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Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations

Nature Genetics volume 36, pages 361–369 (2004)Cite this article

Abstract

The molecular mechanisms by which different mutations in the same gene can result in distinct disease phenotypes remain largely unknown. Truncating mutations of SOX10 cause either a complex neurocristopathy designated PCWH or a more restricted phenotype known as Waardenburg-Shah syndrome (WS4; OMIM 277580). Here we report that although all nonsense and frameshift mutations that cause premature termination of translation generate truncated SOX10 proteins with potent dominant-negative activity, the more severe disease phenotype, PCWH, is realized only when the mutant mRNAs escape the nonsense-mediated decay (NMD) pathway. We observe similar results for truncating mutations of MPZ that convey distinct myelinopathies. Our experiments show that triggering NMD and escaping NMD may cause distinct neurological phenotypes.

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Figure 1: Brain MRI, SOX10 mutations in families with PCWH, distribution of SOX10 mutations and genotype-phenotype correlation.
Figure 2: Transcription assays of SOX10 mutant proteins.
Figure 3: DNA-binding studies of SOX10 mutant proteins.
Figure 4: Nonsense-mediated decay assays of SOX10.
Figure 5: Genotype-phenotype correlation and NMD assays of MPZ.

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Acknowledgements

We thank the affected individuals and their families for their cooperation; M. Quanrud for collecting blood samples from family members; T. Shimotake and Y. Tsuchida for providing clinical information; R. Peirano and E. Sock for advice and assistance; and A. Beaudet, H. Bellen, K. Szigeti and H. Zoghbi for critical reviews. This study was supported in part by grants from the US National Institute for Neurological Disorders and Strokes, the US National Institutes of Health and the Muscular Dystrophy Association to J.R.L. K.I. was a fellow of the Charcot-Marie-Tooth Association when this study was initiated and is currently supported by a development grant from the Muscular Dystrophy Association.

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Author notes

  1. Ken Inoue

    Present address: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan

  2. Ken Inoue and Mehrdad Khajavi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Room 604B, Houston, 77030, Texas, USA

    Ken Inoue, Mehrdad Khajavi, Tomoko Ohyama & James R Lupski

  2. Division of Pediatric Neurology, Nagano Children's Hospital, Nagano, Japan

    Shin-ichi Hirabayashi

  3. Department of Neurology, Great Ormond Street Children's Hospital, London, UK

    John Wilson

  4. Meritcare Neuroscience Clinic, Fargo, North Dakota, USA

    James D Reggin

  5. Department of Neurology, The University of Texas Medical School at Houston, Houston, Texas, USA

    Pedro Mancias & Ian J Butler

  6. Department of Immunology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

    Miles F Wilkinson

  7. Institut für Biochemie, Universität Erlangen-Nürnberg, Erlangen, Germany

    Michael Wegner

  8. Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA

    James R Lupski

  9. Texas Children's Hospital, Houston, Texas, USA

    James R Lupski

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Correspondence to James R Lupski.

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Inoue, K., Khajavi, M., Ohyama, T. et al. Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nat Genet 36, 361–369 (2004). https://doi.org/10.1038/ng1322

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