title: Defects in tRNA Anticodon Loop 2'-O-Methylation Are Implicated in Nonsyndromic X-Linked Intellectual Disability due to Mutations in FTSJ1.
abstract: tRNA modifications are crucial for efficient and accurate protein synthesis, and modification defects are frequently associated with disease. Yeast trm7Δ 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) .
authors: Department of Biochemistry and Biophysics, University of Rochester School of Medicine, Rochester, New York, 14642.
authors: Michael P
authors: MP
authors: Guy
authors: Robinson Research Institute, The University of Adelaide, Adelaide, South Australia 5000, Australia.|School of Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, South Australia 5000, Australia.
authors: Marie
authors: M
authors: Shaw
authors: Department of Biochemistry and Biophysics, University of Rochester School of Medicine, Rochester, New York, 14642.
authors: Catherine L
authors: CL
authors: Weiner
authors: SA Pathology, Women's and Children's Hospital, Adelaide, South Australia 5006, Australia.
authors: Lynne
authors: L
authors: Hobson
authors: Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria 3052, Australia.
authors: Zornitza
authors: Z
authors: Stark
authors: Monash Health, Special Medicine Centre, Monash Medical Centre, Clayton, Victoria 3168, Australia.
authors: Katherine
authors: K
authors: Rose
authors: Department Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin D14195, Germany.
authors: Vera M
authors: VM
authors: Kalscheuer
authors: Robinson Research Institute, The University of Adelaide, Adelaide, South Australia 5000, Australia.|School of Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, South Australia 5000, Australia.
authors: Jozef
authors: J
authors: Gecz
authors: Department of Biochemistry and Biophysics, University of Rochester School of Medicine, Rochester, New York, 14642.
authors: Eric M
authors: EM
authors: Phizicky
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000926:Anticodon; D002460:Cell Line; D003062:Codon; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008745:Methylation; D008780:Methyltransferases / Q000737:chemistry / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D009690:Nucleic Acid Conformation; D010375:Pedigree; D011487:Protein Conformation; D012343:RNA, Transfer / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012360:RNA, Transfer, Phe / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism
chemical_list: D000926:Anticodon; D003062:Codon; D009687:Nuclear Proteins; D012360:RNA, Transfer, Phe; D012343:RNA, Transfer; C490101:FTSJ1 protein, human; D008780:Methyltransferases
keywords: 2′-O-methylation; FTSJ1; NSXLID; TRM7; intellectual disability; tRNA