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

November 2025 in “ Journal of Investigative Dermatology ”

Noy Keller Rosenthal, Ofer Sarig, Moshe Giladi, Kiril Malovitski, Rotem Rubinstein, Yoni Haitin, Jorge Larrondo, Yolanda Lenzy, Ncoza C. Dlova, Amy McMichael, Eli Sprecher

central centrifugal cicatricial alopecia PADI3 peptidyl arginine deiminase 3 S100A3 TCHH hair shaft integrity CCCA

TLDR Genetic variants in specific genes cause 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.

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Research cited in this study

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research Prevalence and Etiology of Central Centrifugal Cicatricial Alopecia

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CCCA is a common scarring hair loss in African descent women, possibly linked to genetics, hair care practices, and health issues like diabetes.

research Specific Citrullination Causes Assembly of a Globular S100A3 Homotetramer

62 citations , December 2007 in “Journal of biological chemistry/The Journal of biological chemistry”

A specific chemical change in the S100A3 protein leads to the formation of a four-part structure important for hair formation.

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research Characterization of the Cysteine-Rich Calcium-Binding S100A3 Protein from Human Hair Cuticles

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Lichen Planopilaris (LPP), a form of permanent hair loss, which can be mistaken for seborrheic dermatitis and is characterized by scalp itching, burning, redness, and dandruff. Treatment options discussed include steroidal creams, finasteride, minoxidil, and RU58841.

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