Variants in the keratin 6A (KRT6A) gene are a major cause of pachyonychia congenita (PC), a rare autosomal dominant disorder characterized by nail hypertrophy and other ectodermal abnormalities. This study aimed to identify the causative mutation in a PC family and investigate the underlying pathogenic mechanism. We performed exome sequencing on this PC pedigree and validated candidate variations using Sanger sequencing. In silico predictions and in vitro experiments showed that the heterozygous missense variant c.512A>G in KRT6A was pathogenic, inducing protein aggregation and disrupting filamentous network structures. Enrichment analysis suggested that the PPAR signaling pathway played a crucial role in PC, with decreased expression of PPARβ/δ in HeLa cells. Comparative analysis of PC patients carrying the p.Asn171 variant revealed marked heterogeneity in clinical manifestations. Notably, oral leukokeratosis, a common phenotype in KRT6A mutation carriers, was not observed in the patients in this study. Interestingly, one patient presented with small papules around the lips and nasal bridge. We conclude that the c.512A>G variant in KRT6A is the genetic cause of this PC family, diagnosed as PC-K6a subtype. This study expands the phenotypic spectrum of congenital PC and suggests the PPAR signaling pathway as a potential therapeutic target.
Ren et al. (Thu,) studied this question.