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

Xiaojie Gao; Hua Li; Songhua Zhao; Xiabin Li; Jiao Zhao; Yang Long; Jun Zhang; Yongmei Liao; Shengbiao Li; Kai Guo; Jingyan Yi; Shaokun Chen; Mingyi Ma

doi:10.1016/j.jdermsci.2022.03.002

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

J Dermatol Sci. 2022 Apr;106(1):37-44. doi: 10.1016/j.jdermsci.2022.03.002. Epub 2022 Mar 14.

Authors

Xiaojie Gao¹, Hua Li², Songhua Zhao³, Xiabin Li⁴, Jiao Zhao³, Yang Long⁵, Jun Zhang³, Yongmei Liao⁶, Shengbiao Li³, Kai Guo³, Jingyan Yi³, Shaokun Chen⁷, Mingyi Ma⁸

Affiliations

¹ School of Basic Medical Sciences, Southwest Medical University, Luzhou, China.
² Department of endocrinology, Affiliated hospital of Southwest Medical University, Luzhou, China.
³ Department of Medical Cell Biology and Genetics, Southwest Medical University, Luzhou, China.
⁴ Department of Pathology, Affiliated hospital of Southwest Medical University, Luzhou, China.
⁵ Experiment Medicine Center of the Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, China.
⁶ Department of Dermatology, Affiliated hospital of Southwest Medical University, Luzhou, China.
⁷ Department of Medical Cell Biology and Genetics, Southwest Medical University, Luzhou, China. Electronic address: chenshaokun@swmu.edu.cn.
⁸ Department of Medical Cell Biology and Genetics, Southwest Medical University, Luzhou, China. Electronic address: mingyimasb@swmu.edu.cn.

PMID: 35346558
DOI: 10.1016/j.jdermsci.2022.03.002

Abstract

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 keratinocytes and lead to the late-onset loricrin keratoderma disease.

Keywords: LORICRIN; Late-onset; Loricrin keratoderma; Mutation; Subcellular localization.

MeSH terms

China
Humans
Membrane Proteins* / genetics
Membrane Proteins* / metabolism
Mutation
Mutation, Missense*
Pedigree
Skin Diseases, Genetic

Substances

loricrin
Membrane Proteins

Supplementary concepts

Vohwinkel Syndrome, Variant Form