Identification of a Novel Keratin 9 Missense Mutation in a Chinese Family with Epidermolytic Palmoplantar Keratoderma

Abstract

Background/Aims: Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant genodermatosis. It is characterized by diffuse yellow keratoses on the palmoplantar epidermis, with an erythematous border. The keratin 9 gene (KRT9) and less frequently the keratin 1 gene (KRT1) are responsible for EPPK. This study aims to identify and analyse genetic defects responsible for EPPK in a Han Chinese pedigree. Methods: A four-generation Han Chinese pedigree containing five individuals affected with EPPK was recruited. Exome sequencing, Sanger sequencing, and bioinformatics tools were conducted to identify the mutation in this pedigree. HaCaT cells were transfected with either wild-type or mutated KRT9. Confocal laser immunofluorescence assay, imaging processing, and statistical analysis were performed to evaluate wild-type and mutant KRT9 groups. Results: A novel heterozygous c.1369C>T transition (p.Leu457Phe) in exon 6 of the KRT9 gene was identified in four patients. It co-segregated with the disorder in the family. Functional analysis showed that withdrawal of the filament network from the cell periphery and particle formation were present in about 10% of Leu457Phe-transfected HaCaT cells, while approximately 3% of cells transfected with wild-type KRT9 showed this phenotype. The particles in mutant group were larger than that in wild-type group (P-value < 0.05). Conclusion: The variant may be the disease-causing missense mutation and produce dominant negative effects by interrupting keratin network formation. This study indicates the pathogenic role of the KRT9 gene mutation in this pedigree with EPPK, and may be helpful in genetic counseling, prenatal diagnosis and gene-targeted therapies of EPPK.

Genetic Analysis of KRT9 Gene Revealed Previously Known Mutations and Genotype-Phenotype Correlations in Epidermolytic Palmoplantar Keratoderma

“…Researchers at home and abroad have found that the 163rd amino acid is the hotspot mutation region of the KRT9 gene (48 of 100 cases) (Rugg et al, 2002). EPPK combined with knuckle pads maybe associated with mutations in many KRT9 genes, such as p.Met157Thr, p.Leu160Phe, p.Asn161Ser,p.Arg163Trp, p.Leu168Ser, p.Cys406Arg, and p.Leu458Pro (Escobar et al, 2007; Codispoti et al, 2009; Li et al, 2009; Wang et al, 2010; Du et al, 2011; Mao et al, 2018; Xiao et al, 2018). In this study, we studied three large Chinese families with EPPK and found 3 heterozygous gene mutations of KRT9: c.482A>G (p.Asn161Ser), c.487C>T (p.Arg163Trp) and c.488G>A (p.Arg163Gln).These mutations were not found in normal members of three families and in 100 healthy controls, indicating that the mutations detected in the families were the pathogenic mutations.…”

Identification of a frame shift mutation in the CCDC151 gene in a Han-Chinese family with Kartagener syndrome

“…Sanger sequencing was also performed on 200 control subjects to confirm the frequency of the identified variant in the cohort from central south China. Primers that were used for PCR amplification were designed and confirmed by Primer3 program and Primer-Basic Local Alignment Search Tool [25,26]. The sequences of the primers were 5 -CTCCTCAGGACCAGGCTTC-3 and 5 -TGACCCTCTGTACCCTCTGG-3 .…”

Exome sequencing identifies a KRT9 pathogenic variant in a Chinese pedigree with epidermolytic palmoplantar keratoderma

“…Palmoplantar keratoderma (PPK) is a group of heterogenous genodermatoses characterized by hyperkeratotic skin in the palms and soles, clinically grouped into four patterns: diffuse, striate, focal, and punctate （Fukunaga, Kubo, Sasaki, Tsuruta, & Fukai, ; Knöbel, O'Toole, & Smith, ; Mao, Zhang, You, Xiao, & Zhao, ; Smith et al, ; Wang et al, ; Xiao et al, ）. Epidermolytic palmoplantar keratoderma (EPPK, OMIM144200) is a rare skin disorder with the main clinical feature of diffuse hyperkeratotic skin in the palms and soles (Wang et al, ; Xiao et al, ). Generally, no subjective symptoms accompany the disorder except mild itching.…”

“…The pathogenesis of this wide group of disorders involves structural proteins (keratins), cornified envelope (loricrin, transglutaminase), cohesion (plakophilin, desmoplakin, desmoglein1), cell‐to‐cell communication (connexins), and transmembrane signal transduction (cathepsin C) proteins (Chen et al, ; Li, Han, Han, Zeng, Zhang, & Ma, ; Li, Wen, et al, ). An autosomal dominant inheritance is usually seen in EPPK （Fukunaga et al, ; Knöbel et al, ; Mao et al, ; Smith et al, ; Wang et al, ; Xiao et al, ）. The genetic basis of EPPK has also been explored.…”