Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation.
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.
Tarpey
Patrick S
PS
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
Raymond
F Lucy
FL
Nguyen
Lam S
LS
Rodriguez
Jayson
J
Hackett
Anna
A
Vandeleur
Lucianne
L
Smith
Raffaella
R
Shoubridge
Cheryl
C
Edkins
Sarah
S
Stevens
Claire
C
O'Meara
Sarah
S
Tofts
Calli
C
Barthorpe
Syd
S
Buck
Gemma
G
Cole
Jennifer
J
Halliday
Kelly
K
Hills
Katy
K
Jones
David
D
Mironenko
Tatiana
T
Perry
Janet
J
Varian
Jennifer
J
West
Sofie
S
Widaa
Sara
S
Teague
John
J
Dicks
Ed
E
Butler
Adam
A
Menzies
Andrew
A
Richardson
David
D
Jenkinson
Andrew
A
Shepherd
Rebecca
R
Raine
Keiran
K
Moon
Jenny
J
Luo
Yin
Y
Parnau
Josep
J
Bhat
Shambhu S
SS
Gardner
Alison
A
Corbett
Mark
M
Brooks
Doug
D
Thomas
Paul
P
Parkinson-Lawrence
Emma
E
Porteous
Mary E
ME
Warner
John P
JP
Sanderson
Tracy
T
Pearson
Pauline
P
Simensen
Richard J
RJ
Skinner
Cindy
C
Hoganson
George
G
Superneau
Duane
D
Wooster
Richard
R
Bobrow
Martin
M
Turner
Gillian
G
Stevenson
Roger E
RE
Schwartz
Charles E
CE
Futreal
P Andrew
PA
Srivastava
Anand K
AK
Stratton
Michael R
MR
Gécz
Jozef
J
D000595:Amino Acid Sequence; D002461:Cell Line, Transformed; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D015151:Immunoblotting; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D013577:Syndrome
D018389:Codon, Nonsense; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C435488:UPF3B protein, human
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