The c.323 G>C mutation in LORICRIN causes new-found late-onset autosomal dominant loricrin keratoderma in a Chinese Han Pedigree

Background: Loricrin keratoderma is a rare early-onset autosomal dominant skin disorder. At present, no clinical reports have been published on characteristics of progressive aggravation and late-onset. Objectives: To identified a new-found pedigree with c.323 G>C mutation leading to progressive aggravation and late-onset loricrin keratoderma. Methods: Targeted next-generation sequencing of 267 genes associated with all skin abnormalities, sanger sequencing, and bioinformatics tools were used to identify the mutation in this new-found pedigree. Palm skin biopsy was used to observe the clinicopathological features of patient. Further, we constructed pcDNA3.1/V5-His-wild-LORICRIN, pcDNA3.1/V5-His-c.323G>C-LORICRIN, and pcDNA3.1/V5-His-730insG-LORICRIN vectors, nucleofected into HaCaT strain to observe the subcellular localization of loricrin by using the laser scanning confocal microscopy. Results: The proband and his affected father carried a heterozygous c.323 G>C missense mutation (p.Gly108Ala) on LORICRIN. Bioinformatics analysis hinted that it had potential pathogenicity; the types of ligands, enzyme commission active sites, and the spatial structure of protein changed enormously. Laser scanning confocal microscopy showed that the signals from cells transfected with the pcDNA3.1/V5-His-730insG-LORICRIN vector were distributed mainly in the nucleus, whereas those from cells transfected with the pcDNA3.1/V5-His-c.323G>C-LORICRIN vector were mainly located in the cytoplasm. Wild type loricrin was distributed in the nucleus and cytoplasm homogeneously Conclusion: The heterozygous c.323G>C missense mutation on LORICRIN caused late-onset and progressive loricrin keratoderma in this large Chinese family. Our study revealed that a large number of loricrin gathered in the cytoplasm may disturb the normal proliferation and terminal differentiation of keratino-cytes and lead to the late-onset loricrin keratoderma disease. (C) 2022 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

Automated summary

This study identified a rare pedigree with loricrin keratoderma carrying a c.323 G>C mutation, which exhibited late-onset and progressive skin symptoms. Further investigation revealed that this mutation may lead to the accumulation of loricrin in the cytoplasm, disrupting the normal functions of keratinocytes.