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<h2 class="element-invisible">You are here</h2><div class="breadcrumb"><a href="/">Home</a> » <a href="/news-events">News & Events</a> » <a href="/news-events/nih-research-matters">NIH Research Matters</a></div> <div class="l-region l-region--section-header">
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<p class="publishdate"><span property="dc:date" datatype="xsd:dateTime" content="2020-11-03T00:00:00-05:00" class="date-display-single">November 3, 2020</span></p><div class='syndicate'><h1>New inflammatory disease discovered</h1><div class="callout callout-with-border"><h3>At a Glance</h3>
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<ul>
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<li>Researchers discovered a new inflammatory disorder, called VEXAS, shared by men with diverse symptoms.</li>
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<li>The study demonstrates a new genomic approach to identify and classify inflammatory and other diseases.</li>
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</ul></div><div class="media-float-right"><div class="ds-1col file file-image file-image-jpeg view-mode-floated_media clearfix">
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<picture title="Doctor talking to mature male patient">
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<!--[if IE 9]><video style="display: none;"><![endif]-->
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-large/public/news-events/research-matters/2020/20201103-inflammatory.jpg?itok=7VSV5w_L&timestamp=1604341679 1x" media="screen and (min-width: 960px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-medium/public/news-events/research-matters/2020/20201103-inflammatory.jpg?itok=uZLz521o&timestamp=1604341679 1x" media="screen and (min-width: 800px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-medium-small/public/news-events/research-matters/2020/20201103-inflammatory.jpg?itok=08y3Vgs3&timestamp=1604341679 1x" media="screen and (min-width: 600px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-small/public/news-events/research-matters/2020/20201103-inflammatory.jpg?itok=2Y1ds8WJ&timestamp=1604341679 1x" media="screen and (min-width: 480px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-tiny/public/news-events/research-matters/2020/20201103-inflammatory.jpg?itok=Yg4IHmw9&timestamp=1604341679 1x" media="screen and (min-width: 0)" />
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<!--[if IE 9]></video><![endif]-->
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<img src="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-medium/public/news-events/research-matters/2020/20201103-inflammatory.jpg?itok=uZLz521o&timestamp=1604341679" alt="Doctor talking to mature male patient" title="Doctor talking to mature male patient" />
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</picture><span class="caption">Instead of looking at similarities in symptoms, the team examined genomes to discover a new disease. </span><span class="credit">AnnaStills / iStock / Getty Images Plus</span></div>
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</div><p>Nearly 125 million people in the U.S. live with some form of chronic inflammatory disease. Chronic inflammation can have many underlying causes: infections that don’t go away, abnormal immune reactions to normal tissues, certain diseases or conditions, or changes in certain genes. Chronic inflammatory diseases often have similar symptoms, which makes it difficult for doctors to diagnose the specific disease.</p>
|
||
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||
<p>Genes related to ubiquitylation have been shown to play a role in some inflammatory diseases. This process alters proteins to regulate their function or tag them for degradation.</p>
|
||
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||
<p>To investigate whether genes related to ubiquitylation play a role in patients with undiagnosed inflammatory disease, a research team led by NIH researchers Drs. Peter Grayson at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Daniel Kastner at the National Human Genome Research Institute (NHGRI), and Achim Werner at the National Institute of Dental and Craniofacial Research (NIDCR) studied the genomes of more than 2,500 patients. Over 1,400 of these individuals had undiagnosed recurrent fevers and body-wide inflammation. The rest, part of the <a href="https://www.genome.gov/Current-NHGRI-Clinical-Studies/Undiagnosed-Diseases-Program-UDN">NIH Undiagnosed Diseases Program</a>, had unusual and unclassified disorders.</p>
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||
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||
