P. Galligan et al., A NOVEL MUTATION IN THE L12 DOMAIN OF KERATIN-5 IN THE KOBNER VARIANTOF EPIDERMOLYSIS-BULLOSA SIMPLEX, Journal of investigative dermatology, 111(3), 1998, pp. 524-527
We have identified a novel mutation within the linker L12 region of ke
ratin 5 (K5) in a family with the Kobner variant of epidermolysis bull
osa simplex. The pattern of inheritance of the disorder in this family
is consistent with an autosomal dominant mode of transmission. Affect
ed individuals develop extensive and generalized blistering at birth o
r early infancy but in later years clinical manifestations are largely
confined to palmo-plantar surfaces. Direct sequencing of polymerase c
hain reaction products revealed a T to C transition within codon 323 o
f K5 in affected individuals, resulting in a valine to alanine substit
ution of the seventh residue within the L12 linker domain. This mutati
on was not observed in unaffected family members or in 100 K5 alleles
of unrelated individuals with normal skin. The other critical regions
of K5 and K14 were unremarkable in this family except for common polym
orphisms that have been previously described. The valine at position 7
of the L12 domain is absolutely conserved in all type II keratins, an
d in other intermediate filament subunits as well, which suggests that
this residue makes an important contribution to filament integrity. S
econdary structure analysis revealed that alanine at this position mar
kedly reduces both the hydrophobicity and the beta-sheet nature of the
L12 domain. This is the first report of a mutation at this position i
n an intermediate filament subunit and reinforces the importance of th
is region to filament biology.