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<title>COlobomatous Microphthalmia, Macrocephaly, Albinism & Deafness (COMMAD) a novel syndrome caused by biallelic mutation of MITF gene | NIH Research Festival</title>
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<article><div class="banner banner--gray banner--compact" style="--banner-background-image: url('/sites/default/files/media/image/2021-03/2015.jpg');--banner-background-focus: 50% 50%"><div class="banner__wrapper"><div class="banner__container"><h2 class="banner__heading">NIH Research Festival</h2><div class="banner__content"><p><strong><time datetime="2015-09-16">September 16</time> – <time datetime="2015-09-18">18, 2015</time></strong></p></div></div></div></div></article>
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<div class="section"><div data-drupal-messages-fallback class="hidden"></div></div><main role="main"><div id="main-content" tabindex="-1"></div><div class="section"><div class="content-sidebar"><div class="content-sidebar__main"><div class="content-sidebar__main-content"><div id="block-mainpagecontent-2"><article><h1>COlobomatous Microphthalmia, Macrocephaly, Albinism & Deafness (COMMAD) a novel syndrome caused by biallelic mutation of MITF gene</h1><div class="schedule"><div class="schedule__label"><div class="schedule__label-text"><time datetime="2015-09-18">Friday, September 18, 2015</time>
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– Poster Session IV
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</div></div><div class="schedule__content"><div class="schedule__item"><div class="schedule__time">12:00 – 1:30 p.m.</div><div class="schedule__description"><p><strong>FAES Terrace</strong></p></div><div class="schedule__description"><p><strong>NEI</strong></p></div><div class="schedule__description"><p><strong>GEN-14</strong></p></div></div></div></div><p><strong>FARE Award Winner</strong></p><h2>Authors</h2><ul><li>A George</li><li>DJ Zand</li><li>R Sharma</li><li>YV Sergeev</li><li>M Rius</li><li>K Bharti</li><li>BP Brooks</li></ul><h2>Abstract</h2><p>Here, we report a family with Waardenburg syndrome (WS) parents having disparate clinical manifestations due to heterozygous MITF mutations and a child with compound heterozygous mutations of MITF. This child exhibited extreme colobomatous microphthalmia, a complete lack of melanin pigment in the skin/hair/eyes, profound hearing loss, macrocephaly and low tone. DNA sequencing revealed a paternally inherited p.R318del mutation and maternally-inherited p.K307N mutation in MITF gene, the latter being previously unreported. Using live cell imaging and western blotting of transfected HEK293 cells with GFP tagged wild type (WT) and mutant expression constructs, it was observed that WT-MITF translocate to the nucleus, whereas R318del was observed only in cytoplasm and K307N mutant localized in both nucleus and cytoplasm. As studied by electro-mobility shift assay, the R318del did not bind to DNA whereas the DNA binding ability of K307N mutant was significantly reduced compared to WT. By co-transfection of RFP tagged WT-MITF and GFP tagged mutant MITF we show that R318del mutant acts in a dominant negative manner. The K307N mutant had modest dominant negative effect on WT-MITF. Upon co-transfection of both the mutant isoforms stronger retention of MITF was observed in the cytoplasm, thus explaining the severe phenotype of the child with the compound heterozygous MITF mutations. We report for the first time the compound heterozygous MITF gene mutations causing coloboma in humans, its occurrence with microphthalmia, macrocephaly, albinism and deafness resulting in a novel syndrome termed COMMAD.</p><p><strong>Scientific Focus Area</strong>: Genetics and Genomics</p><p class="updated"><small>This page was last updated on Friday, March 26, 2021</small></p></article>
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