title: Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability.
abstract: Intellectual disability (ID) is the hallmark of an extremely heterogeneous group of disorders that comprises a wide variety of syndromic and non-syndromic phenotypes. Here, we report on mutations in two aminoacyl-tRNA synthetases that are associated with ID in two unrelated Iranian families. In the first family, we identified a homozygous missense mutation (c.514G>A, p.Asp172Asn) in the cytoplasmic seryl-tRNA synthetase (SARS) gene. The mutation affects the enzymatic core domain of the protein and impairs its enzymatic activity, probably leading to reduced cytoplasmic tRNASerconcentrations. The mutant protein was predicted to be unstable, which could be substantiated by investigating ectopic mutant SARS in transfected HEK293T cells. In the second family, we found a compound heterozygous genotype of the mitochondrial tryptophanyl-tRNA synthetase (WARS2) gene, comprising a nonsense mutation (c.325delA, p.Ser109Alafs*15), which very likely entails nonsense-mediated mRNA decay and a missense mutation (c.37T>G, p.Trp13Gly). The latter affects the mitochondrial localization signal of WARS2, causing protein mislocalization. Including AIMP1, which we have recently implicated in the etiology of ID, three genes with a role in tRNA-aminoacylation are now associated with this condition. We therefore suggest that the functional integrity of tRNAs in general is an important factor in the development and maintenance of human cognitive functions.
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Luciana
authors.initials: L
authors.lastname: Musante
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Lucia
authors.initials: L
authors.lastname: Püttmann
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Kimia
authors.initials: K
authors.lastname: Kahrizi
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Masoud
authors.initials: M
authors.lastname: Garshasbi
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.affiliation: Stanford Cancer Institute, Stanford University, Stanford, California.
authors.forename: Henning
authors.initials: H
authors.lastname: Stehr
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Lipkowitz
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Otto
authors.affiliation: Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Lars R
authors.initials: LR
authors.lastname: Jensen
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Tzschach
authors.affiliation: Shahroud Welfare Organization, Semnan, Iran.
authors.forename: Payman
authors.initials: P
authors.lastname: Jamali
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wienker
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Najmabadi
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Hans Hilger
authors.initials: HH
authors.lastname: Ropers
authors.affiliation: Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Kuss
mesh_terms: D000293:Adolescent; D000328:Adult; D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics*; D002648:Child; D016207:Cytokines / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D007492:Iran; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D059365:Nonsense Mediated mRNA Decay / Q000235:genetics*; D010375:Pedigree; D016601:RNA-Binding Proteins / Q000235:genetics
chemical_list: D016207:Cytokines; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; C077219:small inducible cytokine subfamily E, member 1; D000604:Amino Acyl-tRNA Synthetases
keywords: SARS; WARS2; aminoacyl-tRNA-synthetase; aminoacylation; brain; cognition; intellectual disability; tRNA