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

Vernersson Lindahl, E., Garcia, E. L., Mills, A. A. (June 2013) An allelic series of Trp63 mutations defines TAp63 as a modifier of EEC syndrome. American Journal of Medical Genetics Part A, 161 (8). pp. 1961-1971. ISSN 1552-4825

URL: http://www.ncbi.nlm.nih.gov/pubmed/23775923
DOI: 10.1002/ajmg.a.36074

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. (c) 2013 Wiley Periodicals, Inc.

Item Type: Paper
Subjects: diseases & disorders > congenital hereditary genetic diseases
diseases & disorders > congenital hereditary genetic diseases > EEC syndrome
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types
organism description > model organism
organism description > animal > mammal > rodent > mouse
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > TAp63
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > TP63
CSHL Authors:
Communities: CSHL labs > Mills lab
CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > Gene Targeting Service
CSHL Cancer Center Shared Resources > Microscopy Service
Depositing User: Matt Covey
Date: 14 June 2013
Date Deposited: 27 Jun 2013 20:23
Last Modified: 02 Feb 2017 16:22
PMCID: PMC4066377
Related URLs:
URI: http://repository.cshl.edu/id/eprint/28389

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