Dohi memorial lecture. Clinical implications of basic research on heritable skin diseases

Spectacular success has recently been made in understanding the molecular basis of various heritable skin diseases. A prototype of such conditions is epidermolysis bullosa (EB), a heterogenous group of mechano-bullous disorders, characterized by fragility of the skin and other specialized epithelia. The fragility of the skin in EB results from defective attachment of the epidermis to the underlying dermis due to genetic lesions within molecules of the basement membrane zone (BMZ) at the dermal-epidermal junction. Specifically, distinct mutations have been disclosed thus far in ten different genes encoding the macromolecular components of the BMZ, and the combinations and the types of mutations as well as their positions along the altered gene products collectively reflect the phenotypic variability observed in this group of heritable skin diseases. This information has major implications for genetic counseling of families at risk for recurrence of EB in subsequent pregnancies and in future generations. Furthermore, examination of specific mutations in an affected newborn allows prognostication of the severity of the clinical outcome. Finally, mutation analyses have provided the basis to develop DNA-based prenatal testing by chorionic villus sampling or early aminocentesis during the first trimester of gestation. Collectively, the advances on EB exemplify the potential of molecular biology for improved diagnosis and patient care of genetic skin disorders.