A mouse model of Waardenburg syndrome type IV resulting from an ENU-induced mutation in endothelin 3

Authors

  • Ivana Matera,

    1. Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20855, USA
    2. Laboratorio di Genetica Molecolare, Instituto G. Gaslini, Genova, Italy
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  • Jody L. Cockroft,

    1. University of Tennessee Research Center of Excellence in Genomics and Bioinformatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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  • Jennifer L. Moran,

    1. Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
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  • David R. Beier,

    1. Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
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  • Dan Goldowitz,

    1. University of Tennessee Research Center of Excellence in Genomics and Bioinformatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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  • William J. Pavan

    1. Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20855, USA
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*Address correspondence to Dr William J. Pavan,
e-mail: bpavan@mail.nih.gov

Summary

A line of mutant mice (114-CH19) exhibiting white spotting and preweaning lethality was identified during an N-ethyl-N-nitrosourea (ENU) mutagenesis screen. The trait segregated as a semidominant bellyspot with reduced penetrance. Homozygous mutant mice showed preweaning lethality, and exhibited white spotting over the majority of the body surface, with pigmented patches remaining around the pinnae, eyes and tail. Linkage analysis localized 114-CH19 on mouse chromosome 2, suggesting endothelin 3 (Edn3) as a candidate gene. Sequence analysis of Edn3 identified a G > A transversion that encodes an arginine to histidine substitution (R96H). This mutation is predicted to disrupt furin-mediated proteolytic cleavage of pro-endothelin that is necessary to form biologically active EDN3. This mutation is novel among human and mouse EDN3 mutants, is the first reported EDN3 ENU mutant, and is the second reported EDN3 point mutation. This study demonstrates the power of using ENU mutagenesis screens to generate new animal models of human disease, and expands the spectrum of EDN3 mutant alleles.

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