Title: Defects in tRNA Anticodon Loop 2′-<i>O</i>-Methylation Are Implicated in Nonsyndromic X-Linked Intellectual Disability due to Mutations in<i>FTSJ1</i>
Abstract: Human MutationVolume 36, Issue 12 p. 1176-1187 Research Article Defects in tRNA Anticodon Loop 2′-O-Methylation Are Implicated in Nonsyndromic X-Linked Intellectual Disability due to Mutations in FTSJ1 Michael P. Guy, Michael P. Guy Department of Biochemistry and Biophysics, University of Rochester School of Medicine, Rochester, New York, 14642 These authors contributed equally to this work.Search for more papers by this authorMarie Shaw, Marie Shaw 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 These authors contributed equally to this work.Search for more papers by this authorCatherine L. Weiner, Catherine L. Weiner Department of Biochemistry and Biophysics, University of Rochester School of Medicine, Rochester, New York, 14642 Catherine L. Weiner's present address is Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138.Search for more papers by this authorLynne Hobson, Lynne Hobson SA Pathology, Women's and Children's Hospital, Adelaide, South Australia 5006, AustraliaSearch for more papers by this authorZornitza Stark, Zornitza Stark Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria 3052, AustraliaSearch for more papers by this authorKatherine Rose, Katherine Rose Monash Health, Special Medicine Centre, Monash Medical Centre, Clayton, Victoria 3168, AustraliaSearch for more papers by this authorVera M. Kalscheuer, Vera M. Kalscheuer Department Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin D14195, GermanySearch for more papers by this authorJozef Gecz, Corresponding Author Jozef Gecz 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, AustraliaCorrespondence to: Jozef Gecz, Robinson Research Institute, School of Paediatrics and Reproductive Health, The University of Adelaide at the Women's and Children's Hospital, 72 King William Road, North Adelaide, SA 5006. E-mail: [email protected] for more papers by this authorEric M. Phizicky, Eric M. Phizicky Department of Biochemistry and Biophysics, University of Rochester School of Medicine, Rochester, New York, 14642 Correspondence to: Eric M. Phizicky, Department of Biochemistry and Biophysics, Center for RNA Biology, University of Rochester School of Medicine, 601 Elmwood Avenue, Box 712, Rochester, NY 14642. E-mail: [email protected] for more papers by this author Michael P. Guy, Michael P. Guy Department of Biochemistry and Biophysics, University of Rochester School of Medicine, Rochester, New York, 14642 These authors contributed equally to this work.Search for more papers by this authorMarie Shaw, Marie Shaw 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 These authors contributed equally to this work.Search for more papers by this authorCatherine L. Weiner, Catherine L. Weiner Department of Biochemistry and Biophysics, University of Rochester School of Medicine, Rochester, New York, 14642 Catherine L. Weiner's present address is Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138.Search for more papers by this authorLynne Hobson, Lynne Hobson SA Pathology, Women's and Children's Hospital, Adelaide, South Australia 5006, AustraliaSearch for more papers by this authorZornitza Stark, Zornitza Stark Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria 3052, AustraliaSearch for more papers by this authorKatherine Rose, Katherine Rose Monash Health, Special Medicine Centre, Monash Medical Centre, Clayton, Victoria 3168, AustraliaSearch for more papers by this authorVera M. Kalscheuer, Vera M. Kalscheuer Department Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin D14195, GermanySearch for more papers by this authorJozef Gecz, Corresponding Author Jozef Gecz 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, AustraliaCorrespondence to: Jozef Gecz, Robinson Research Institute, School of Paediatrics and Reproductive Health, The University of Adelaide at the Women's and Children's Hospital, 72 King William Road, North Adelaide, SA 5006. E-mail: [email protected] for more papers by this authorEric M. Phizicky, Eric M. Phizicky Department of Biochemistry and Biophysics, University of Rochester School of Medicine, Rochester, New York, 14642 Correspondence to: Eric M. Phizicky, Department of Biochemistry and Biophysics, Center for RNA Biology, University of Rochester School of Medicine, 601 Elmwood Avenue, Box 712, Rochester, NY 14642. E-mail: [email protected] for more papers by this author First published: 27 August 2015 https://doi.org/10.1002/humu.22897Citations: 96 Contract grant sponsors: National Institutes of Health (grant GM052347); National Health and Medical Research Council of Australia (grants APP628952, APP1041920, and APP1008077). Communicated by Sergio Ottolenghi. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat 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 tRNAPhe, 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 tRNAPhe 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, tRNAPhe from an NSXLID patient with a novel FTSJ1-p.A26P missense allele specifically lacks Gm34, but has normal levels of Cm32 and o2yW37. tRNAPhe 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 tRNAPhe as the critical modification. These results also underscore the widespread conservation of the circuitry for Trm7-dependent anticodon loop modification of eukaryotic tRNAPhe. Citing Literature Supporting Information Filename Description humu22897-sup-0001-SuppMat.pdf733.1 KB Supporting Material Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume36, Issue12December 2015Pages 1176-1187 RelatedInformation