Today I learned about a concept (new to me) called gain of function mutation. A mutation in Loricin gene (LOR 730insG) leads to a frame-shift and delayed termination, thus elongating the protein by 22 amino acids. And changing the Gly/Lys-rich domain into an Arg/Leu-rich terminal domain. Instead of being incorporated into the cell envelope, the mutant loricin is translocated into the neucleus as the mutant C-terminus acquires a new function of a nuclear targeting sequence.
The authors have named the resulting phenotype as honeycomb palmoplantar keratoderma with ichthyosis with occasional features like pseudoainhums, prominent knuckle pads and collodion baby. This is however different from Vohwinkel syndrome (hearing impairment but no ichthyosis) and Olmsted syndrome (severe mutilation and periorificial keratotic plaques). The chapter on hereditary PPKs is already a nightmare for dermatology post graduates with umpteen syndromes. The recent advances make it no better.
M.M. Gedicke et al. Palmoplantar keratoderma with mutation in loricin. Brit Journal of Dermatol 2006;154:167-171
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