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Mutations in ZDHHC9, which encodes a palmitoyltransferase of NRAS and HRAS, cause X-linked mental retardation associated with a Marfanoid habitus |
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| Authors: | Raymond F Lucy Tarpey Patrick S Edkins Sarah Tofts Calli O'Meara Sarah Teague Jon Butler Adam Stevens Claire Barthorpe Syd Buck Gemma Cole Jennifer Dicks Ed Gray Kristian Halliday Kelly Hills Katy Hinton Jonathon Jones David Menzies Andrew Perry Janet Raine Keiran Shepherd Rebecca Small Alexandra Varian Jennifer Widaa Sara Mallya Uma Moon Jenny Luo Ying Shaw Marie Boyle Jackie Kerr Bronwyn Turner Gillian Quarrell Oliver Cole Trevor Easton Douglas F Wooster Richard Bobrow Martin Schwartz Charles E Gecz Jozef Stratton Michael R Futreal P Andrew |
| Affiliation: | a Cambridge Institute of Medical Research, University of Cambridge b Genetic Epidemiology Unit, Cancer Research UK Cambridge, United Kingdom c Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom d Regional Genetics Service, St Mary’s Hospital, Manchester, United Kingdom e Genetics of Learning Disability (GOLD) f Service, University of Newcastle, Newcastle, Australia g Clinical Genetics, Sheffield Children’s Hospital, Sheffield, United Kingdom h Clinical Genetics, Birmingham Women’s Hospital, Birmingham, United Kingdom i JC Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC j and Department of Genetic Medicine, Women’s and Children’s Hospital, and Departments of Paediatrics and Molecular Biosciences, University of Adelaide Adelaide, Australia |
| Abstract: | We have identified one frameshift mutation, one splice-site mutation, and two missense mutations in highly conserved residues in ZDHHC9 at Xq26.1 in 4 of 250 families with X-linked mental retardation (XLMR). In three of the families, the mental retardation phenotype is associated with a Marfanoid habitus, although none of the affected individuals meets the Ghent criteria for Marfan syndrome. ZDHHC9 is a palmitoyltransferase that catalyzes the posttranslational modification of NRAS and HRAS. The degree of palmitoylation determines the temporal and spatial location of these proteins in the plasma membrane and Golgi complex. The finding of mutations in ZDHHC9 suggests that alterations in the concentrations and cellular distribution of target proteins are sufficient to cause disease. This is the first XLMR gene to be reported that encodes a posttranslational modification enzyme, palmitoyltransferase. Furthermore, now that the first palmitoyltransferase that causes mental retardation has been identified, defects in other palmitoylation transferases become good candidates for causing other mental retardation syndromes. |
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