Variants in KLF4 affecting residue Asp441 cause an autosomal dominant syndromic ichthyosis

作者：Zijuan Wang, Jun Liu, Oded Wechsberg, Lina Liang, Catherine E. Keegan, Christina Sloan-Heggen, You Mo, Yangyang Luo, Huijun Wang, Zhimiao Lin · 发表于：British Journal of Dermatology · 年份：2025 · DOI：10.1093/bjd/ljaf062 · 被引用次数：6 · 研究领域：Skin and Cellular Biology Research、Dermatological and Skeletal Disorders、Genetic and rare skin diseases.

BACKGROUND: Congenital ichthyoses comprise a group of skin scaling diseases with clinical and genetic heterogeneity. They can be subclassified into syndromic and nonsyndromic forms. Syndromic ichthyoses affect organs beyond the skin. An increasing number of causative genes have been identified. OBJECTIVES: To identify the causative gene and the underlying pathogenesis of a previously unreported syndromic ichthyosis. METHODS: Whole-exome sequencing (WES), combined with Sanger sequencing, was used to identify the genetic defect. Protein structural modelling and dual-luciferase reporter assays were used to investigate the effects of the pathogenic variants on Krüppel-like factor 4 (KLF4). A human embryonic stem cell (hESC) H9 line harbouring the pathogenic variant was developed into a skin organoid for morphological observation and RNA sequencing analysis. The expression of candidate target genes was further validated in patient skin samples using quantitative reverse transcriptase polymerase chain reaction and immunofluorescence. RESULTS: We enrolled four unrelated patients with a syndromic ichthyosis that predominantly manifested as ichthyosis, palmoplantar keratoderma, hypotrichosis, periorificial keratosis, nail dystrophy and extracutaneous involvement. WES identified two heterozygous missense variants, c.1322A>G (p.Asp441Gly) and c.1323T>A (p.Asp441Glu), in KLF4 in all four patients. Protein modelling predicted that the substitutions of the affected residue, Asp441, were li...