Two groups have produced a transgenic mice without a functional p63 gene (Mills et al, 1999, Yang et al, 1999). These mice die soon after birth and carry developmental defect of formation of stratified epithelium. The skin lacks stratification which presumably causes huge loss of water and death as a result of dehydration (Mills et al, 1999). Failure of formation of apical ectodermal ridge apparently leads to truncation of forelimbs and lack of hindlimbs (Mills et al, 1999). The knockout mice also lack all teeth, hair, and mammary, salivary and lacrymal glands, and also the stratified squamous epithelium elsewhere is abnormal (Mills et al, 1999, Yang et al, 1999).
The failure of development of several organs is reflected in the perturbation of the epithelial-mesenchymal signaling. In p63 knockouts, Fgf8 expression in apical ectodermal ridge is strongly decreased, and accordingly, the expression of transcription factor Msx1 in the underlying mesenchyme is not seen (Mills et al, 1999). In skin, the expression of Lef1, a transcription factor is not seen in the ectoderm overlying hair follicles and mammary buds (Mills et al, 1999). The analysis of skin differentiation markers was contradictory in the two reports.Mills et al, 1999 reported that in the p63 deficient mice the skin epithelium didn't express any differentiation markers studied, while Yang et al, 1999 found the presence of the differentiation markers but not the markers of the basal layer.
Mutations in p63 (3q27) has been found in EEC syndrome type 3. The characteristics of EEC syndrome are ectrodactyly of the hands and feet, ectodermal dysplasia, and cleft lip and/or palate (Gorlin et al, 1990). Features of ectodermal dysplasia in 77% of the patients include sparse hair, dystrophic nails, hypopigmentation or pigmented nevi of the skin, and abnormal dentition (Roelfsema et al, 1996). Congenitally missing permanent teeth and conical teeth are common. Missing of maxillary first primary molars has been reported (Gorlin et al, 1990). Cleft lip and/or palate is seen in 68% of the patients (Roelfsema et al, 1996). Buss (Buss et al, 1995) reported dental features of 24 patients with EEC syndrome: The permanent dentitions of all patients were affected with oligodontia and microdontia. The teeth were not as strongly conical as in cases of X-linked EDA, being more often straight-edged with gaps; taurodontism was also common. The number of teeth was normal in the primary dentitions, but with abnormal morphology of the tooth crowns.
Microcephaly and mental retardation have been reported in about 10% of the patients (Gorlin et al, 1990). In addition, anomalies of the lacrimal ducts, urogenital defects, and conductive hearing loss have been reported (Roelfsema et al, 1996).
Autosomal dominant transmission with reduced penetrance and variable expression is shown in EEC, with proven genetic heterogeneity. EEC1 syndrome is associated with chromosome 7 (7q11.2-q21.3) (Qumsiyeh, 1992). Linkage of EEC2 to a locus on the chromosome 19 pericentromeric region has been reported in a Dutch kindred (O'Quinn et al, 1998).
EEC3 is allelic to two other EEC-like disorders, limb-mammary syndrome and ADULT syndrome (acro-dermato-ungual-lacrimal-tooth syndrome) (Propping et al, 2000).
Parts of text adapted from Sirpa Arte: Phenotypic and genotypic features of familial hypodontia. Dissertation, Institute of Dentistry, University of Helsinki, Finland, 2001.
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