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An allelic series of Trp63 mutations defines TAp63 as a modifier of EEC syndrome

Authors

  • Emma Vernersson Lindahl,

    1. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
    Current affiliation:
    1. Umeå Center for Molecular Medicin, Umeå University, Umeå, Sweden
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  • Elvin L. Garcia,

    1. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
    2. Graduate Program in Genetics, Stony Brook University, Stony Brook, New York
    Current affiliation:
    1. Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO
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  • Alea A. Mills PhD

    Corresponding author
    • Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
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  • Conflict of interest: none.

Correspondence to:

Alea A. Mills, Ph.D., Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724.

E- mail: mills@cshl.edu

Abstract

Human Ectrodactyly, Ectodermal dysplasia, Clefting (EEC) syndrome is an autosomal dominant developmental disorder defined by limb deformities, skin defects, and craniofacial clefting. Although associated with heterozygous missense mutations in TP63, the genetic basis underlying the variable expressivity and incomplete penetrance of EEC is unknown. Here, we show that mice heterozygous for an allele encoding the Trp63 p.Arg318His mutation, which corresponds to the human TP63 p.Arg279His mutation found in patients with EEC, have features of human EEC. Using an allelic series, we discovered that whereas clefting and skin defects are caused by loss of Trp63 function, limb anomalies are due to gain- and/or dominant-negative effects of Trp63. Furthermore, we identify TAp63 as a strong modifier of EEC-associated phenotypes with regard to both penetrance and expressivity. © 2013 Wiley Periodicals, Inc.

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