title: Mutations in the glutaminyl-tRNA synthetase gene cause early-onset epileptic encephalopathy.
abstract: Aminoacylation is the process of attaching amino acids to their cognate tRNA, and thus is essential for the translation of mRNA into protein. This direct interaction of tRNA with amino acids is catalyzed by aminoacyl-tRNA synthetases. Using whole-exome sequencing, we identified compound heterozygous mutations [c.169T>C (p.Tyr57His) and c.1485dup (p.Lys496*)] in QARS, which encodes glutaminyl-tRNA synthetase, in two siblings with early-onset epileptic encephalopathy (EOEE). Recessive mutations in QARS, including the loss-of-function missense mutation p.Tyr57His, have been reported to cause intractable seizures with progressive microcephaly. The p.Lys496* mutation is novel and causes truncation of the QARS protein, leading to a deletion of part of the catalytic domain and the entire anticodon-binding domain. Transient expression of the p.Lys496* mutant in neuroblastoma 2A cells revealed diminished and aberrantly aggregated expression, indicating the loss-of-function nature of this mutant. Together with the previous report, our data suggest that abnormal aminoacylation is one of the underlying pathologies of EOEE.
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kodera
authors.affiliation: Division of Neurology, Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Osaka
authors.affiliation: Division of Neurology, Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Mizue
authors.initials: M
authors.lastname: Iai
authors.affiliation: Division of Radiology, Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Aida
authors.affiliation: Department of Molecular Biology, Yokohama City University School of Medicine and Graduate School of Medical Science, Yokohama, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Yamashita
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tsurusaki
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics*; D001927:Brain Diseases / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D004569:Electroencephalography; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005192:Family Health; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D035781:Siblings
chemical_list: D000604:Amino Acyl-tRNA Synthetases; C020659:glutaminyl-tRNA synthetase