Letter abstract
Nature Genetics 39, 1127 - 1133 (2007)
Published online: 19 August 2007 | doi:10.1038/ng2100
Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation
Patrick S Tarpey1,14, F Lucy Raymond2,14, Lam S Nguyen3,14, Jayson Rodriguez4,14, Anna Hackett5, Lucianne Vandeleur3, Raffaella Smith1, Cheryl Shoubridge3, Sarah Edkins1, Claire Stevens1, Sarah O'Meara1, Calli Tofts1, Syd Barthorpe1, Gemma Buck1, Jennifer Cole1, Kelly Halliday1, Katy Hills1, David Jones1, Tatiana Mironenko1, Janet Perry1, Jennifer Varian1, Sofie West1, Sara Widaa1, John Teague1, Ed Dicks1, Adam Butler1, Andrew Menzies1, David Richardson1, Andrew Jenkinson1, Rebecca Shepherd1, Keiran Raine1, Jenny Moon2, Yin Luo2, Josep Parnau2, Shambhu S Bhat4,13, Alison Gardner3, Mark Corbett3, Doug Brooks3,6, Paul Thomas7, Emma Parkinson-Lawrence3, Mary E Porteous8, John P Warner8, Tracy Sanderson8, Pauline Pearson8, Richard J Simensen4, Cindy Skinner4, George Hoganson9, Duane Superneau10, Richard Wooster1, Martin Bobrow2, Gillian Turner5, Roger E Stevenson4, Charles E Schwartz4, P Andrew Futreal1, Anand K Srivastava4, Michael R Stratton1,11 & Jozef Gécz3,7,12
Nonsense-mediated mRNA decay (NMD) is of universal biological significance1, 2, 3. It has emerged as an important global RNA, DNA and translation regulatory pathway4. By systematically sequencing 737 genes (annotated in the Vertebrate Genome Annotation database) on the human X chromosome in 250 families with X-linked mental retardation, we identified mutations in the UPF3 regulator of nonsense transcripts homolog B (yeast) (UPF3B) leading to protein truncations in three families: two with the Lujan-Fryns phenotype5, 6 and one with the FG phenotype7. We also identified a missense mutation in another family with nonsyndromic mental retardation. Three mutations lead to the introduction of a premature termination codon and subsequent NMD of mutant UPF3B mRNA. Protein blot analysis using lymphoblastoid cell lines from affected individuals showed an absence of the UPF3B protein in two families. The UPF3B protein is an important component of the NMD surveillance machinery8, 9. Our results directly implicate abnormalities of NMD in human disease and suggest at least partial redundancy of NMD pathways.
- Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
- Cambridge Institute of Medical Research, Cambridge CB2 2XY, UK.
- Department of Genetic Medicine, Women's and Children's Hospital, North Adelaide, South Australia 5006, Australia.
- JC Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina 29646, USA.
- GOLD Service, Hunter Genetics, Waratah, New South Wales 2298, Australia.
- Sansom Institute, University of South Australia, Adelaide, South Australia 5001, Australia.
- School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5001, Australia.
- Southeast Scotland Genetic Service, Edinburgh EH4 2XU, Scotland, UK.
- Medical Genetics, Rockford Memorial Hospital, Rockford, Illinois 61103, USA.
- Genetic Services of Louisiana, Baton Rouge, Louisiana 70884, USA.
- Institute of Cancer Research, Surrey SM2 5NG, UK.
- Department of Paediatrics, University of Adelaide, Adelaide, South Australia 5001, Australia.
- Present address: Institute of Genetic Medicine, Johns Hopkins Medical Institute, Baltimore, Maryland, USA.
- These authors contributed equally to this manuscript.
Correspondence to: Jozef Gécz3,7,12 e-mail: jozef.gecz@adelaide.edu.au
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