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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 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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Figure 1: UPF3B mutations identified in this study.
Figure 2: Schematic of wild–type UPF3B and UPF3B from affected individuals.
Figure 3: Analysis of RNA expression of the UPF3B and other genes in controls and affected individuals.
Figure 4: Protein blot analysis of UPF3B.
Figure 5: Tissue expression profile of human UPF3B and UPF3A mRNA isoforms.
Figure 6: Facial features of the probands from families 1, 2, 3 and 4.

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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).

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Authors and Affiliations



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.

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Correspondence to Jozef Gécz.

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Supplementary Methods, Supplementary Figures 1–2, Supplementary Table 1 (PDF 4443 kb)

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Tarpey, P., Lucy Raymond, F., Nguyen, L. et al. Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation. Nat Genet 39, 1127–1133 (2007).

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