Allelic variations of human keratins K4 and K5 provide polymorphic markers within the type II keratin gene cluster on chromosome 12.

To appreciate point mutations in keratin genes as causes for hereditary epithelial diseases, the normal variation of these gene sequences in the population must be known. Because genetic polymorphism of keratins at the protein level due to allelic variation has been described for the type II keratins 4 and 5, we have analyzed their corresponding genes using single-strand conformation polymorphism gel electrophoresis and sequence analysis of polymerase chain reaction amplified genomic DNA. Although no sequence variations were found in the carboxyl-terminal and rod domains we were able to map the molecular differences among the alleles to their amino-terminal domains. In particular, we have identified three alleles of keratin 4. Two alleles differed by a nucleotide transition causing a neutral amino acid substitution (alanine to valine) and one allele had a 42-bp in-frame deletion corresponding to 14 amino acids within the V1 subdomain. Three alleles were also recognized for the keratin 5 locus, all being elicited by single nucleotide substitutions. Of these, only one altered the amino acid sequence, replacing an uncharged (glycine) with a charged (glutamic acid) amino acid in the H1 subdomain. Pedigree analyses in three families showed the alleles to be inherited as autosomal Mendelian traits. Thus, these normal alleles of keratins 4 and 5 will provide favorable polymorphic markers for linkage analysis directly within the cluster of type II keratin genes located on chromosome 12q to elucidate the potential involvement of these and other keratin genes in disorders of squamous cell differentiation.