Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation

Patrick S. Tarpey, F. Lucy Raymond, Lam S. Nguyen, Jayson Rodriguez, Anna Hackett, Lucianne Vandeleur, Raffaella Smith, Cheryl Shoubridge, Sarah Edkins, Claire Stevens, Sarah O'Meara, Calli Tofts, Syd Barthorpe, Gemma Buck, Jennifer Cole, Kelly Halliday, Katy Hills, David Jones, Tatiana Mironenko, Janet PerryJennifer Varian, Sofie West, Sara Widaa, John Teague, Ed Dicks, Adam Butler, Andrew Menzies, David Richardson, Andrew Jenkinson, Rebecca Shepherd, Keiran Raine, Jenny Moon, Yin Luo, Josep Parnau, Shambhu S. Bhat, Alison Gardner, Mark Corbett, Doug Brooks, Paul Thomas, Emma Parkinson-Lawrence, Mary E. Porteous, John P. Warner, Tracy Sanderson, Pauline Pearson, Richard J. Simensen, Cindy Skinner, George Hoganson, Duane Superneau, Richard Wooster, Martin Bobrow, Gillian Turner, Roger E. Stevenson, Charles E. Schwartz, P. Andrew Futreal, Anand K. Srivastava, Michael R. Stratton, Jozef Gécz

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196 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1127-1133
Number of pages7
JournalNature Genetics
Issue number9
Publication statusPublished or Issued - Sep 2007
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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