Two novel mutations in the LOR gene in three families with loricrin keratoderma

Novel autosomal dominant mutation in loricrin presenting as prominent ichthyosis

“…It is caused by mutations in loricrin, a small basic protein synthesized in the upper granular layer, which becomes a major constituent of the cornified cell envelope . Seven distinct mutations in loricrin have been reported in 15 unrelated pedigrees to date . We report a multi‐generation family with prominent ichthyosis and palmoplantar involvement due to a novel mutation in loricrin.…”

“…Six different heterozygous insertion mutations in loricrin in 14 unrelated pedigrees have previously been reported and one heterozygous deletion in a further pedigree (see Supporting Information; Table S1). All six insertion mutations are single base‐pair insertions leading to delayed termination codons with the most frequent mutation 730insG being present in eight of the 14 published families .…”

“…This region of the loricrin gene is thought to be a mutation hotspot because of the presence of six consecutive guanine nucleotides except for two pedigrees of Brazilian origin, where the new protein is 25 amino acids longer than wild‐type protein . The mechanism of action of these mutations is thought to relate to preferential localization of mutant loricrin in the nucleus due to the formation of nuclear localization sequences within the arginine‐rich mutant loricrin .…”

“…It has been suggested that the abnormal nuclear protein may disrupt the apoptotic process in terminal differentiation of keratinocytes in mouse models, thus supporting the hypothesis that the phenotype of loricrin keratoderma is caused by the synthesis of mutant loricrin rather than by the lack of wild‐type loricrin . No clear genotype‐phenotype associations for pedigrees with specific mutations have currently been identified …”

“…12 All single-base-pair insertion and deletion mutations lead to a frameshift 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, 2 except for two pedigrees of Brazilian origin, where the new protein is 25 amino acids longer than wild-type protein. 5 The mechanism of action of these mutations is thought to relate to preferential localization of mutant loricrin in the nucleus due to the formation of nuclear localization sequences within the arginine-rich mutant loricrin. 14 It has been suggested that the abnormal nuclear protein may disrupt the apoptotic process in terminal differentiation of keratinocytes in mouse models, thus supporting the hypothesis that the phenotype of loricrin keratoderma is caused by the synthesis of mutant loricrin rather than by the lack of wild-type loricrin.…”