Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation by Tarpey Patrick S, Raymond F Lucy, Nguyen Lam S, Rodriguez Jayson, Hackett Anna, Vandeleur Lucianne, Smith Raffaella, Shoubridge Cheryl, Edkins Sarah, Stevens Claire, O'Meara Sarah, Tofts Calli, Barthorpe Syd, Buck Gemma, Cole Jennifer, Halliday Kelly, Hills Katy, Jones David, Mironenko Tatiana, Perry Janet, Varian Jennifer, West Sofie, Widaa Sara, Teague John, Dicks Ed, Butler Adam, Menzies Andrew, Richardson David, Jenkinson Andrew, Shepherd Rebecca, Raine Keiran, Moon Jenny, Luo Yin, Parnau Josep, Bhat Shambhu S, Gardner Alison, Corbett Mark, Brooks Doug, Thomas Paul, Parkinson-Lawrence Emma, Porteous Mary E, Warner John P, Sanderson Tracy, Pearson Pauline, Simensen Richard J, Skinner Cindy, Hoganson George, Superneau Duane, Wooster Richard, Bobrow Martin, Turner Gillian, Stevenson Roger E, Schwartz Charles E, Futreal P Andrew, Srivastava Anand K, Stratton Michael R, G├ęcz Jozef in Nature genetics (2007).

[PMID: 17704778] PubMed


Nonsense-mediated mRNA decay (NMD) is of universal biological significance. It has emerged as an important global RNA, DNA and translation regulatory pathway. 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 phenotype and one with the FG phenotype. 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 machinery. Our results directly implicate abnormalities of NMD in human disease and suggest at least partial redundancy of NMD pathways.

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