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<p class="publishdate"><span property="dc:date" datatype="xsd:dateTime" content="2014-08-18T00:00:00-04:00" class="date-display-single">August 18, 2014</span></p><div class='syndicate'><h1>Gene Linked to Rare Inflammatory Disease in Children</h1><div class="callout callout-with-border"><h3>At a Glance</h3>
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<ul class="spaced">
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<li>Scientists identified a gene that underlies a rare but devastating autoinflammatory condition in children.</li>
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<li>The study suggests a potential treatment for this and other autoinflammatory diseases.</li>
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<picture title="Inflamed blood vessels">
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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/2014/20140818-inflammatory-lowers.jpg?itok=HSx9u-dz&timestamp=1431528411 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/2014/20140818-inflammatory-lowers.jpg?itok=85FyYIKP&timestamp=1431528411 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/2014/20140818-inflammatory-lowers.jpg?itok=qhU_vVg5&timestamp=1431528411 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/2014/20140818-inflammatory-lowers.jpg?itok=mfPfTeXG&timestamp=1431528411 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/2014/20140818-inflammatory-lowers.jpg?itok=RrzpPJVZ&timestamp=1431528411 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/2014/20140818-inflammatory-lowers.jpg?itok=85FyYIKP&timestamp=1431528411" alt="Inflamed blood vessels." title="Inflamed blood vessels" />
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</picture><span class="caption">Blood vessels (yellow) of children with SAVI become inflamed and damaged, indicated here in red.</span><span class="credit">Dr. Manfred Boehm, NIH National Heart, Lung, and Blood Institute</span></div>
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</div><p>Autoinflammatory diseases are conditions in which the innate immune system, for unknown reasons, becomes activated and triggers inflammation. The innate immune system is the body’s rapid first line of defense against infection. The heat, swelling, and redness of inflammation are a normal part of the body’s protective response to injury or infection. However, prolonged inflammation can seriously damage the body.</p>
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<p>In 2004, Dr. Raphaela Goldbach-Mansky of NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) examined a 10-year-old girl who had signs of systemic inflammation, especially in the blood vessels. The girl hadn’t responded to any medications her doctors had tried. She had blistering rashes on her fingers, toes, ears, nose, and cheeks, and she’d lost parts of her fingers to the disease. She also had severe scarring in her lungs and was having trouble breathing. Signs of her disease had appeared in infancy and progressively worsened. She died a few years later.</p>
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||
<p>After seeing 2 other patients with the same symptoms, Goldbach-Mansky’s team suspected that all 3 had the same disease, and that it might be caused by a genetic defect that arose in the children themselves, rather than being inherited. The scientists, including co-lead authors Drs. Yin Liu, Adriana A. Jesus, and Bernadette Marrero, investigated the genetic basis of the syndrome. They began by sequencing the whole exomes (protein-coding regions of DNA) of the first patient and her parents. The study appeared online on July 16, 2014, in the <em>New England Journal of Medicine</em>.</p>
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||
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||
<p>The team identified a mutation in a candidate gene, <em>TMEM173,</em> that was carried by the girl but not her parents. <em>TMEM173 </em>encodes a protein called stimulator of interferon genes (STING). STING is part of a pathway that recognizes foreign DNA—such as that from viruses and bacteria—and signals cells to produce interferons, which stimulate the innate immune system.</p>
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||
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||