<p>The study was funded by several NIH Institutes. Results were published on October 27, 2020 in the<em> New England Journal of Medicine.</em></p>
|
||
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||
<p>The team focused on a set of about 840 genes related to ubiquitylation. Out of those, one stood out: the <em>UBA1</em> gene. Three middle-aged males had rare and potentially damaging genomic mutations in the gene. <em>UBA1</em> holds the instructions to make the E1 enzyme, which is needed to initiate ubiquitin signaling in cells.</p>
|
||
|
||
<p>Men normally carry only one copy of this gene since it resides in the X chromosome. (Males have only one X chromosome and one Y chromosome). However, DNA-sequencing revealed that each of the men appeared to carry two different versions of the gene. Further investigation showed that that some cells in their bodies carried the <em>UBA1 </em>gene in its normal form while others carried the gene in a mutated form. This phenomenon is known as mosaicism, where a cell picks up a genetic mutation at some time during early development.</p>
|
||
|
||
<p>The mutated gene was found in the patients’ myeloid cells, which are responsible for systemic inflammation and act as the first line of defense against infections.</p>
|
||
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||
<p>The researchers then discovered an additional 22 adult males, most of them participants in other NIH studies, with the <em>UBA1</em> gene mutations. Symptoms of the 25 patients included blood clots in veins, recurrent fevers, lung abnormalities, and unusual vacuoles (cavity-like structures) in myeloid cells. The team called the new disease VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic syndrome).</p>
|
||
|
||
<p>“By using this genomic approach, we have managed to find a thread that ties together patients carrying all of these seemingly unrelated, disparate diagnoses,” Kastner says.</p>
|
||
|
||
<p>The severe condition has devastating consequences. So far, 40% of VEXAS patients who the team studied have died. The researchers hope that this new genomic strategy will help health care professionals improve disease assessments and treatments for various inflammation-related conditions.</p></div><h2 class="label-above">Related Links</h2><ul class="spaced print-urls"><li><a href="https://www.nih.gov/news-events/nih-research-matters/researchers-find-cause-new-autoinflammatory-disease" target="_top">Researchers Find Cause of New Autoinflammatory Disease </a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/gut-microbe-drives-autoimmunity" target="_top">Gut Microbe Drives Autoimmunity</a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/gene-linked-rare-inflammatory-disease-children" target="_top">Gene Linked to Rare Inflammatory Disease in Children</a></li><li><a href="https://www.niams.nih.gov/health-topics/autoinflammatory-diseases" target="_top">Autoinflammatory Diseases</a></li><li><a href="https://www.cancer.gov/about-cancer/causes-prevention/risk/chronic-inflammation" target="_top">Chronic Inflammation</a></li><li><a href="https://www.niehs.nih.gov/health/topics/conditions/inflammation/index.cfm" target="_top">Inflammation</a></li><li><a href="https://www.genome.gov/Current-NHGRI-Clinical-Studies/Undiagnosed-Diseases-Program-UDN" target="_top">The Undiagnosed Diseases Program</a></li></ul><p class="footnote"><strong class="label-inline">References: </strong><a href="https://pubmed.ncbi.nlm.nih.gov/33108101/">Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease.</a> Beck DB, Ferrada MA, Sikora KA, Ombrello AK, Collins JC, Pei W, Balanda N, Ross DL, Ospina Cardona D, Wu Z, Patel B, Manthiram K, Groarke EM, Gutierrez-Rodrigues F, Hoffmann P, Rosenzweig S, Nakabo S, Dillon LW, Hourigan CS, Tsai WL, Gupta S, Carmona-Rivera C, Asmar AJ, Xu L, Oda H, Goodspeed W, Barron KS, Nehrebecky M, Jones A, Laird RS, Deuitch N, Rowczenio D, Rominger E, Wells KV, Lee CR, Wang W, Trick M, Mullikin J, Wigerblad G, Brooks S, Dell'Orso S, Deng Z, Chae JJ, Dulau-Florea A, Malicdan MCV, Novacic D, Colbert RA, Kaplan MJ, Gadina M, Savic S, Lachmann HJ, Abu-Asab M, Solomon BD, Retterer K, Gahl WA, Burgess SM, Aksentijevich I, Young NS, Calvo KR, Werner A, Kastner DL, Grayson PC. <em>N Engl J Med</em>. 2020 Oct 27. doi: 10.1056/NEJMoa2026834. Online ahead of print. PMID: 33108101.</p><p class="footnote"><strong class="label-inline">Funding: </strong>NIH’s National Human Genome Research Institute (NHGRI), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Heart, Lung, and Blood Institute (NHLBI), National Institute of Dental and Craniofacial Research (NIDCR), Office of the Director (OD), National Institute of Allergy and Infectious Diseases (NIAID), and NIH Clinical Center (CC); European Union’s Horizon 2020.</p>
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