A mutation in the
glycine-rich cornified envelope
protein loricrin has recently been reported in Vohwinkel's keratoderma (honeycomb keratoderma with
pseudoainhum), in a pedigree amongst whom
ichthyosis was also a feature. We have studied two further families with Vohwinkel's keratoderma for evidence ofloricrin mutations. Our first family (VK1) also had
ichthyosis but not
deafness. In lesional and nonlesional skin, granular and transitional cell layers were increased. In immunoelectron-microscopic studies cornified envelopes were abnormally thin and were labeled densely by anti-
involucrin antibodies, but only sparsely by antiloricrin
antibodies; however, abnormal intranuclear granules seen in granular and cornified layer cells were labeled by
antibodies to both C- and N-terminal
loricrin. Microsatellite markers in VK1 supported linkage to the
loricrin locus in the epidermal differentiation complex at 1q21 (Zmax = 2.48). The
loricrin gene was sequenced, identifying a heterozygous mutation as previously reported: a G insertion producing a frameshift after
codon 231 and an abnormal C-terminal
peptide lacking residues necessary for cross-linking. In our second family (VK2), affected members had sensorineural
deafness but not
ichthyosis. Immunoelectron-microscopic studies showed normal
loricrin distribution, and assuming complete penetrance, linkage to 1q21 was excluded. Vohwinkel's keratoderma is thus clinically and genetically heterogeneous. Only the variant with
ichthyosis appears to be due to
loricrin mutation. As the
arginine-rich domain in C-terminal
loricrin caused by the frameshift contains several potential bipartite
nuclear localization signals, we suggest that the intranuclear accumulation of
loricrin in VK1 is due to these motifs, and may be unique to insertional mutation.