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 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.

Figure 1.

Radiologic and clinical features of patient 1 of family 1938. A-D, Radiographs of the hands (A), right foot (B), and upper limbs (C and D) at age 18 years, demonstrating subluxations (broken arrows), with well-preserved joint spaces and articular surfaces, and dense calcifications of tendon insertions at the elbows (solid arrows), which were not palpable. E and F, Photographs of the hands (E) and feet (F) at age 18 years, demonstrating camptodactyly, subluxation, and plantar collapse. Note the pigmentary abnormalities on the hands. G, Computed tomography image of the brain at age 18 years, demonstrating dense calcification of the basal ganglia (in the absence of any neurologic signs or symptoms).

Figure 2.

Radiologic and clinical features of patient 2 of family 1938. A-D, Radiographs of the hands (A), left knee (B), left femur and hip (C), and left foot (D) at age 45 years, demonstrating significant deformities and ectopic calcification at the sites of tendon insertions (arrows). E, Radiograph of the jaw, demonstrating a complete absence of teeth. F and G, Photographs of the hands (F) and feet (G) at age 45 years, demonstrating musculoskeletal deformities. H, Transverse computed tomography image of the chest, demonstrating dense ectopic calcification of the aortic valve. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/art.40179/abstract.

Figure 3.

Radiologic features of patients 1 and 2 of family 1972. A, Radiograph of the left hand of patient 1 of family 1972 at age 8 years. There were no major radiologic changes other than slight osteopenia. B-E, Radiographs of the hands (B and C) and feet (D and E) of her father, patient 2 of family 1972, at age 47 years. Bilateral subluxation of the thumbs and hallux deformity of the large toes can be seen. Note a suggestion of acro-osteolysis of the phalanges in B and C.

Figure 4.

Schematic illustration of melanoma differentiation-associated protein 5 (MDA-5) and disease-associated mutations. The protein domains and their amino acid boundaries within the 1,025-amino acid protein MDA-5 are shown. Hel1 and Hel2 are the 2 conserved core helicase domains, and Hel2i is an insertion domain that is conserved in the retinoic acid-inducible gene 1-like helicase family. P denotes the pincer or bridge region that connects Hel2 to the C-terminal domain (CTD) involved in binding double-stranded RNA. Mutations shown above the line have been recorded in patients with a Singleton-Merton syndrome phenotype. Mutations shown below the line have been identified in patients with a neurologic phenotype. Numbers in parentheses are the numbers of families with each mutation described in the literature. Asterisk denotes a variant identified in 3 members of the same family, 2 with a neurologic phenotype and 1 with a Singleton-Merten syndrome phenotype (3). ¶ denotes a variant identified in 3 families segregating a Singleton-Merten syndrome phenotype (7), an individual with predominant neurologic involvement more consistent with Aicardi-Goutières syndrome (13), and a further family including a patient with features of Singleton-Merten syndrome, spastic paraparesis, and systemic lupus erythematosus (12). CARD=caspase activation recruitment domain.

Figure 5.

Type I interferon (IFN) status in families 1938 (F1938) and 1972. A, Expression of 6 IFN-stimulated genes. Values in parentheses are the patient’s age (years); IFN score. Scores of >2.466 are considered abnormal. RQ=relative quantification. B, IFNβ reporter activity in Flag-tagged wild-type and mutant IFN-induced helicase C domain-containing protein 1 (IFIH-1) left unstimulated, stimulated with 162-bp double-stranded RNA (dsRNA), or stimulated with poly(I-C) in HEK 293T cells. IFIH-1 mutants activated the IFN signaling pathway more efficiently than did wild-type IFIH-1. Bars show the mean±SD of 3 independent experiments.