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

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 HEK293T 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.

A case of Singleton–Merten syndrome without cardiac involvement harboring a novel IFIH1 variant

“…A recent review reported multiple instances of overlap between SGMRT and Aicardi-Gouiteres syndrome, suggesting incomplete penetrance and variable expressivity (Rice et al, 2020). Another variant, p.Thr331Ile, was reported in three families described as having interferon I disease overlapping with SGMRT (de Carvalho et al, 2017). We present a patient who harbors a novel de novo variant in IFIH1, p.Leu329Pro and has features of SGMRT but lacks cardiac calcifications.…”

Cardiac valve involvement in ADAR-related type I interferonopathy

“…Of note, heterozygous mutations in IFIH1 can cause Singleton-Merten syndrome (SMS), characterised by deforming arthropathy, abnormal tooth development and aortic and cardiac valve calcification frequently leading to death 5. Although previously considered to represent a distinct phenotype, recent studies have indicated that SMS constitutes part of the type I interferonopathy disease spectrum 6 7. Here we report, for the first time, three children with biallelic ADAR mutations presenting with calcifying cardiac valve disease, further emphasising the phenotypic overlap across the type I interferonopathies.…”

Primary immunodeficiencies in cytosolic pattern‐recognition receptor pathways: Toward host‐directed treatment strategies

“…In 2015, the clinical picture was further expanded by the observation that IFIH1 GoF mutations cause SGMRT, an AD disorder characterized by deforming arthropathy, dental dysplasia, glaucoma, psoriasis, and cardiac valve calcification 132 . Subsequent reports have elucidated that IFIH1 GoF mutations cause a broad and variable disease spectrum related to type I interferon overload, with musculoskeletal and dermatological involvement, overlapping neuroinflammatory phenotypes and SLE 129,133‐135 …”