<p>Sequencing the gene in 5 unrelated children with similar symptoms revealed a total of 3 STING mutations in the patients that weren’t in any of their parents. The scientists found that these mutations boosted STING activity. In addition, STING is expressed in the cells lining the blood vessels and the lungs, which would likely explain why these tissues are predominantly affected by the disease. The team named the disease STING-associated vasculopathy with onset in infancy (SAVI).</p>
|
||
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||
<p>The scientists tested 3 drugs that belong to a new class called JAK inhibitors (tofacitinib, ruxolitinib, and baricitinib). These drugs inhibit the interferon pathway. All 3 inhibitors blocked the effects of the mutations on patient cell samples in the laboratory.</p>
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<p>“Blood tests on the affected children had shown high levels of interferon-induced proteins,” Goldbach-Mansky notes, “so we were not surprised when the mutated gene turned out to be related to interferon signaling.”</p>
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<p>The researchers are now enrolling patients in a <a href="https://clinicaltrials.gov/ct2/show/NCT01724580" target="_blank">clinical trial</a> to test JAK inhibitors in patients with SAVI and other rare autoinflammatory syndromes for which there are no satisfactory treatments.</p>
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</div><h2 class="label-above">Related Links</h2><ul class="spaced print-urls"><li><a href="http://www.niams.nih.gov/Health_Info/Autoinflammatory/" target="_top">Autoinflammatory Diseases</a></li></ul><p class="footnote"><strong class="label-inline">References: </strong><a href="http://www.ncbi.nlm.nih.gov/pubmed/25029335" target="_blank">Activated STING in a Vascular and Pulmonary Syndrome.</a> Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Sanchez GA, Tenbrock K, Wittkowski H, Jones OY, Kuehn HS, Lee CC, DiMattia MA, Cowen EW, Gonzalez B, Palmer I, DiGiovanna JJ, Biancotto A, Kim H, Tsai WL, Trier AM, Huang Y, Stone DL, Hill S, Kim HJ, St Hilaire C, Gurprasad S, Plass N, Chapelle D, Horkayne-Szakaly I, Foell D, Barysenka A, Candotti F, Holland SM, Hughes JD, Mehmet H, Issekutz AC, Raffeld M, McElwee J, Fontana JR, Minniti CP, Moir S, Kastner DL, Gadina M, Steven AC, Wingfield PT, Brooks SR, Rosenzweig SD, Fleisher TA, Deng Z, Boehm M, Paller AS, Goldbach-Mansky R. <em>N Engl J Med.</em> 2014 Jul 16. [Epub ahead of print]. PMID: 25029335.</p><p class="footnote"><strong class="label-inline">Funding: </strong>NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI), National Human Genome Research Institute (NHGRI), National Institute on Deafness and Other Communication Disorders (NIDCD), and National Institute of Allergy and Infectious Diseases (NIAID); Dalhousie University, Halifax, Nova Scotia; RWTH Aachen University, Aachen, Germany; University Hospital of Muenster, Germany; Walter Reed National Military Medical Center; Luis Calvo Mackenna Hospital, Santiago, Chile; Merck Research Laboratories; and Northwestern University Feinberg School of Medicine.</p>
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<p><a href="https://www.nih.gov/news-events/nih-research-matters/research-context-can-we-slow-aging">Research in Context: Can we slow aging?</a></p>
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<p><a href="https://www.nih.gov/news-events/nih-research-matters/brain-changes-observed-during-pregnancy">Brain changes observed during pregnancy</a></p>
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<p><a href="https://www.nih.gov/news-events/nih-research-matters/risk-future-burden-dementia-united-states">Risk and future burden of dementia in the United States </a></p>
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<p><a href="https://www.nih.gov/news-events/nih-research-matters/complete-wiring-map-adult-fruit-fly-brain">Complete wiring map of an adult fruit fly brain</a></p>
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<p><strong>Editor:</strong> Harrison Wein, Ph.D.</p>
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<p><strong>Assistant Editors:</strong> Vicki Contie and Brian Doctrow, Ph.D.</p>
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<p><strong><em>NIH Research Matters </em></strong>is a weekly update of NIH research highlights reviewed by NIH’s experts. It's published by the <a href="/institutes-nih/nih-office-director/office-communications-public-liaison">Office of Communications and Public Liaison</a> in the <a href="/institutes-nih/nih-office-director">NIH Office of the Director</a>.</p>
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