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Article
Nature Genetics  36, 361 - 369 (2004)
Published online: 7 March 2004; | doi:10.1038/ng1322

Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations

Ken Inoue1, 10, 11, Mehrdad Khajavi1, 11, Tomoko Ohyama1, Shin-ichi Hirabayashi2, John Wilson3, James D Reggin4, Pedro Mancias5, Ian J Butler5, Miles F Wilkinson6, Michael Wegner7 & James R Lupski1, 8, 9

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

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

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

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

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

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

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

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

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

10  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.

11  These authors contributed equally to this work.

Correspondence should be addressed to James R Lupski jlupski@bcm.tmc.edu
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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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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