Complete cytolysis and neonatal lethality in keratin 5 knockout mice reveal its fundamental role in skin integrity and in epidermolysis bullosa simplex

In human patients, a wide range of mutations in keratin (K) 5 or K14 lead t o the blistering skin disorder epidermolysis bullosa simplex. Given that K1 4 deficiency does not lead to the ablation of a basal cell cytoskeleton bec ause of a compensatory role of K15, we have investigated the requirement fo r the keratin cytoskeleton in basal cells by inactivating the K5 gene in mi ce. We report that the K5(-/-) mice die shortly after birth, lack keratin f ilaments in the basal epidermis, and are more severely affected than K14(-/ -) mice. In contrast to the K14(-/-) mice, we detected a strong induction o f the wound-healing keratin K6 in the suprabasal epidermis of cytolyzed are as of postnatal K5(-/-) mice. In addition, K5 and K14 mice differed with re spect to tongue lesions. Moreover, we show that in the absence of K5 and ot her type II keratins, residual K14 and K15 aggregated along hemidesmosomes, demonstrating that individual keratins without a partner are stable in viv o. Our data indicate that K5 may be the natural partner of K15 and K17. We suggest that K5 null mutations may be lethal in human epidermolysis bullosa simplex patients.