title: 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.
abstract: 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.
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Tarpey
authors.forename: F Lucy
authors.initials: FL
authors.lastname: Raymond
authors.forename: Sarah
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authors.lastname: O'Meara
authors.forename: Sarah
authors.initials: S
authors.lastname: Edkins
authors.forename: Jon
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authors.lastname: Teague
authors.forename: Adam
authors.initials: A
authors.lastname: Butler
authors.forename: Ed
authors.initials: E
authors.lastname: Dicks
authors.forename: Claire
authors.initials: C
authors.lastname: Stevens
authors.forename: Calli
authors.initials: C
authors.lastname: Tofts
authors.forename: Tim
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authors.lastname: Avis
authors.forename: Syd
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authors.lastname: Barthorpe
authors.forename: Gemma
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authors.lastname: Buck
authors.forename: Jennifer
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authors.lastname: Cole
authors.forename: Kristian
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authors.lastname: Gray
authors.forename: Kelly
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authors.lastname: Halliday
authors.forename: Rachel
authors.initials: R
authors.lastname: Harrison
authors.forename: Katy
authors.initials: K
authors.lastname: Hills
authors.forename: Andrew
authors.initials: A
authors.lastname: Jenkinson
authors.forename: David
authors.initials: D
authors.lastname: Jones
authors.forename: Andrew
authors.initials: A
authors.lastname: Menzies
authors.forename: Tatiana
authors.initials: T
authors.lastname: Mironenko
authors.forename: Janet
authors.initials: J
authors.lastname: Perry
authors.forename: Keiran
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authors.lastname: Raine
authors.forename: David
authors.initials: D
authors.lastname: Richardson
authors.forename: Rebecca
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authors.lastname: Shepherd
authors.forename: Alexandra
authors.initials: A
authors.lastname: Small
authors.forename: Jennifer
authors.initials: J
authors.lastname: Varian
authors.forename: Sofie
authors.initials: S
authors.lastname: West
authors.forename: Sara
authors.initials: S
authors.lastname: Widaa
authors.forename: Uma
authors.initials: U
authors.lastname: Mallya
authors.forename: Jenny
authors.initials: J
authors.lastname: Moon
authors.forename: Ying
authors.initials: Y
authors.lastname: Luo
authors.forename: Susan
authors.initials: S
authors.lastname: Holder
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Smithson
authors.forename: Jane A
authors.initials: JA
authors.lastname: Hurst
authors.forename: Jill
authors.initials: J
authors.lastname: Clayton-Smith
authors.forename: Bronwyn
authors.initials: B
authors.lastname: Kerr
authors.forename: Jackie
authors.initials: J
authors.lastname: Boyle
authors.forename: Marie
authors.initials: M
authors.lastname: Shaw
authors.forename: Lucianne
authors.initials: L
authors.lastname: Vandeleur
authors.forename: Jayson
authors.initials: J
authors.lastname: Rodriguez
authors.forename: Rachel
authors.initials: R
authors.lastname: Slaugh
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.forename: Richard
authors.initials: R
authors.lastname: Wooster
authors.forename: Martin
authors.initials: M
authors.lastname: Bobrow
authors.forename: Anand K
authors.initials: AK
authors.lastname: Srivastava
authors.forename: Roger E
authors.initials: RE
authors.lastname: Stevenson
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
authors.forename: Gillian
authors.initials: G
authors.lastname: Turner
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: Michael
authors.initials: M
authors.lastname: Partington
mesh_terms: 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*
chemical_list: C517832:CUL4B protein, human; D044842:Cullin Proteins; D021122:Protein Subunits; D044767:Ubiquitin-Protein Ligases