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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 |
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| Authors: | Tarpey Patrick S Raymond F Lucy O'Meara Sarah Edkins Sarah Teague Jon Butler Adam Dicks Ed Stevens Claire Tofts Calli Avis Tim Barthorpe Syd Buck Gemma Cole Jennifer Gray Kristian Halliday Kelly Harrison Rachel Hills Katy Jenkinson Andrew Jones David Menzies Andrew Mironenko Tatiana Perry Janet Raine Keiran Richardson David Shepherd Rebecca Small Alexandra Varian Jennifer West Sofie Widaa Sara Mallya Uma Moon Jenny Luo Ying Holder Susan Smithson Sarah F Hurst Jane A Clayton-Smith Jill Kerr Bronwyn Boyle Jackie Shaw Marie Vandeleur Lucianne Rodriguez Jayson Slaugh Rachel Easton Douglas F |
| Institution: | a From the Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom b Cambridge Institute of Medical Research, Adelaide, Australia c and Cancer Research UK Genetic Epidemiology Unit, Adelaide, Australia d Cambridge, United Kingdom; GOLD Service, Hunter Genetics and the University of Newcastle, New South Wales, Australia, Adelaide, Australia e Department of Genetic Medicine, Women’s and Children’s Hospital, Adelaide, Australia f Department of Paediatrics and Molecular Biosciences, University of Adelaide, Adelaide, Australia g Department of JC Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC h Department of Pediatrics, Division of Genetics, Washington University School of Medicine, St. Louis, MO i North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, United Kingdom (S.H) j Clinical Genetics, St. Michael’s Hospital, Bristol, United Kingdom (S.F.S.) k Clinical Genetics, Oxford Radcliffe Hospital, The Churchill, Oxford, United Kingdom (J.A.H.) l and Clinical Genetics, St. Mary’s Hospital, Manchester, United Kingdom (J.C.-S.; B.K.) |
| 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. |
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