• intermediate filaments
• keratin
• liver disorders
• mutation
• polymorphism

Keratins (K) 8 and 18 are the first intermediate filament proteins present in the early embryo, and form the backbone of the intermediate filament cytoskeleton in all simple internal epithelia. Mice with a combined deficiency in K8/K19 and K18/K19 suffer from midgestational lethality with full penetrance, which strongly supports an essential keratin function in extraembryonic epithelia. Moreover, mutations in K8 and K18 have been reported to present risk factors in liver disease of multiple aetiologies. This mutation analysis of the complete K8 and K18 genes, using DHPLC technology, involved screening blood samples from 256 patients diagnosed positive for various liver disorders, and from 100 individuals serving as controls. None of the previously reported mutations in K8 and K18 was found in any of the samples, nor was a positive correlation observed between K8 and K18 mutations to cryptogenic cirrhosis or to chronic liver disease of other origin. However, a novel polymorphism was detected in exon 4 of the K8 gene, leaving L227 unaltered, in both patient and control samples.

Type I and type II keratins belong to the large gene family coding for intermediate filament proteins. Among the 27 type I and 27 type II keratins known to exist in the human genome, type I K18 and type II K8 form copolymers and are coexpressed in all embryonic and internal epithelia.¹ DNA linkage analysis and transgenic animal experiments have established that dominant acting point mutations in epidermal keratin genes lead to a large number of skin fragility syndromes, including epidermolysis bullosa simplex. The majority of these mutations are highly conserved with regard to their position.² The molecular mechanism leading to cell fragility is not well understood, but it is clear that an intact cytoskeleton is required for epithelial homeostasis. A more detailed biochemical analysis has demonstrated a strong …