med. 352: 306 only, 2005.
|
|
|
|
|
|
[PubMed: 15659737]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1056/NEJM200501203520319]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Risma, K. A., Frayer, R. W., Filipovich, A. H., Sumegi, J.
|
|
<strong>Aberrant maturation of mutant perforin underlies the clinical diversity of hemophagocytic lymphohistiocytosis.</strong>
|
|
J. Clin. Invest. 116: 182-192, 2006.
|
|
|
|
|
|
[PubMed: 16374518]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1172/JCI26217]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Shinkai, Y., Takio, K., Okumura, K.
|
|
<strong>Homology of perforin to the ninth component of complement (C9).</strong>
|
|
Nature 334: 525-527, 1988.
|
|
|
|
|
|
[PubMed: 3261391]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/334525a0]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Shinkai, Y., Yoshida, M. C., Maeda, K., Kobata, T., Maruyama, K., Yodoi, J., Yagita, H., Okumura, K.
|
|
<strong>Molecular cloning and chromosomal assignment of a human perforin (PFP) gene.</strong>
|
|
Immunogenetics 30: 452-457, 1989.
|
|
|
|
|
|
[PubMed: 2592021]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/BF02421177]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Smyth, M. J., Thia, K. Y. T., Street, S. E. A., MacGregor, D., Godfrey, D. I., Trapani, J. A.
|
|
<strong>Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma.</strong>
|
|
J. Exp. Med. 192: 755-760, 2000.
|
|
|
|
|
|
[PubMed: 10974040]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1084/jem.192.5.755]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Solomou, E. E., Gibellini, F., Stewart, B., Malide, D., Berg, M., Visconte, V., Green, S., Childs, R., Chanock, S. J., Young, N. S.
|
|
<strong>Perforin gene mutations in patients with acquired aplastic anemia.</strong>
|
|
Blood 109: 5234-5237, 2007.
|
|
|
|
|
|
[PubMed: 17311987]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1182/blood-2006-12-063495]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Stanley, K., Luzio, P.
|
|
<strong>A family of killer proteins.</strong>
|
|
Nature 334: 475-476, 1988.
|
|
|
|
|
|
[PubMed: 3261390]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/334475a0]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Stepp, S. E., Dufourcq-Lagelouse, R., Le Deist, F., Bhawan, S., Certain, S., Mathew, P. A., Henter, J.-I., Bennett, M., Fischer, A., de Saint Basile, G., Kumar, V.
|
|
<strong>Perforin gene defects in familial hemophagocytic lymphohistiocytosis.</strong>
|
|
Science 286: 1957-1959, 1999.
|
|
|
|
|
|
[PubMed: 10583959]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.286.5446.1957]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Trapani, J. A., Kwon, B. S., Kozak, C. A., Chintamaneni, C., Young, J. D.-E., Dupont, B.
|
|
<strong>Genomic organization of the mouse pore-forming protein (perforin) gene and localization to chromosome 10: similarities to and differences from C9.</strong>
|
|
J. Exp. Med. 171: 545-557, 1990.
|
|
|
|
|
|
[PubMed: 2303785]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1084/jem.171.2.545]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Trizzino, A., zur Stadt, U., Ueda, I., Risma, K., Janka, G., Ishii, E., Beutel, K., Sumegi, J., Cannella, S., Pende, D., Mian, A., Henter, J.-I., Griffiths, G., Santoro, A., Filipovich, A., Arico, M.
|
|
<strong>Genotype-phenotype study of familial haemophagocytic lymphohistiocytosis due to perforin mutations.</strong>
|
|
J. Med. Genet. 45: 15-21, 2008.
|
|
|
|
|
|
[PubMed: 17873118]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1136/jmg.2007.052670]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ueda, I., Morimoto, A., Inaba, T., Yagi, T., Hibi, S., Sugimoto, T., Sako, M., Yanai, F., Fukushima, T., Nakayama, M., Ishii, E., Imashuku, S.
|
|
<strong>Characteristic perforin gene mutations of haemophagocytic lymphohistiocytosis patients in Japan.</strong>
|
|
Brit. J. Haemat. 121: 503-510, 2003.
|
|
|
|
|
|
[PubMed: 12716377]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1046/j.1365-2141.2003.04298.x]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Voskoboinik, I., Sutton, V. R., Ciccone, A., House, C. M., Chia, J., Darcy, P. K., Yagita, H., Trapani, J. A.
|
|
<strong>Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function.</strong>
|
|
Blood 110: 1184-1190, 2007.
|
|
|
|
|
|
[PubMed: 17475905]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1182/blood-2007-02-072850]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Voskoboinik, I., Thia, M.-C., De Bono, A., Browne, K., Cretney, E., Jackson, J. T., Darcy, P. K., Jane, S. M., Smyth, M. J., Trapani, J. A.
