Mutations in ZDHHC9, which encodes a palmitoyltransferase of NRAS and HRAS, cause X-linked mental retardation associated with a Marfanoid habitus.
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.
Raymond
F Lucy
FL
Cambridge Institute of Medical Research, University of Cambridge, Cambridge, CB2 2XY, UK. flr24@cam.ac.uk.
Tarpey
Patrick S
PS
Edkins
Sarah
S
Tofts
Calli
C
O'Meara
Sarah
S
Teague
Jon
J
Butler
Adam
A
Stevens
Claire
C
Barthorpe
Syd
S
Buck
Gemma
G
Cole
Jennifer
J
Dicks
Ed
E
Gray
Kristian
K
Halliday
Kelly
K
Hills
Katy
K
Hinton
Jonathon
J
Jones
David
D
Menzies
Andrew
A
Perry
Janet
J
Raine
Keiran
K
Shepherd
Rebecca
R
Small
Alexandra
A
Varian
Jennifer
J
Widaa
Sara
S
Mallya
Uma
U
Moon
Jenny
J
Luo
Ying
Y
Shaw
Marie
M
Boyle
Jackie
J
Kerr
Bronwyn
B
Turner
Gillian
G
Quarrell
Oliver
O
Cole
Trevor
T
Easton
Douglas F
DF
Wooster
Richard
R
Bobrow
Martin
M
Schwartz
Charles E
CE
Gecz
Jozef
J
Stratton
Michael R
MR
Futreal
P Andrew
PA
D000217:Acyltransferases / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000150:complications* / Q000201:enzymology / Q000235:genetics*; D038901:X-Linked Intellectual Disability / Q000150:complications* / Q000201:enzymology / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017386:Sequence Homology, Amino Acid; D018631:ras Proteins / Q000378:metabolism
D004247:DNA; D000217:Acyltransferases; C504825:ZDHHC9 protein, human; D018631:ras Proteins