Central centrifugal cicatricial alopecia (CCCA) is the most common form of scarring alopecia among women of African ancestry (prevalence 2.7%-5.6%). The disease usually manifests clinically after intense hair grooming. Autosomal dominant inheritance of CCCA in some families suggests the existence of a genetically determined predisposition. Here, we aimed at identifying genetic risk variants for CCCA. Using whole exome sequencing in a discovery set of 16 patients, we identified one splice site and three heterozygous missense mutations in PADI3. PADI3 encodes peptidyl arginine deiminase, type III (PADI3), an enzyme that post-translationally modifies proteins that are essential to hair-shaft formation. All three CCCA-associated missense mutations in PADI3 affect highly conserved residues and are predicted to be pathogenic. Protein modeling suggested that the mutations result in protein misfolding. Accordingly, CCCA-associated mutations were found to result in reduced PADI3 expression, abnormal intracellular localization of the protein, and decreased PAD enzymatic activity. Immunofluorescence staining showed decreased expression of PADI3 in scalp skin obtained from CCCA patients. Finally, we directly sequenced PADI3 in a replication set of 42 patients. Combining the data sets, we found pathogenic variants in 24% of all CCCA patients. In conclusion, mutations in PADI3, which encodes a protein that is essential to proper hair shaft formation, may result in CCCA.

Deciphering the pathogenesis of central centrifugal cicatricial alopecia