PATHOGENETIC MECHANISMS UNDERLYING THE AEC SYNDROME: GENERATION OF MOUSE MODELS AND CHARACTERIZATION OF TARGET GENES

Ankyloblepharon-Ectodermal Defect-Cleft Lip and/or Palate (AEC) is a rare genetic disorder that belongs to a larger, heterogeneous group of inherited disorders called Ectodermal Dysplasias (ED). AEC, also known as Hay-Wells syndrome, after the physicians who first described the syndrome in 1976, causes a severe involvement of the skin including severe skin erosion at birth, alopecia, scalp infection, dystrophic nails and irregular teeth. The AEC syndrome is inherited as an autosomal dominant trait, meaning that both males and females may be affected and that either is expected to pass the trait to half of his or her children. Recent discoveries have linked AEC and a closely related ED, Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome (EEC), to mutations in the p63 gene. In parallel it has been shown in animal models that the p63 gene is essential for skin development. Although AEC syndrome causes severe skin abnormalities, little is known about the molecular defects underlying the AEC syndrome due to the complexity of p63 functions and to the early onset of the disorder. Our project will aim at understanding the molecular mechanisms that are controlled by p63 in healthy individuals and in AEC patients, by directly identifying the biological processes in which p63 is involved. In addition we will take advantage of recent developments in the field of gene-engineered mice technology, to generate a mouse model that faithfully recapitulate the human disorder. We anticipate that development and characterization of this unique animal model for the AEC syndrome will shed light on the pathogenesis of the AEC syndrome, and will ultimately lead to testing and developing novel therapeutic approaches.