Cc. Chipev et al., PREFERENTIAL SITES IN KERATIN-10 THAT ARE MUTATED IN EPIDERMOLYTIC HYPERKERATOSIS, American journal of human genetics, 54(2), 1994, pp. 179-190
Epidermolytic hyperkeratosis (EH) is a rare autosomal dominant skin di
sease. Recent studies in our laboratory established genetic linkage to
the type II keratin gene locus on chromosome 12q in one family with E
H and identified a single amino acid mutation in keratin 1 that is res
ponsible for the disease. Other point mutations in the keratin 1 or ke
ratin 10 genes have now been reported in other patients with EH. We ha
ve examined a series of probands with EH in order to develop a catalog
of mutations in keratin 10. Using direct sequencing of PCR-amplified
genomic DNA, we have identified mutations in six families, in which fi
ve mutations occur in the beginning of the 1A rod domain of keratin 10
-namely, two Arg10 to His, one Arg10 to Cys, an Asn8 to His, and a Tyr
14 to Asp. This region contains highly conserved residues among all ke
ratins. An additional mutation (Leu103 to Gln) was found in the conser
ved region late in the 2B rod domain in keratin 10. We developed sever
al allele-specific assays to assess the frequency of these mutations i
n the general population. No evidence was found for the presence of su
ch changes in unaffected individuals. In vitro functional assays perfo
rmed with peptides corresponding to the 1A mutations in these families
show severely diminished capacity to disaggregate preformed keratin i
ntermediate filaments, in comparison with a wild-type control peptide.
Results from this work support the hypothesis that the beginning of t
he 1A rod domain segment in keratin 10 contains preferential sites for
disease-causing mutation in EH. This should be of considerable use wh
en developing prenatal diagnostic tests and biologically based therapi
es for this disease.