LORICRIN MUTATION IN VOHWINKELS KERATODERMA IS UNIQUE TO THE VARIANT WITH ICHTHYOSIS

A mutation in the glycine-rich cornified envelope protein loricrin has recently been reported in Vohwinkel's keratoderma (honeycomb keratode rma with pseudoainhum), in a pedigree amongst whom ichthyosis was also a feature. We have studied two further families with Vohwinkel's kera toderma for evidence of loricrin mutations. Our first family (VK1) als o had ichthyosis but not deafness. In lesional and nonlesional skin, g ranular 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 a ntiloricrin antibodies; however, abnormal intranuclear granules seen i n granular and cornified layer cells were labeled by antibodies to bot h 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 lacki ng residues necessary for cross-linking. In our second family (VK2), a ffected members had sensorineural deafness but not ichthyosis. Immunoe lectron-microscopic studies showed normal loricrin distribution, and a ssuming complete penetrance, linkage to 1q21 was excluded. Vohwinkel's keratoderma is thus clinically and genetically heterogeneous. Only th e variant with ichthyosis appears to be due to loricrin mutation. As t he arginine-rich domain in C-terminal loricrin caused by the frameshif t contains several potential bipartite nuclear localization signals, w e suggest that the intranuclear accumulation of loricrin in VK1 is due to these motifs, and may be unique to insertional mutation.