1. 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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Janet Perry, Oliver Quarrell, Jennifer Varian, Jennifer Cole, Sarah Edkins, Jenny Moon, Richard Wooster, Bronwyn Kerr, Syd Barthorpe, Douglas F. Easton, F. Lucy Raymond, Jackie Boyle, Calli Tofts, Trevor Cole, Claire Stevens, Kelly Halliday, Gillian Turner, Alexandra Small, Michael R. Stratton, Andrew Menzies, Rebecca Shepherd, Keiran Raine, Sarah O’Meara, Jozef Gecz, Katy Hills, Uma Mallya, Charles E. Schwartz, Martin Bobrow, Jonathon Hinton, Ying Luo, Patrick S. Tarpey, Sara Widaa, Ed Dicks, David T. Jones, P. Andrew Futreal, Gemma Buck, Kristian Gray, Adam Butler, Jon W. Teague, and Marie Shaw
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Neuroblastoma RAS viral oncogene homolog ,Male ,Molecular Sequence Data ,Biology ,medicine.disease_cause ,Frameshift mutation ,Marfan Syndrome ,Palmitoylation ,Report ,medicine ,Genetics ,Missense mutation ,Humans ,Genetics(clinical) ,HRAS ,Amino Acid Sequence ,Genetics (clinical) ,X chromosome ,Mutation ,Base Sequence ,Sequence Homology, Amino Acid ,DNA ,Phenotype ,Pedigree ,Mental Retardation, X-Linked ,ras Proteins ,Female ,Acyltransferases - 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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