RIG-I-Like Receptor Signaling in Singleton-Merten Syndrome

Abstract

Singleton-Merten syndrome (SMS) is an autosomal dominant, multi-system innate immune disorder characterized by early and severe aortic and valvular calcification, dental and skeletal abnormalities, psoriasis, glaucoma, and other varying clinical findings. Recently we identified a specific gain-of-function mutation in IFIH1, interferon induced with helicase C domain 1, segregated with this disease. SMS disease without hallmark dental anomalies, termed atypical SMS, has recently been reported caused by variants in DDX58, DEXD/H-box helicase 58. IFIH1 and DDX58 encode retinoic acid-inducible gene I (RIG-I)-like receptors family members melanoma differentiation-associated gene 5 and RIG-I, respectively. These cytosolic pattern recognition receptors function in viral RNA detection initiating an innate immune response through independent pathways that promote type I and type III interferon expression and proinflammatory cytokines. In this review, we focus on SMS as an innate immune disorder summarizing clinical features, molecular aspects of the pathogenetic pathway and discussing underlying mechanisms of the disease.

Keywords: DDX58; IFIH1; MDA5; RIG-I; Singleton-Merten syndrome.

FIGURE 1

Sustained retinoic acid-inducible gene I (RIG-I)-like receptor signaling in Singleton-Merten syndrome (SMS). (A) Structure of melanoma differentiation-associated gene 5 (MDA5) and RIG-I indicating identified SMS mutations in the DEAD helicase domain. MDA5 and RIG-I shared structural features that include: the N-terminal region with two tandem caspase activation and recruitment domains (CARDs); the central DEAD helicase region with HEL1 and HEL2 domains and a helicase-insert domain (HEL2i); the pincer domain; and the C-terminal domain (CTD), also called the regulatory or repressor domain. The most common SMS MDA5 p.Arg822Gln substitution is located in the end of the HEL2 domain. The MDA5 p.Thr331Ile, p.Thr331Arg, p.Ala489Thr and the RIG-I p.Cys268Phe and p.Glu373Ala substitutions associated are located in the HEL1 domain. (B) Sustained RIG-I receptor signaling in SMS cells through self-dsRNA recognition. In healthy wild type cells, ATP hydrolysis prevents MDA5 and RIG-I to recognize self-dsRNA thus preventing triggering of signaling. In atypical SMS cells, Glu373Ala mutation (SMS-RIG-I) allows ATP promoted binding of dsRNA to RIG-I, but prevents ATP hydrolysis dependent dissociation of helicase domain from dsRNA, which result in sustained RIG-I signaling and excessive production of IFN, proinflammatory cytokines, chemokines, and others. Similar mechanism may functional related to the MDA5 Ile331, MDA5 Arg331, MDA5 Thr489, and MDA5 Gln822 (SMS-MDA5) identified in classic SMS.