title: Congenital Visual Impairment and Progressive Microcephaly Due to Lysyl-Transfer Ribonucleic Acid (RNA) Synthetase (KARS) Mutations: The Expanding Phenotype of Aminoacyl-Transfer RNA Synthetase Mutations in Human Disease.
abstract: Aminoacyl-transfer ribonucleic acid (RNA) synthetases (ARSs) are a group of enzymes required for the first step of protein translation. Each aminoacyl-transfer RNA synthetase links a specific amino acid to its corresponding transfer RNA component within the cytoplasm, mitochondria, or both. Mutations in ARSs have been linked to a growing number of diseases. Lysyl-transfer RNA synthetase (KARS) links the amino acid lysine to its cognate transfer RNA. We report 2 siblings with severe infantile visual loss, progressive microcephaly, developmental delay, seizures, and abnormal subcortical white matter. Exome sequencing identified mutations within the KARS gene (NM_005548.2):c.1312C>T; p.Arg438Trp and c.1573G>A; p.Glu525Lys occurring within a highly conserved region of the catalytic domain. Our patients' phenotype is remarkably similar to a phenotype recently reported in glutaminyl-transfer RNA synthetase (QARS), another bifunctional ARS gene. This finding expands the phenotypic spectrum associated with mutations in KARS and draws attention to aminoacyl-transfer RNA synthetase as a group of enzymes that are increasingly being implicated in human disease.
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada hmcmillan@cheo.on.ca.
authors.forename: Hugh J
authors.initials: HJ
authors.lastname: McMillan
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Humphreys
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Amanda
authors.initials: A
authors.lastname: Smith
authors.affiliation: McGill University and Genome Quebec Innovation Centre, Montréal, Quebec, Canada.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Pranesh
authors.initials: P
authors.lastname: Chakraborty
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Bulman
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Chandree L
authors.initials: CL
authors.lastname: Beaulieu
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Quebec, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Geraghty
mesh_terms: D002648:Child; D004252:DNA Mutational Analysis; D018450:Disease Progression; D006801:Humans; D008137:Longitudinal Studies; D008250:Lysine-tRNA Ligase / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000150:complications* / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D014786:Vision Disorders / Q000150:complications* / Q000151:congenital / Q000235:genetics*
chemical_list: D008250:Lysine-tRNA Ligase
keywords: aminoacyl–tRNA; epilepsy; lysyl-tRNA synthetase; microcephaly; vision disorders