Pathogenic Variants Affecting Peptidyl Arginine Deiminase 3 and Its Major Substrates Underlie Central Centrifugal Cicatricial Alopecia

This study explores the genetic basis of central centrifugal cicatricial alopecia (CCCA) by analyzing whole-exome sequences from 75 patients, identifying 9 pathogenic variants in the PADI3 gene, including 4 new missense variants. These variants disrupt protein function, leading to reduced expression, abnormal localization, and diminished enzymatic activity. Additionally, pathogenic variants in the S100A3 and TCHH genes, which are key substrates of PADI3, affect hair shaft integrity. The study highlights the genetic heterogeneity of CCCA, with 40% of patients having a pathogenic variant in at least one of these genes. The findings enhance understanding of CCCA's genetic mechanisms and suggest potential therapeutic approaches targeting PADI3 activity.