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C.E. Willoughby, I. Chen, I. Ellis, J.A. McGrath, S. Kaye; Mutations in p63 Gene in Ectrodactyly–ectodermal Dysplasia–clefting (EEC) Syndrome and Their Relevance to the Ocular Phenotype . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1833.
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Purpose: To determine the mutational spectrum of p63 and define its role in the pathogenesis of the ocular phenotype in EEC syndrome (MIM#604292). Methods: Patients with EEC syndrome from across the UK were recruited for a general and ocular examination and p63 mutational analysis. p63 expression was analysed by immunohistochemistry in normal murine (129/Sv) skin and ocular tissue. Results: 12 families with EEC syndrome were recruited and screened for mutations in the DNA binding domain (DBD) of p63. Sequence changes were detected in 11/12 families tested and consisted of 8 heterozygous missense mutations in p63 causing EEC syndrome (R304Q, R279H, R279S, R311G, S272N, R280C, and H208R). 4 mutations were previously reported in p63 and 4 were novel, previously unreported mutations (H208R, H208Y, R279S and R311G). All patients had ocular involvement and the major cause of visual morbidity was limbal stem cell failure which resulted in recurrent corneal ulceration, neovascularisation and /or scarring. p63 staining was identified in the putative stem cells of the skin, hair follicle, corneal limbal epithelium of normal 129/Sv mice. p63 positive cells were also detected in the murine conjunctival fornix and muco–cutaneous junction and so this represents the first immunohistochemical localisation of putative stem cells in these areas. Conclusions: All mutations detected affected specific amino acids in the DNA binding domain of the p63 and resulted in EEC phenotype. The ocular phenotype in EEC syndrome results from defective epithelial–mesenchymal interactions during development and failure to maintain ectodermal homeostasis due to defective stem cell regulation resulting from p63 mutations.
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