Pathogenic variants affecting peptidyl arginine deiminase 3 and its major substrates underlie central centrifugal cicatricial alopecia

Central centrifugal cicatricial alopecia (CCCA) is the most common form of primary scarring alopecia in women of African descent, typically characterized by progressive hair loss originating at the vertex of the scalp. While genetic susceptibility has been implicated in the pathogenesis of CCCA, only one gene (PADI3, encoding peptidyl arginine deiminase 3) has been thus far associated with CCCA. The present study aimed to broaden our understanding of the genetic basis of CCCA by analyzing whole exome sequences from 75 patients with clinically and histologically confirmed CCCA. We identified nine pathogenic heterozygous variants in PADI3, including, to our knowledge, four previously unreported missense variants, all predicted to disrupt protein function. Functional analyses revealed reduced expression, abnormal intracellular localization and diminished enzymatic activity in cells transfected with constructs expressing the PADI3 variants. More interestingly, pathogenic variants were identified in 2 additional genes, S100A3 and TCHH, which encode the main substrates of PADI3, S100 calcium-binding protein A3 and trichohyalin. Both proteins play critical roles in hair shaft integrity. The S100A3 variant was found to cause reduced citrullination by PADI3, while TCHH variants altered intracellular localization and resulted in significantly reduced expression of the protein. These findings provide further insights into disease mechanisms and may inform future strategies for genetic testing and targeted therapies.