title: PARS2 and NARS2 mutations in infantile-onset neurodegenerative disorder.
abstract: Here we present four unrelated families with six individuals that have infantile-onset developmental delay/regression and epilepsy. Whole-exome sequencing revealed compound heterozygous mutations, c.[283G>A];[607G>A] in a gene encoding prolyl-tRNA synthetase (PARS2) in one family. Two pairs of compound heterozygous mutations, c.[151C>T];[1184T>G] and c.[707T>G];[594+1G>A], and a homozygous mutation, c.[500A>G];[500A>G], in a gene encoding asparaginyl-tRNA synthetase (NARS2) were also identified in the other three families. Mutations in genes encoding aminoacyl-tRNA synthetases cause gene-specific mitochondrial disorders. Biallelic PARS2 or NARS2 mutations are reported to cause Alpers' syndrome, which is an autosomal recessive neurodegenerative disorder characterized by psychomotor regression and epilepsy with variable degree of liver involvement. Moreover, it is known that NARS2 mutations cause various clinical phenotypes, including non-syndromic hearing loss, Leigh syndrome, intellectual disability with epilepsy and severe myopathy. The individuals with PARS2 and NARS2 mutations, we have reported here demonstrate similar neurological features as those previously reported, with diversity in clinical presentation such as hearing loss and seizure type. Our data broaden the clinical and mutational spectrum of PARS2- and NARS2-related disorders.
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Mizuguchi
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 Pediatrics, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kato
authors.affiliation: Division of Pediatric Neurology, Aichi Prefectural Colony Central Hospital, Aichi, Japan.
authors.forename: Keitaro
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Child Neurology, Comprehensive Epilepsy Center, Seirei Hamamatsu General Hospital, Hamamatsu, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Okanishi
authors.affiliation: The Genetics Institute and Metabolic Unit, Rambam Health Care Campus, Haifa, Israel.|Rappaport School of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Nina
authors.initials: N
authors.lastname: Ekhilevitch
authors.affiliation: The Genetics Institute and Metabolic Unit, Rambam Health Care Campus, Haifa, Israel.|Rappaport School of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Hanna
authors.initials: H
authors.lastname: Mandel
authors.affiliation: Department of Radiology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Eran
authors.affiliation: Department of Pediatrics, Akita Prefectural Center on Development and Disability, Akita, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Toyono
authors.affiliation: Department of Pediatrics, Akita Prefectural Center on Development and Disability, Akita, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Sawaishi
authors.affiliation: Department of Child Neurology, Comprehensive Epilepsy Center, Seirei Hamamatsu General Hospital, Hamamatsu, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Motoi
authors.affiliation: Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Shiina
authors.affiliation: Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ogata
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Miyatake
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.|Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, 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: D017668:Age of Onset; D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics*; D001226:Aspartate-tRNA Ligase / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005190:Family; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000235:genetics*; D010375:Pedigree
chemical_list: D000604:Amino Acyl-tRNA Synthetases; D001226:Aspartate-tRNA Ligase; C000625848:PARS2 protein, human; C000601756:NARS2 protein, human