title: Mutation in the nuclear-encoded mitochondrial isoleucyl-tRNA synthetase IARS2 in 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.
authors.affiliation: McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.forename: Daniela
authors.initials: D
authors.lastname: Buhas
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Florin
authors.initials: F
authors.lastname: Sasarman
authors.forename: Simon
authors.initials: S
authors.lastname: Papillon-Cavanagh
authors.forename: Isabelle
authors.initials: I
authors.lastname: Thiffault
authors.forename: Isabelle
authors.initials: I
authors.lastname: Thiffaut
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Sheldon
authors.forename: Christine
authors.initials: C
authors.lastname: Massicotte
authors.forename: Lysanne
authors.initials: L
authors.lastname: Patry
authors.forename: Mariella
authors.initials: M
authors.lastname: Simon
authors.forename: Amir S
authors.initials: AS
authors.lastname: Zare
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: McKernan
authors.forename: Jacques
authors.initials: J
authors.lastname: Michaud
authors.forename: Richard G
authors.initials: RG
authors.lastname: Boles
authors.forename: Cheri L
authors.initials: CL
authors.lastname: Deal
authors.forename: Valerie
authors.initials: V
authors.lastname: Desilets
authors.forename: Eric A
authors.initials: EA
authors.lastname: Shoubridge
authors.forename: Mark E
authors.initials: ME
authors.lastname: Samuels
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001921:Brain / Q000473:pathology; D002386:Cataract / Q000175:diagnosis / Q000235:genetics*; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004393:Dwarfism, Pituitary / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007533:Isoleucine-tRNA Ligase / Q000737:chemistry / Q000235:genetics*; D007888:Leigh Disease / Q000175:diagnosis / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010523:Peripheral Nervous System Diseases / Q000175:diagnosis / Q000235:genetics*; D010641:Phenotype; D016415:Sequence Alignment; D013577:Syndrome
chemical_list: D007533:Isoleucine-tRNA Ligase
keywords: IARS2; exome sequencing; mitochondrial disorder; mitochondrial tRNA synthetase