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

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.

SUBMITTER: Vernersson Lindahl E

PROVIDER: S-EPMC4066377 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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

Vernersson Lindahl Emma E Garcia Elvin L EL Mills Alea A AA

American journal of medical genetics. Part A 20130614 8

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 f ...[more]

PMID: 23775923

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