Abstract

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.

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Acknowledgements

We thank the families studied for their participation and K. Dowling of the Faculty of Health Sciences, University of Adelaide for assistance with statistical analysis of the data. This work was supported by grants from the Australian National Health and Medical Research Council project grant 453457, the State of New South Wales (NSW) Health Department through their support of the NSW GOLD Service, a US National Institute of Child Health and Human Development grant (HD26202) to C.E.S., a grant from the South Carolina Department of Disabilities and Special Needs and the Wellcome Trust. Dedicated to the memory of E.F. Schwartz (1996–1998).

Author information

Author notes

    • Shambhu S Bhat

    Present address: Institute of Genetic Medicine, Johns Hopkins Medical Institute, Baltimore, Maryland, USA.

    • Patrick S Tarpey
    • , F Lucy Raymond
    • , Lam S Nguyen
    •  & Jayson Rodriguez

    These authors contributed equally to this manuscript.

Affiliations

  1. Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.

    • Patrick S Tarpey
    • , Raffaella Smith
    • , Sarah Edkins
    • , Claire Stevens
    • , Sarah O'Meara
    • , Calli Tofts
    • , Syd Barthorpe
    • , Gemma Buck
    • , Jennifer Cole
    • , Kelly Halliday
    • , Katy Hills
    • , David Jones
    • , Tatiana Mironenko
    • , Janet Perry
    • , Jennifer Varian
    • , Sofie West
    • , Sara Widaa
    • , John Teague
    • , Ed Dicks
    • , Adam Butler
    • , Andrew Menzies
    • , David Richardson
    • , Andrew Jenkinson
    • , Rebecca Shepherd
    • , Keiran Raine
    • , Richard Wooster
    • , P Andrew Futreal
    •  & Michael R Stratton
  2. Cambridge Institute of Medical Research, Cambridge CB2 2XY, UK.

    • F Lucy Raymond
    • , Jenny Moon
    • , Yin Luo
    • , Josep Parnau
    •  & Martin Bobrow
  3. Department of Genetic Medicine, Women's and Children's Hospital, North Adelaide, South Australia 5006, Australia.

    • Lam S Nguyen
    • , Lucianne Vandeleur
    • , Cheryl Shoubridge
    • , Alison Gardner
    • , Mark Corbett
    • , Doug Brooks
    • , Emma Parkinson-Lawrence
    •  & Jozef Gécz
  4. JC Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina 29646, USA.

    • Jayson Rodriguez
    • , Shambhu S Bhat
    • , Richard J Simensen
    • , Cindy Skinner
    • , Roger E Stevenson
    • , Charles E Schwartz
    •  & Anand K Srivastava
  5. GOLD Service, Hunter Genetics, Waratah, New South Wales 2298, Australia.

    • Anna Hackett
    •  & Gillian Turner
  6. Sansom Institute, University of South Australia, Adelaide, South Australia 5001, Australia.

    • Doug Brooks
  7. School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5001, Australia.

    • Paul Thomas
    •  & Jozef Gécz
  8. Southeast Scotland Genetic Service, Edinburgh EH4 2XU, Scotland, UK.

    • Mary E Porteous
    • , John P Warner
    • , Tracy Sanderson
    •  & Pauline Pearson
  9. Medical Genetics, Rockford Memorial Hospital, Rockford, Illinois 61103, USA.

    • George Hoganson
  10. Genetic Services of Louisiana, Baton Rouge, Louisiana 70884, USA.

    • Duane Superneau
  11. Institute of Cancer Research, Surrey SM2 5NG, UK.

    • Michael R Stratton
  12. Department of Paediatrics, University of Adelaide, Adelaide, South Australia 5001, Australia.

    • Jozef Gécz

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Contributions

P.S.T., F.L.R., L.S.N., J.R. contributed equally to this work. P.S.T. supervised the X chromosome gene content screening; F.L.R. contributed to the design of the experiments and contributed with clinical material; L.S.N. and J.R. carried on molecular studies; J.M., A.H., M.E.P., T.S., P.P., R.J.S., C. Skinner, G.H., D.S., G.T., C.E.S. and R.E.S. were involved in family material and clinical data collection and writing; L.V., C. Shoubridge, Y.L., J. Parnau, S.S.B., A.G., M.C., D.B., E.P.-L. and P.T. contributed with cell and molecular studies, family segregation analyses and antibody production; S.E., C. Stevens, S.O'M., C.T., S.B., G.B., J.C., K. Halliday, K. Hills, D.J., T.M., J. Perry, J.V., S. West, S. Widaa, J.T., E.D., A.B., A.M., D.R., A.J., R. Smith, R. Shepherd and K.R. conducted the screening and data analysis; M.B., R.W., P.A.F, A.K.S., M.R.S. and J.G. designed the experiments and J.G. wrote the manuscript. All authors contributed to the discussion of the results and manuscript writing.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jozef Gécz.

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    Supplementary Methods, Supplementary Figures 1–2, Supplementary Table 1

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DOI

https://doi.org/10.1038/ng2100

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