Recently we generated keratin 10 knockout mice which provided a valuab
le model for the dominantly inherited skin disorder epidermolytic hype
rkeratosis, Here we investigated the molecular basis for their phenoty
pe, Hetero- and homozygotes expressed a truncated keratin 10 peptide w
hich has been identified directly by microsequencing. Epitope mapping
of monoclonal antibodies to keratin 10T enabled us to study its distri
bution relative to keratin 6, which is highly expressed in keratin 10
knockout mice, by double-immunogold electron microscopy. This revealed
that keratin 10T was restricted to complexes with keratin 1 but did n
ot mix with keratin 6. The latter did not form extended filaments with
keratins 16/17 but aggregates, Keratins 6/16 were unable to compensat
e for the lack of normal keratin 1/10 filaments, Remarkably keratin 6
aggregates strictly colocalized with keratohyalin granules. Residual k
eratin 1/10T clumps were located in the cell periphery and at desmosom
es which maintained a normal architecture, Surprisingly keratin 2e, a
keratin tailored to sustain mechanical stress, was completely lost in
paw sole epidermis of homozygous keratin 10 knockout mice, pointing to
keratin 10 as its partner. The selective pairing of keratin 10T and t
he loss of keratin 2e indicate that in vivo keratins are less promiscu
ous than in vitro. Skin fragility in keratin 10 knockout mice and in e
pidermolytic hyperkeratosis is probably the consequence of two complem
enting mechanisms namely a decrease of normal keratin 1/10 filaments a
nd an increase in keratins 6/16 with a poor filament-forming capacity.