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- Title
Musculoskeletal Disease in MDA5-Related Type I Interferonopathy: A Mendelian Mimic of Jaccoud's Arthropathy.
- Authors
de Carvalho, Luciana Martins; Ngoumou, Gonza; Park, Ji Woo; Ehmke, Nadja; Deigendesch, Nikolaus; Kitabayashi, Naoki; Melki, Isabelle; Souza, Flávio Falcäo L.; Tzschach, Andreas; Nogueira‐Barbosa, Marcello H.; Ferriani, Virgínia; Louzada‐Junior, Paulo; Marques, Wilson; Lourenço, Charles M.; Horn, Denise; Kallinich, Tilmann; Stenzel, Werner; Hur, Sun; Rice, Gillian I.; Crow, Yanick J.
- Abstract
Objective 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. Methods We identified 2 families segregating an autosomal-dominant 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)-stimulated genes in the peripheral blood and skin, and undertook targeted Sanger sequencing of the IFIH1 gene encoding the cytosolic double-stranded RNA (dsRNA) sensor melanoma differentiation-associated protein 5 (MDA-5). We also assessed the functional consequences of IFIH1 gene variants using an in vitro IFNβ reporter assay in HEK 293T cells. Results We recorded an up-regulation of type I IFN-induced gene transcripts in all 5 patients tested and identified a heterozygous gain-of-function mutation in IFIH1 in each family, resulting in different substitutions of the threonine residue at position 331 of MDA-5. Both of these variants were associated with increased IFNβ expression in the absence of exogenous dsRNA ligand, consistent with constitutive activation of MDA-5. Conclusion These cases highlight the significant musculoskeletal involvement that can be associated with mutations in MDA-5, and emphasize the value of testing for up-regulation of IFN signaling as a marker of the underlying molecular lesion. Our data indicate that both Singleton-Merten syndrome and neuroinflammation described in the context of MDA-5 gain-of-function constitute part of the same type I interferonopathy disease spectrum, and provide possible novel insight into the pathology of Jaccoud's arthropathy.
- Subjects
GENE expression; GENES; INTERFERONS; JOINT diseases; MELANOMA; MUSCULOSKELETAL system diseases; GENETIC mutation; PROTEINS; RNA; PHENOTYPES
- Publication
Arthritis & Rheumatology, 2017, Vol 69, Issue 10, p2081
- ISSN
2326-5191
- Publication type
Article
- DOI
10.1002/art.40179