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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.

Original publication

DOI

10.1086/513609

Type

Journal

American journal of human genetics

Publication Date

05/2007

Volume

80

Pages

982 - 987

Addresses

Cambridge Institute of Medical Research, University of Cambridge, Cambridge, CB2 2XY, UK. flr24@cam.ac.uk.

Keywords

Humans, Marfan Syndrome, Mental Retardation, X-Linked, ras Proteins, Acyltransferases, DNA, Pedigree, Amino Acid Sequence, Base Sequence, Sequence Homology, Amino Acid, Phenotype, Mutation, Molecular Sequence Data, Female, Male