A Specific IFIH1 Gain-of-Function Mutation Causes Singleton-Merten Syndrome

Abstract

Singleton-Merten syndrome (SMS) is an infrequently described autosomal-dominant disorder characterized by early and extreme aortic and valvular calcification, dental anomalies (early-onset periodontitis and root resorption), osteopenia, and acro-osteolysis. To determine the molecular etiology of this disease, we performed whole-exome sequencing and targeted Sanger sequencing. We identified a common missense mutation, c.2465G>A (p.Arg822Gln), in interferon induced with helicase C domain 1 (IFIH1, encoding melanoma differentiation-associated protein 5 [MDA5]) in four SMS subjects from two families and a simplex case. IFIH1 has been linked to a number of autoimmune disorders, including Aicardi-Goutières syndrome. Immunohistochemistry demonstrated the localization of MDA5 in all affected target tissues. In vitro functional analysis revealed that the IFIH1 c.2465G>A mutation enhanced MDA5 function in interferon beta induction. Interferon signature genes were upregulated in SMS individuals' blood and dental cells. Our data identify a gain-of-function IFIH1 mutation as causing SMS and leading to early arterial calcification and dental inflammation and resorption.

Type I interferonopathies—an expanding disease spectrum of immunodysregulation

“…In addition, patients may suffer from psoriasis, early-onset glaucoma and recurrent infections. Singleton-Merton syndrome is inherited in an autosomal dominant manner and caused by heterozygous mutations in IFIH1 (SGMRT1; OMIM 182250) or RIGI (SGMRT2; OMIM 616298) encoding cytosolic pattern recognition receptors for dsRNA [74,75]. Functional studies have shown that IFIH1 or RIGI mutations in patients act as gain-offunction mutations which results in constitutive type IFN activation.…”

Aicardi–Goutières syndrome and the type I interferonopathies

“…Following the identification of IFIH1 mutations in various neuroimmunological disease states 9 , it was reported that a specific IFIH1 gain-of-function mutation can cause Singleton-Merten syndrome (SMS), an auto somal dominant disorder variably characterized by dental anomalies (early-onset periodontitis and root resorption), aortic and valvular calcification, glaucoma, psoriasis, contractures and acro-osteolysis 81 . Simultaneously, two distinct mutations in DDX58 (which encodes the cytosolic sensor of 5ʹ-triphosphate and 5ʹ-diphosphate RNA, RIG-I 82 ) were described that cause what the authors refer to as atypical SMS -in which glaucoma, aortic calcification and skeletal abnormalities are present in the absence of obvious dental problems 83 .…”

Where do we stand on vascular calcification?

“…Calcification per se may also enhance inflammation when present in the form of hyperphosphatemia-induced nanocrystals or calcium phosphate crystals [40,71]. It was recently shown that the Singleton-Merten syndrome, which includes both vascular and valvular calcification, might be due to mutations resulting in increased interferon activity [72], thereby supporting the concept that inflammation leads to calcification. It is interesting to note that infection, such as tuberculosis, commonly leads to calcified lesions, a process likely driven by inflammation.…”