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Mutation in The Nuclear‐Encoded Mitochondrial Isoleucyl–t RNA Synthetase IARS2 in Patients with Cataracts, Growth Hormone Deficiency with Short Stature, Partial Sensorineural Deafness, and Peripheral Neuropathy or with Leigh Syndrome
Author(s) -
Schwartzentruber Jeremy,
Buhas Daniela,
Majewski Jacek,
Sasarman Florin,
PapillonCavanagh Simon,
Thiffaut Isabelle,
Sheldon Katherine M.,
Massicotte Christine,
Patry Lysanne,
Simon Mariella,
Zare Amir S.,
McKernan Kevin J.,
Michaud Jacques,
Boles Richard G.,
Deal Cheri L.,
Desilets Valerie,
Shoubridge Eric A.,
Samuels Mark E.
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22629
Subject(s) - biology , missense mutation , short stature , genetics , exome sequencing , cataracts , compound heterozygosity , mutation , mitochondrial disease , sensorineural hearing loss , hearing loss , mitochondrial dna , endocrinology , gene , medicine , audiology
Mutations in the nuclear‐encoded mitochondrial aminoacyl–t RNA 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–t RNA synthetase. The mutation is homozygous in the affected patients, heterozygous in carriers, and absent in control chromosomes. IARS 2 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 L eigh syndrome. This is the first report of clinical findings associated with IARS2 mutations.