|
|
<strong>The functional basis for hemophagocytic lymphohistiocytosis in a patient with co-inherited missense mutations in the perforin (PFN1) gene.</strong>
|
|
J. Exp. Med. 200: 811-816, 2004.
|
|
|
|
|
|
[PubMed: 15365097]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1084/jem.20040776]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Voskoboinik, I., Thia, M.-C., Trapani, J. A.
|
|
<strong>A functional analysis of the putative polymorphisms A91V and N252S and 22 missense perforin mutations associated with familial hemophagocytic lymphohistiocytosis.</strong>
|
|
Blood 105: 4700-4706, 2005.
|
|
|
|
|
|
[PubMed: 15755897]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1182/blood-2004-12-4935]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Wagner, R., Morgan, G., Strobel, S.
|
|
<strong>A prospective study of CD45 isoform expression in haemophagocytic lymphohistiocytosis; an abnormal inherited immunophenotype in one family.</strong>
|
|
Clin. Exp. Immun. 99: 216-220, 1995.
|
|
|
|
|
|
[PubMed: 7851014]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1111/j.1365-2249.1995.tb05535.x]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Zur Stadt, U., Beutel, K., Kolberg, S., Schneppenheim, R., Kabisch, H., Janka, G., Hennies, H. C.
|
|
<strong>Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A.</strong>
|
|
Hum. Mutat. 27: 62-68, 2006.
|
|
|
|
|
|
[PubMed: 16278825]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/humu.20274]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
zur Stadt, U., Beutel, K., Weber, B., Kabisch, H., Schneppenheim, R., Janka, G.
|
|
<strong>A91V is a polymorphism in the perforin gene not causative of an FHLH phenotype. (Letter)</strong>
|
|
Blood 104: 1909 only, 2004.
|
|
|
|
|
|
[PubMed: 15342365]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1182/blood-2004-02-0733]
|
|
|
|
|
|
</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">
|
|
Ada Hamosh - updated : 11/30/2016<br>Cassandra L. Kniffin - updated : 12/4/2013<br>Ada Hamosh - updated : 1/31/2011<br>Marla J. F. O'Neill - updated : 11/6/2008<br>Cassandra L. Kniffin - updated : 10/2/2007<br>Cassandra L. Kniffin - updated : 9/20/2007<br>Paul J. Converse - updated : 4/12/2007<br>Cassandra L. Kniffin - updated : 3/13/2006<br>Victor A. McKusick - updated : 1/20/2006<br>Cassandra L. Kniffin - updated : 10/6/2005<br>Victor A. McKusick - updated : 8/11/2005<br>Victor A. McKusick - updated : 1/31/2005<br>Paul J. Converse - updated : 1/5/2005<br>Victor A. McKusick - updated : 10/22/2004<br>Marla J. F. O'Neill - updated : 9/29/2004<br>Victor A. McKusick - updated : 9/17/2004<br>Victor A. McKusick - updated : 3/21/2003<br>Victor A. McKusick - updated : 3/19/2001<br>Paul J. Converse - updated : 11/30/2000<br>Ada Hamosh - updated : 12/15/1999
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div class="row">
|
|
<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
|
<span class="text-nowrap mim-text-font">
|
|
Creation Date:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Victor A. McKusick : 9/15/1988
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div class="row">
|
|
<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
|
<span class="text-nowrap mim-text-font">
|
|
Edit History:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
carol : 08/18/2023<br>carol : 08/21/2019<br>carol : 05/31/2018<br>alopez : 04/10/2018<br>carol : 10/20/2017<br>alopez : 12/01/2016<br>carol : 12/01/2016<br>carol : 11/30/2016<br>carol : 05/05/2015<br>alopez : 4/29/2015<br>mcolton : 4/20/2015<br>carol : 11/18/2014<br>carol : 12/6/2013<br>carol : 12/6/2013<br>ckniffin : 12/4/2013<br>carol : 9/5/2013<br>terry : 1/17/2012<br>alopez : 2/4/2011<br>terry : 1/31/2011<br>terry : 11/19/2008<br>wwang : 11/12/2008<br>terry : 11/6/2008<br>wwang : 10/9/2007<br>ckniffin : 10/2/2007<br>terry : 9/26/2007<br>wwang : 9/25/2007<br>ckniffin : 9/20/2007<br>ckniffin : 9/20/2007<br>mgross : 4/13/2007<br>terry : 4/12/2007<br>carol : 1/31/2007<br>carol : 9/8/2006<br>wwang : 3/17/2006<br>ckniffin : 3/13/2006<br>alopez : 3/9/2006<br>alopez : 3/9/2006<br>terry : 1/20/2006<br>ckniffin : 10/17/2005<br>carol : 10/11/2005<br>ckniffin : 10/6/2005<br>wwang : 8/12/2005<br>terry : 8/11/2005<br>tkritzer : 2/4/2005<br>terry : 