Genetic and phenotypic spectrum associated with IFIH1 gain-of-function

Abstract

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.

Keywords: Aicardi-Goutières syndrome; IFIH1; MDA5; Singleton Merten syndrome; Type I interferonopathy.

FIGURE 1

Schematic showing the positions of protein domains and their amino acid boundaries within the 1,025-residue IFIH1 protein. The 27 mutations ascertained in the present study are annotated, with the numbers in brackets indicating the number of families in which each mutation was observed. Three previously published mutations (p.Leu372Phe; p.Ala452Thr; p.Glu813Asp), not ascertained in our series, are also denoted (below the cartoon). CARD, caspase activation recruitment domain; Hel, helicase domain, where Hel1 and Hel2 are the two conserved core helicase domains and Hel2i is an insertion domain that is conserved in the RIG-I-like helicase family; P, pincer or bridge region connecting Hel2 to the C-terminal domain (CTD) involved in binding double stranded RNA

FIGURE 2

Overview of phenotypes observed in the IFIH1-mutation-positive cohort. Classification of 68 of 74 individuals according to phenotype. For clarity, six individuals displaying characteristics difficult to classify were omitted from this analysis

FIGURE 3

Mutation mapping. Structure of human IFIH1 (4GL2) in complex with double stranded RNA (dsRNA; blue stick model in the center). Only the RNA binding domain (helicase domain and C-terminal domain, CTD) are included in the crystal structure. Note that the helicase domain consists of Hel1, Hel2i, and Hel2. Mutations are indicated by spheres using the following color code: residues in the ATP binding pocket (magenta), residues in the dsRNA binding surface (blue), residues within the main cluster but not directly involved in RNA binding or ATP binding (green), residues outside the main cluster (cyan), and residues previously reported by others but not in our cohort (orange). We considered all 27 mutations reported here plus three previously published mutations (p.Leu372Phe; p.Ala452Thr; p.Glu813Asp) not ascertained in our series. Residues p.Arg822, p.Arg824, and p.Ile956 are not shown because they are disordered in the crystal structure, but are expected to be located in the ATP binding (p.Arg822 and p.Arg824) and RNA binding (p.Ile956) pockets