THE MOLECULAR-BASIS FOR INHERITED BULLOUS DISEASES

In the past 5 years enormous progress have been made in our understand ing of the molecular basis for a number of inherited skin diseases cha racterized by easy blistering of the skin and the mucous membranes aft er minor physical trauma. This increased fragility of the skin or its appendages is due to molecular defects in genes coding for different i ntra-and extracellular structural proteins which are responsible for m echanical strength at their sites of expression. These diseases encomp ass the group of epidermolysis bullosa and disorders of cornification such as bullous forms of ichthyosis, palmoplantar keratoderma, and pac hyonychia congenita. On the basis of clinical, morphological, and ultr astructural observations the epidermolysis bullosa group has been divi ded into three major categories. In epidermolysis bullosa simplex blis ter formation appears within the basal cell layer of the epidermis, an d many mutations have been found in the genes of keratin 5 and 14 whic h are both expressed in basal keratinocytes. Epidermolytic hyperkerato sis leads to an epidermal separation in the suprabasal cell layers. In these patients numerous point mutations have now been described in th e suprabasally expressed genes of keratin 1 and 10. In ichthyosis bull osa of Siemens blisters occur in the more upper suprabasal epidermis c oincidental with the expression of keratin 2e, and mutations have been detected in the corresponding gene. In epidermolytic palmoplantar hyp erkeratosis the suprabasal epidermal splitting is restricted to palms and soles of the patient. In keratin 9, which reveals such an exclusiv e expression pattern, molecular defects have indeed been recognized. M ost recently in two different clinical subtypes of pachyonychia congen ita, which is characterized by defective nails and focal ge palmoplant ar hyperkeratosis, point mutations have been found in the genes coding for keratins 6, 16, and 17. In junctional epidermolysis bullosa the s eparation takes place within the dermal-epidermal basement membrane at the level of the lamina lucida, and mutations have been found in thre e genes coding for different laminin chains, in the beta(4) gene of al pha(6) beta(4) integrin, and in the gene of collagen XVII. In dystroph ic epidermolysis bullosa the tissue separation occurs beneath the base ment membrane within the papillary dermis at the level of the anchorin g fibrils, and several mutations have been identified in the collagen VII gene. The rapid unraveling of molecular defects in these disabling or even lethal inherited skin diseases makes possible a more precise and earlier prenatal diagnosis, creates new options for suitable thera peutic regimens, and even offers the hope of curing these diseases by means of somatic cell gene therapy.