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  Defects in tRNA Anticodon Loop 2'-O-Methylation Are Implicated in Nonsyndromic X-Linked Intellectual Disability due to Mutations in FTSJ1

Guy, M. P., Shaw, M., Weiner, C. L., Hobson, L., Stark, Z., Rose, K., et al. (2015). Defects in tRNA Anticodon Loop 2'-O-Methylation Are Implicated in Nonsyndromic X-Linked Intellectual Disability due to Mutations in FTSJ1. Human Mutation, 36(12), 1176-1187. doi:10.1002/humu.22897.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0000-D043-9 Version Permalink: http://hdl.handle.net/21.11116/0000-0000-D044-8
Genre: Journal Article

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 Creators:
Guy, M. P., Author
Shaw, M., Author
Weiner, C. L., Author
Hobson, L., Author
Stark, Z., Author
Rose, K., Author
Kalscheuer, V. M.1, Author              
Gecz, J., Author
Phizicky, E. M., Author
Affiliations:
1Chromosome Rearrangements and Disease (Vera Kalscheuer), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385702              

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Free keywords: Alleles Amino Acid Sequence Amino Acid Substitution *Anticodon Cell Line Codon Female Gene Expression Genotype Humans Male Mental Retardation, X-Linked/diagnosis/*genetics Methylation Methyltransferases/chemistry/*genetics Models, Molecular *Mutation Nuclear Proteins/chemistry/*genetics Nucleic Acid Conformation Pedigree Protein Conformation RNA, Transfer/chemistry/*genetics/metabolism RNA, Transfer, Phe/genetics/metabolism Saccharomyces cerevisiae/genetics/metabolism
 Abstract: tRNA modifications are crucial for efficient and accurate protein synthesis, and modification defects are frequently associated with disease. Yeast trm7Delta mutants grow poorly due to lack of 2'-O-methylated C32 (Cm32 ) and Gm34 on tRNA(Phe) , catalyzed by Trm7-Trm732 and Trm7-Trm734, respectively, which in turn results in loss of wybutosine at G37 . Mutations in human FTSJ1, the likely TRM7 homolog, cause nonsyndromic X-linked intellectual disability (NSXLID), but the role of FTSJ1 in tRNA modification is unknown. Here, we report that tRNA(Phe) from two genetically independent cell lines of NSXLID patients with loss-of-function FTSJ1 mutations nearly completely lacks Cm32 and Gm34 , and has reduced peroxywybutosine (o2yW37 ). Additionally, tRNA(Phe) from an NSXLID patient with a novel FTSJ1-p.A26P missense allele specifically lacks Gm34 , but has normal levels of Cm32 and o2yW37 . tRNA(Phe) from the corresponding Saccharomyces cerevisiae trm7-A26P mutant also specifically lacks Gm34 , and the reduced Gm34 is not due to weaker Trm734 binding. These results directly link defective 2'-O-methylation of the tRNA anticodon loop to FTSJ1 mutations, suggest that the modification defects cause NSXLID, and may implicate Gm34 of tRNA(Phe) as the critical modification. These results also underscore the widespread conservation of the circuitry for Trm7-dependent anticodon loop modification of eukaryotic tRNA(Phe) .

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Language(s): eng - English
 Dates: 2015-09-102015-12
 Publication Status: Published in print
 Pages: 12
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1002/humu.22897
ISSN: 1098-1004 (Electronic)1059-7794 (Print)
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Title: Human Mutation
  Alternative Title : Human mutation
Source Genre: Journal
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Publ. Info: Hoboken, NJ : John Wiley & Sons, Inc.
Pages: - Volume / Issue: 36 (12) Sequence Number: - Start / End Page: 1176 - 1187 Identifier: -