Mutation in The Nuclear-Encoded Mitochondrial Isoleucyl-tRNA SynthetaseIARS2in Patients with Cataracts, Growth Hormone Deficiency with Short Stature, Partial Sensorineural Deafness, and Peripheral Neuropathy or with Leigh Syndrome

Abstract

Mutations in the nuclear-encoded mitochondrial aminoacyl-tRNA synthetases are associated with a range of clinical phenotypes. Here, we report a novel disorder in three adult patients with a phenotype including cataracts, short-stature secondary to growth hormone deficiency, sensorineural hearing deficit, peripheral sensory neuropathy, and skeletal dysplasia. Using SNP genotyping and whole-exome sequencing, we identified a single likely causal variant, a missense mutation in a conserved residue of the nuclear gene IARS2, encoding mitochondrial isoleucyl-tRNA synthetase. The mutation is homozygous in the affected patients, heterozygous in carriers, and absent in control chromosomes. IARS2 protein level was reduced in skin cells cultured from one of the patients, consistent with a pathogenic effect of the mutation. Compound heterozygous mutations in IARS2 were independently identified in a previously unreported patient with a more severe mitochondrial phenotype diagnosed as Leigh syndrome. This is the first report of clinical findings associated with IARS2 mutations.

Clinical and genetic characteristics of Chinese patients with familial or sporadic pediatric cataract

“…Two novel compound heterozygous mutations in IARS2 , a nuclear gene encoding mitochondrial isoleucyl-tRNA synthetase [22], were found in family #10 and sporadic case #6 (Fig. 5b).…”

Mutations in the mitochondrial cysteinyl-tRNA synthase gene,CARS2,lead to a severe epileptic encephalopathy and complex movement disorder

“…In several mt-ARSs defects, a very limited phenotype has been observed in the skin fibroblasts from patients, including normal respiratory chain enzyme activities, normal BN-PAGE gel analysis and normal mitochondrial translation assays 37 39 40. However, the identification of a functional defect using BN-PAGE in the proband's cultured skin fibroblasts provided us a means to evaluate the causality of a novel gene through correction of the functional defect by transfection with the native gene and mitochondrial tRNA aminoacylation analysis by northern blotting.…”

Recessive Mutation in a Nuclear-Encoded Mitochondrial tRNA Synthetase Associated With Infantile Cataract, Congenital Neurotrophic Keratitis, and Orbital Myopathy

“…1,2 Genetic mapping of the mutation has been achieved by homozygosity mapping using carried high-density single-nucleotide polymorphism genotyping and whole-exome sequencing on the 3 phenotypically similar patients. 1 Here, we report in more detail the ocular findings associated with this disorder.…”

“…1 This disorder has been recently coined CAGSSS in relation to its ocular (presence of cataracts/CA), endocrine (growth hormone deficiency/G), neurological (sensory neuropathy/S), cochlear (sensorineural hearing loss/S), and musculoskeletal (skeletal dysplasia/S) findings. It is part of a new group of mitochondrial diseases related to mutation in tRNA synthetase, a nuclear protein responsible for translation of mitochondrial-encoded proteins.…”