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

Nat Genet. 2007 Sep;39(9):1127-33. doi: 10.1038/ng2100. Epub 2007 Aug 19.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Line, Transformed
  • Codon, Nonsense
  • DNA Mutational Analysis
  • Family Health
  • Female
  • Gene Expression Profiling
  • Humans
  • Immunoblotting
  • Male
  • Mental Retardation, X-Linked / genetics*
  • Mental Retardation, X-Linked / pathology
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • RNA Stability
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Homology, Amino Acid
  • Syndrome


  • Codon, Nonsense
  • RNA, Messenger
  • RNA-Binding Proteins
  • UPF3B protein, human

Associated data

  • RefSeq/NM_023010
  • RefSeq/NM_023011
  • RefSeq/NM_080632
  • RefSeq/NM_080687
  • RefSeq/NP_075386
  • RefSeq/NP_075387
  • RefSeq/NP_542199
  • RefSeq/NP_542418