Background: Clues from clinicopathologic studies of epidermolysis bullosa simplex (EBS) and epidermolytic hyperkeratosis (EH) have implicated abnormalities in keratin filaments as possibly underlying the pathogenesis of these diseases. Multiple avenues of study have now converged, which confirm this hypothesis.
Observations: The clinical spectrum of EBS and EH is reviewed together with classic histologic, electron microscopic, and immuno-electron microscopic studies. Linkage analyses have shown in EBS and EH that the disease traits are linked to the keratin gene clusters on chromosomes 12 and 17. Transgenic mice bearing mutations or deletions in genes coding for basal cell keratin K14 express the phenotype of EBS, and transgenic mice bearing abnormal K1/K10 genes resemble EH. Increasing numbers of point mutations in the human keratin genes have been found in both sporadic and familial cases of EBS in keratins 5/14 and EH in keratins K1/K10 genes, respectively, particularly in highly conserved subdomains of the keratin proteins.
Conclusions: The recent and rapid progress in understanding the molecular biology of EBS and EH will also enhance knowledge about intermediate filament structure and function. Further studies of the effects of these mutations on the control of keratinocyte growth and differentiation are required. They will lead the way to rational pharmacologic or gene therapy.