Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor.
We have identified three truncating, two splice-site, and three missense variants at conserved amino acids in the CUL4B gene on Xq24 in 8 of 250 families with X-linked mental retardation (XLMR). During affected subjects' adolescence, a syndrome emerged with delayed puberty, hypogonadism, relative macrocephaly, moderate short stature, central obesity, unprovoked aggressive outbursts, fine intention tremor, pes cavus, and abnormalities of the toes. This syndrome was first described by Cazebas et al., in a family that was included in our study and that carried a CUL4B missense variant. CUL4B is a ubiquitin E3 ligase subunit implicated in the regulation of several biological processes, and CUL4B is the first XLMR gene that encodes an E3 ubiquitin ligase. The relatively high frequency of CUL4B mutations in this series indicates that it is one of the most commonly mutated genes underlying XLMR and suggests that its introduction into clinical diagnostics should be a high priority.
Tarpey
Patrick S
PS
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
Raymond
F Lucy
FL
O'Meara
Sarah
S
Edkins
Sarah
S
Teague
Jon
J
Butler
Adam
A
Dicks
Ed
E
Stevens
Claire
C
Tofts
Calli
C
Avis
Tim
T
Barthorpe
Syd
S
Buck
Gemma
G
Cole
Jennifer
J
Gray
Kristian
K
Halliday
Kelly
K
Harrison
Rachel
R
Hills
Katy
K
Jenkinson
Andrew
A
Jones
David
D
Menzies
Andrew
A
Mironenko
Tatiana
T
Perry
Janet
J
Raine
Keiran
K
Richardson
David
D
Shepherd
Rebecca
R
Small
Alexandra
A
Varian
Jennifer
J
West
Sofie
S
Widaa
Sara
S
Mallya
Uma
U
Moon
Jenny
J
Luo
Ying
Y
Holder
Susan
S
Smithson
Sarah F
SF
Hurst
Jane A
JA
Clayton-Smith
Jill
J
Kerr
Bronwyn
B
Boyle
Jackie
J
Shaw
Marie
M
Vandeleur
Lucianne
L
Rodriguez
Jayson
J
Slaugh
Rachel
R
Easton
Douglas F
DF
Wooster
Richard
R
Bobrow
Martin
M
Srivastava
Anand K
AK
Stevenson
Roger E
RE
Schwartz
Charles E
CE
Turner
Gillian
G
Gecz
Jozef
J
Futreal
P Andrew
PA
Stratton
Michael R
MR
Partington
Michael
M
D000015:Abnormalities, Multiple / Q000235:genetics*; D000374:Aggression; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D044842:Cullin Proteins / Q000235:genetics*; D005530:Foot Deformities / Q000235:genetics; D006257:Head / Q000002:abnormalities; D006801:Humans; D007006:Hypogonadism / Q000235:genetics; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D009765:Obesity / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics; D012640:Seizures / Q000235:genetics; D014202:Tremor / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
C517832:CUL4B protein, human; D044842:Cullin Proteins; D021122:Protein Subunits; D044767:Ubiquitin-Protein Ligases