Transgenic mice expressing a mutant keratin 10 gene reveal the likely genetic basis for epidermolytic hyperkeratosis.
Epidermolytic hyperkeratosis (EH; previously called bullous congenital ichthyosiform erythroderma) is an autosomal dominant skin disease of unknown etiology, affecting approximately 1 out of 300,000 people. It is typified by hyperkeratotic scaliness, blistering due to cytolysis within suprabasal epidermal cells, and hyperproliferation in basal cells. Histologically, EH epidermis exhibits a thickened stratum corneum and granular layer, with enlarged and irregular-shaped cells. Ultrastructurally, only suprabasal layers are affected, with three major aberrancies: (i) tonofilament clumping, (ii) nuclei and keratohyalin granules of irregular shape and size, and (iii) cell degeneration. We have discovered that transgenic mice expressing a mutant keratin 10 gene have the EH phenotype, thereby suggesting that a genetic basis for human EH residues in mutations in genes encoding suprabasal keratins K1 and K10. In addition, we show that (i) stimulation of basal cell proliferation can arise from a defect in suprabasal cells, and (ii) distortion of nuclear shape or aberrations in cytokinesis can occur when an intermediate filament network is perturbed.
Fuchs
E
E
Howard Hughes Medical Institute, Department of Molecular Genetics and Cell Biology, University of Chicago, IL 60637.
Esteves
R A
RA
Coulombe
P A
PA
D000818:Animals; D003599:Cytoskeleton / Q000648:ultrastructure; D005799:Genes, Dominant; D015698:Genomic Library; D006801:Humans; D016113:Ichthyosiform Erythroderma, Congenital / Q000235:genetics* / Q000473:pathology; D007633:Keratins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D015183:Restriction Mapping; D012867:Skin / Q000473:pathology* / Q000648:ultrastructure
D007633:Keratins