Musculoskeletal Disease in MDA5-Related Type I Interferonopathy: A Mendelian Mimic of Jaccoud's Arthropathy

Objectives 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 ascertained two 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-stimulated genes in peripheral blood and skin, and undertook targeted Sanger sequencing of the IFIH1 gene encoding the cytosolic double-stranded RNA sensor MDA5. We also assessed the functional consequences of IFIH1 gene variants using an in vitro interferon beta reporter assay in HEK293 cells. Results We recorded an upregulation of type I interferon-induced gene transcripts in all five 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 MDA5. Both of these variants were associated with increased interferon beta expression in the absence of exogenous dsRNA ligand, consistent with constitutive activation of MDA5. Conclusions These cases highlight the significant musculoskeletal involvement that can be associated with mutations in MDA5, and emphasize the value of testing for an upregulation of interferon signalling as a marker of the underlying molecular lesion. Our data both indicate that Singleton-Merten syndrome and neuroinflammation described in the context of MDA5 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. This article is protected by copyright. All rights reserved.