1/31/2005<br>mgross : 1/5/2005<br>mgross : 1/5/2005<br>carol : 11/17/2004<br>ckniffin : 11/2/2004<br>terry : 10/29/2004<br>terry : 10/22/2004<br>tkritzer : 9/29/2004<br>tkritzer : 9/24/2004<br>tkritzer : 9/21/2004<br>alopez : 9/20/2004<br>terry : 9/17/2004<br>terry : 5/16/2003<br>tkritzer : 4/7/2003<br>tkritzer : 4/3/2003<br>terry : 3/21/2003<br>cwells : 3/29/2001<br>terry : 3/19/2001<br>mgross : 3/2/2001<br>mgross : 11/30/2000<br>mgross : 11/30/2000<br>alopez : 2/10/2000<br>alopez : 12/17/1999<br>alopez : 12/17/1999<br>terry : 12/15/1999<br>carol : 12/19/1994<br>carol : 4/7/1993<br>carol : 8/17/1992<br>carol : 8/14/1992<br>supermim : 3/16/1992<br>carol : 7/2/1990
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div id="mimFooter">
|
|
|
|
|
|
<div class="container ">
|
|
<div class="row">
|
|
<br />
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div class="hidden-print mim-footer">
|
|
<div class="container">
|
|
<div class="row">
|
|
<p />
|
|
</div>
|
|
<div class="row text-center small">
|
|
NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers,
|
|
and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal
|
|
medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
|
|
<br />
|
|
OMIM<sup>®</sup> and Online Mendelian Inheritance in Man<sup>®</sup> are registered trademarks of the Johns Hopkins University.
|
|
<br />
|
|
Copyright<sup>®</sup> 1966-2025 Johns Hopkins University.
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div class="visible-print-block mim-footer" style="position: relative;">
|
|
<div class="container">
|
|
<div class="row">
|
|
<p />
|
|
</div>
|
|
<div class="row text-center small">
|
|
NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers,
|
|
and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal
|
|
medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
|
|
<br />
|
|
OMIM<sup>®</sup> and Online Mendelian Inheritance in Man<sup>®</sup> are registered trademarks of the Johns Hopkins University.
|
|
<br />
|
|
Copyright<sup>®</sup> 1966-2025 Johns Hopkins University.
|
|
<br />
|
|
Printed: March 5, 2025
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="modal fade" id="mimDonationPopupModal" tabindex="-1" role="dialog" aria-labelledby="mimDonationPopupModalTitle">
|
|
<div class="modal-dialog" role="document">
|
|
<div class="modal-content">
|
|
<div class="modal-header">
|
|
<button type="button" id="mimDonationPopupCancel" class="close" data-dismiss="modal" aria-label="Close"><span aria-hidden="true">×</span></button>
|
|
<h4 class="modal-title" id="mimDonationPopupModalTitle">
|
|
OMIM Donation:
|
|
</h4>
|
|
</div>
|
|
<div class="modal-body">
|
|
<div class="row">
|
|
<div class="col-lg-offset-1 col-md-offset-1 col-sm-offset-1 col-xs-offset-1 col-lg-10 col-md-10 col-sm-10 col-xs-10">
|
|
<p>
|
|
Dear OMIM User,
|
|
</p>
|
|
</div>
|
|
</div>
|
|
<div class="row">
|
|
<div class="col-lg-offset-1 col-md-offset-1 col-sm-offset-1 col-xs-offset-1 col-lg-10 col-md-10 col-sm-10 col-xs-10">
|
|
<p>
|
|
To ensure long-term funding for the OMIM project, we have diversified
|
|
our revenue stream. We are determined to keep this website freely
|
|
accessible. Unfortunately, it is not free to produce. Expert curators
|
|
review the literature and organize it to facilitate your work. Over 90%
|
|
of the OMIM's operating expenses go to salary support for MD and PhD
|
|
science writers and biocurators. Please join your colleagues by making a
|
|
donation now and again in the future. Donations are an important
|
|
component of our efforts to ensure long-term funding to provide you the
|
|
information that you need at your fingertips.
|
|
</p>
|
|
</div>
|
|
</div>
|
|
<div class="row">
|
|
<div class="col-lg-offset-1 col-md-offset-1 col-sm-offset-1 col-xs-offset-1 col-lg-10 col-md-10 col-sm-10 col-xs-10">
|
|
<p>
|
|
Thank you in advance for your generous support, <br />
|
|
Ada Hamosh, MD, MPH <br />
|
|
Scientific Director, OMIM <br />
|
|
</p>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div class="modal-footer">
|
|
<button type="button" id="mimDonationPopupDonate" class="btn btn-success btn-block" data-dismiss="modal"> Donate To OMIM! </button>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
</body>
|
|
|
|
</html>
|
|
|
|
|