Autosomal-Dominant Mutation in PADI3 Responsible for up to 25% of Central Centrifugal Cicatricial Alopecia Cases

Abstract

Central centrifugal cicatricial alopecia (CCCA) is the most common type of scaring alopecia in women of African heritage, with a prevalence of 2.7% to 5.6%. It usually starts on the vertex and progresses centrifugally; once scarred, the hair loss is irreversible. Its etiology is not fully understood. A novel pathogenic mechanism has been recently proposed: An environmental trigger (ie, damaging hair care practice and/or other) abates the immune privilege in genetically predisposed scalp hair and induces an autoimmune destructive response involving peroxisome proliferator-activated receptor gamma and TGFβ pathways. In most cases of CCCA, a premature desquamation of the inner root sheet epithelium is seen. Because of its unique clinicopathological and demographic features, and reports of familial clustering, Malki et al explored the genetics behind this disfiguring condition and published their findings in the recent edition of the New England Journal of Medicine. The team conducted RNA sequencing-based whole-exome sequencing on a discovery cohort of 16 women of African ancestry with biopsy-proven CCCA. Candidate genes first had to meet 3 criteria: 1) have a minor allele frequency of < 0.05 in African and < 0.0001 in European ethnic backgrounds, 2) variants should be identified in several patients, and 3) have a plausible pathogenic link. Using these criteria, the authors discovered 4 heterozygous mutations in the peptidyl arginine deiminase 3 (PADI3) gene in 5 of the 16 patients. Of these 5 patients, 4 had a missense mutation resulting in a misfolded protein and 1 had a splice-site mutation causing a fatal phase-shift mutation. PADI3 is an essential protein in normal hair-shaft development and has previously been associated with autosomalrecessive cases of uncombable hair syndrome. To confirm the clinical relevance of this mutation, the team compared PADI3 expression in 3 mutation-positive CCCA patients and 4 ageand sex-matched controls using RNA-sequencing and reverse transcription-polymerase chain reaction. There was a significant reduction in the expression of PADI3 in the CCCA group. Mutant PADI3-transfected keratinocyte cell-line model (HaCaT cells) further confirmed decreased protein expression. A second group of 42 participants with similar admission criteria were enlisted in the study and referred to as the replication set. Skin and scalp biopsies were obtained and analyzed via exome sequencing to determine whether variant mutations in the PADI3 gene also existed in this sample; 9 heterogeneous mutations were found in this group of patients. In a post hoc analysis of both groups of patients combined, a significant difference was found in the presence of mutations in the PADI3 gene for the CCCA group vs a control group of ageand ethnicity-matched women. This study documented for the first time a genetic cause with a probable autosomal-dominant transmission in a subset (~25%) of patients with CCCA. CCCA is clinically and genetically heterogeneous. In addition to genetic predisposition due to PADI3 mutation and intrinsically more fragile hair seen in women of African ancestry, environmental factors such as grooming techniques likely play an important role. More work is required to better elucidate the pathogenesis of CCCA and the role of PADI3 in healthy and diseased hair.