{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T20:22:39Z","timestamp":1791490959436,"version":"4.3.4"},"reference-count":31,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2017,8,22]],"date-time":"2017-08-22T00:00:00Z","timestamp":1503360000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100010663","name":"European Research Council","doi-asserted-by":"publisher","award":["GA309449"],"award-info":[{"award-number":["GA309449"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2017,10]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To define the molecular basis of a multisystem phenotype with progressive musculoskeletal disease of the hands and feet, including camptodactyly, subluxation, and tendon rupture, reminiscent of Jaccoud's arthropathy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We identified 2 families segregating an autosomal\u2010dominant phenotype encompassing musculoskeletal disease and variable additional features, including psoriasis, dental abnormalities, cardiac valve involvement, glaucoma, and basal ganglia calcification. We measured the expression of interferon (IFN)\u2013stimulated genes in the peripheral blood and skin, and undertook targeted Sanger sequencing of the <jats:italic>IFIH1<\/jats:italic> gene encoding the cytosolic double\u2010stranded RNA (dsRNA) sensor melanoma differentiation\u2013associated protein 5 (MDA\u20105). We also assessed the functional consequences of <jats:italic>IFIH1<\/jats:italic> gene variants using an in vitro IFN\u03b2 reporter assay in HEK 293T cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We recorded an up\u2010regulation of type I IFN\u2013induced gene transcripts in all 5 patients tested and identified a heterozygous gain\u2010of\u2010function mutation in <jats:italic>IFIH1<\/jats:italic> in each family, resulting in different substitutions of the threonine residue at position 331 of MDA\u20105. Both of these variants were associated with increased IFN\u03b2 expression in the absence of exogenous dsRNA ligand, consistent with constitutive activation of MDA\u20105.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These cases highlight the significant musculoskeletal involvement that can be associated with mutations in MDA\u20105, and emphasize the value of testing for up\u2010regulation of IFN signaling as a marker of the underlying molecular lesion. Our data indicate that both Singleton\u2010Merten syndrome and neuroinflammation described in the context of MDA\u20105 gain\u2010of\u2010function constitute part of the same type I interferonopathy disease spectrum, and provide possible novel insight into the pathology of Jaccoud's arthropathy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40179","type":"journal-article","created":{"date-parts":[[2017,6,12]],"date-time":"2017-06-12T12:52:42Z","timestamp":1497271962000},"page":"2081-2091","source":"Crossref","is-referenced-by-count":65,"title":["Musculoskeletal Disease in MDA5\u2010Related Type I Interferonopathy: A Mendelian Mimic of Jaccoud's Arthropathy"],"prefix":"10.1002","volume":"69","author":[{"given":"Luciana Martins","family":"de Carvalho","sequence":"first","affiliation":[{"name":"Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo S\u00e3o Paulo 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