Functional Significance of Mutations in Helicase Genes in Patients with Juvenile Dermatomyositis and anti-MDA5 Autoantibodies

National Institute On Aging

Investigators

Abstract

Recent research conducted at NIEHS, in collaboration with NIAID, indicates mutations in three genes, two encoding helicase-like proteins (CHD3, DHX37) and one encoding a helicase-interacting ATPase protein (WRNIP1 or WHIP), with anti-MDA5 autoantibody (Ab)-positive Juvenile Dermatomyositis (JDM). Abs to MDA5, a cytoplasmic dsRNA helicase, define a subset of JDM that presents with systemic inflammation, skin and lung disease, but the pathomechanisms that lead to the development of anti-MDA5 Abs and their pathogenic roles in disease remain poorly understood. Three patients have recessive mutations in CHD3, DHX37, or WRNIP1; two patients have mutations in CHD3 and DHX37, with a mutation in an arginine (R) of a conserved LRK domain, a domain also conserved in MDA5. We propose to characterize the functions and cellular roles of these helicases in nucleic acid transactions and DNA repair by characterization of the nucleic acid substrates and catalytic activities of the wild type and mutated helicases and the helicase-associated protein WRNIP1. We will determine the ability of patient anti-MDA5 Abs to impair wild type and mutant protein functions. These studies will clarify the roles of the helicases CHD3 and DHX37, and WRNIP1, in viral sensing and DNA repair, and attempt to establish their role in the etiology of JDM.