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Title: Personalized Stem Cell Therapy to Correct Corneal Defects Due to a Unique Homozygous-Heterozygous Mosaicism of Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome
Authors: Barbaro, Vanessa
Nasti, Annamaria Assunta 
Raffa, Paolo
Migliorati, Angelo 
Nespeca, Patrizia 
Ferrari, Stefano
Palumbo, Elisa 
Bertolin, Marina
Breda, Claudia
Miceli, Francesco
Russo, Antonella 
Caenazzo, Luciana 
Ponzin, Diego 
Palù, Giorgio 
Parolin, Cristina 
Di Iorio, Enzo 
Keywords: Cell therapy;Ectrodactyly-ectodermal dysplasia-clefting syndrome;Gene conversion;Mosaicism;p63
Mesh headings: Cleft Lip;Cleft Palate;Corneal Diseases;Corneal Transplantation;Ectodermal Dysplasia;Heterozygote;Homozygote;Mosaicism;Mouth Mucosa;Precision Medicine;Stem Cell Transplantation;Transcription Factors;Tumor Suppressor Proteins
Secondary Mesh headings: 3T3 Cells;Adolescent;Animals;Case-Control Studies;Coculture Techniques;DNA Mutational Analysis;Feeder Cells;Female;Genetic Predisposition to Disease;HEK293 Cells;Humans;Mice;Mutation, Missense;Patient Selection;Phenotype;Predictive Value of Tests;Transfection;Transplantation, Autologous
Issue Date: Aug-2016
Publisher: WILEY
Journal: Stem cells translational medicine 
: Ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome is a rare autosomal dominant disease caused by mutations in the p63 gene. To date, approximately 40 different p63 mutations have been identified, all heterozygous. No definitive treatments are available to counteract and resolve the progressive corneal degeneration due to a premature aging of limbal epithelial stem cells. Here, we describe a unique case of a young female patient, aged 18 years, with EEC and corneal dysfunction, who was, surprisingly, homozygous for a novel and de novo R311K missense mutation in the p63 gene. A detailed analysis of the degree of somatic mosaicism in leukocytes from peripheral blood and oral mucosal epithelial stem cells (OMESCs) from biopsies of buccal mucosa showed that approximately 80% were homozygous mutant cells and 20% were heterozygous. Cytogenetic and molecular analyses excluded genomic alterations, thus suggesting a de novo mutation followed by an allelic gene conversion of the wild-type allele by de novo mutant allele as a possible mechanism to explain the homozygous condition. R311K-p63 OMESCs were expanded in vitro and heterozygous holoclones selected following clonal analysis. These R311K-p63 OMESCs were able to generate well-organized and stratified epithelia in vitro, resembling the features of healthy tissues. This study supports the rationale for the development of cultured autologous oral mucosal epithelial stem cell sheets obtained by selected heterozygous R311K-p63 stem cells, as an effective and personalized therapy for reconstructing the ocular surface of this unique case of EEC syndrome, thus bypassing gene therapy approaches.
ISSN: 2157-6564
DOI: 10.5966/sctm.2015-0358
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