Jm. Yang et al., MUTATIONS IN THE H1 AND 1A DOMAINS IN THE KERATIN-1 GENE IN EPIDERMOLYTIC HYPERKERATOSIS, Journal of investigative dermatology, 102(1), 1994, pp. 17-23
In the autosomal dominant disorder epidermolytic hyperkeratosis, the s
tructural integrity of the keratin intermediate filaments is altered i
n the suprabasal layers of the epidermis. We and others have used gene
tic linkage studies and mutation analysis to establish that single ami
no acid substitutions in either the keratin 1 or keratin 10 chains can
cause epidermolytic hyperkeratosis. However, a larger database of mut
ations is required to better understand the relationship between speci
fic mutations in these keratin chains and their effect on keratin fila
ment structure. A larger database will also provide a catalog that may
be useful for genetic counseling purposes. In this paper, we report t
he identification of three new mutations of the keratin 1 chain of epi
dermolytic hyperkeratosis probands in highly conserved residues in the
H1 or beginning of the 1A rod domain segments. These correspond to re
gions involved in molecular overlaps between neighboring molecules in
keratin filaments. Using an in vitro assay, synthetic peptides bearing
these substitutions show diminished capacity to disassemble preformed
filaments in vitro in comparison to the wild type peptides. Moreover,
analyses of all mutations in epidermolytic hyperkeratosis known to da
te demonstrate remarkable clustering in the molecular overlap region.
We conclude that non-conservative substitutions in the overlap region
are likely to interfere with normal keratin filament structure and fun
ction, leading to pathology.