Ym. Chan et al., A HUMAN KERATIN-14 KNOCKOUT - THE ABSENCE OF K14 LEADS TO SEVERE EPIDERMOLYSIS-BULLOSA SIMPLEX AND A FUNCTION FOR AN INTERMEDIATE FILAMENT PROTEIN, Genes & development, 8(21), 1994, pp. 2574-2587
Since their discovery, the function of intermediate filaments (IFs) ha
s remained obscure. In skin, epidermal cells have extensive cytoskelet
al architectures of IFs, composed of type I and type II keratin hetero
dimers. Clues to possible functions of these proteins have come from r
ecent studies showing that several autosomal-dominant, blistering skin
disorders are caused by defects in genes that encode epidermal kerati
ns. These diseases all exhibit cell degeneration and keratin network p
erturbations in cells that express the particular mutant keratin gene.
However, it is not clear from these studies whether cytolysis arises
from the presence of large insoluble keratin aggregates that compromis
e cellular physiology or from the absence of an extensive keratin fila
ment network, which jeopardizes mechanical integrity. We report here t
he analysis of an extremely rare case of severe recessive epidermolysi
s bullosa simplex (EBS), where the patient lacks a discernible keratin
filament network in basal epidermal cells. Genetic analyses revealed
a homozygous point mutation that yielded a premature termination codon
in the major basal type I keratin gene and caused complete ablation o
f K14. The consanguineous parents were normal, each harboring one copy
of the null K14 mutation. Analysis of cultured keratinocytes enabled
us to document that the loss of K14 is not compensated for by the up-r
egulation of any other type I keratin. When taken together with the in
vivo studies showing the presence of cell fragility generated from th
e lack of an extensive basal keratin network, these findings provide t
he first clear demonstration of loss of function associated with the a
bsence of an IF protein in vivo.