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  Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability

Musante, L., Püttmann, L., Kahrizi, K., Garshasbi, M., Hu, H., Stehr, H., et al. (2017). Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability. Human Mutations, 38(6), 621-636. doi:10.1002/humu.23205.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0000-BF8B-D Version Permalink: http://hdl.handle.net/21.11116/0000-0000-BF8C-C
Genre: Journal Article

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 Creators:
Musante, L.1, Author              
Püttmann, L.1, Author
Kahrizi, K., Author
Garshasbi, M.1, Author
Hu, H.1, Author
Stehr, H., Author
Lipkowitz, B.1, Author
Otto, S.1, Author
Jensen, L. R., Author
Tzschach, A.1, Author
Jamali, P., Author
Wienker, T. F.2, Author              
Najmabadi, H., Author
Ropers, H. H.1, Author              
Kuss, A. W., Author
Affiliations:
1Emeritus Group of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385695              
2Clinical Genetics (Thomas F. Wienker), Emeritus Group of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385696              

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Free keywords: Sars Wars2 aminoacyl-tRNA-synthetase aminoacylation brain cognition intellectual disability tRNA
 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 tRNA(Ser) concentrations. 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.

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Language(s): eng - English
 Dates: 2017-03-232017-06
 Publication Status: Published in print
 Pages: 16
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1002/humu.23205
ISSN: 1098-1004 (Electronic)1059-7794 (Print)
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Title: Human Mutations
  Other : Hum Mut
Source Genre: Journal
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Publ. Info: New York, N.Y. : Wiley-Liss
Pages: - Volume / Issue: 38 (6) Sequence Number: - Start / End Page: 621 - 636 Identifier: ISSN: 1059-7794
CoNE: /journals/resource/954925597586