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

Studysummary This study identified nine pathogenic variants in the PADI3 gene and variants in the S100A3 and TCHH genes in patients with central centrifugal cicatricial alopecia, suggesting a broader genetic basis for the disease and potential targets for genetic testing and therapies.

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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 Proteomic Profiling of Central Centrifugal Cicatricial Alopecia Reveals Role of Humoral Immune Response Pathway and Metabolic Dysregulation

5 citations , January 2024 in “JID Innovations”

In this study, researchers identified significant differences in protein expression patterns in scalps affected by central centrifugal cicatricial alopecia, notably upregulation of immune pathways and fibrosis markers and downregulation of metabolic proteins, suggesting unique disease mechanisms and potential therapeutic targets.

research Deimination In Epidermal Barrier And Hair Formation

2 citations , October 2023 in “Philosophical transactions - Royal Society. Biological sciences”

This article reports that mutations in the PADI3 gene, affecting its activity or localization, cause uncombable hair syndrome and are linked to central centrifugal cicatricial alopecia, particularly among women of African ancestry.

research Clinical Factors and Hair Care Practices Influencing Outcomes in Central Centrifugal Cicatricial Alopecia

May 2023 in “Archives of dermatological research”

This study found that clinical characteristics, concurrent medical conditions, and hair care practices may affect treatment outcomes in patients with central centrifugal cicatricial alopecia.

research Variant PADI3 in Central Centrifugal Cicatricial Alopecia

95 citations , February 2019 in “The New England Journal of Medicine”

This article discusses the potential genetic basis of central centrifugal cicatricial alopecia in women of African ancestry but does not provide new research results.

Premature Desquamation of the Inner Root Sheath in Noninflamed Hair Follicles as a Specific Marker for Central Centrifugal Cicatricial Alopecia

research Premature Desquamation of the Inner Root Sheath in Noninflamed Hair Follicles as a Specific Marker for Central Centrifugal Cicatricial Alopecia

6 citations , December 2018 in “The American Journal of Dermatopathology”

This study found that the presence of premature desquamation of the inner root sheath in noninflamed hair follicles is a relatively specific marker for diagnosing central centrifugal cicatricial alopecia.

research Mutations in Three Genes Encoding Proteins Involved in Hair Shaft Formation Cause Uncombable Hair Syndrome

119 citations , November 2016 in “American journal of human genetics”

This study reports the discovery of mutations in the PADI3, TGM3, and TCHH genes as molecular genetic causes of uncombable hair syndrome in children, indicating an autosomal-recessive inheritance pattern.

research Blockade of S100A3 Activity Inhibits Murine Hair Growth

1 citations , January 2015 in “Genetics and Molecular Research”

This study demonstrated that blocking S100A3 in mice inhibited hair growth by delaying the anagen phase and reducing the number of hair follicles, suggesting S100A3 as a potential target for hair loss treatments.

research Dermatoscopic Features of Central Centrifugal Cicatricial Alopecia

64 citations , June 2014 in “Journal of The American Academy of Dermatology”

This study found that a peripilar white gray halo around hair emergence is a highly specific and sensitive dermatoscopic feature for diagnosing central centrifugal cicatricial alopecia in African American patients with mild central thinning.

research The Biology of Hair Diversity

47 citations , January 2013 in “International Journal of Cosmetic Science”

This review explores genetic and lifestyle factors influencing hair diversity and reports no new findings, calling attention to the potential for future discoveries in genetic and epigenetic research.

research Prevalence and Etiology of Central Centrifugal Cicatricial Alopecia

19 citations , August 2011 in “Archives of Dermatology”

This abstract contains no research findings but is a snippet of a website interface for JAMA Dermatology.

research Specific Citrullination Causes Assembly of a Globular S100A3 Homotetramer

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

This study found that enzymatic conversion of Arg-51 in S100A3 protein to citrulline promotes homotetramer assembly, potentially increasing Ca²⁺ binding required for hair cuticular barrier formation.

research Trichohyalin Mechanically Strengthens the Hair Follicle

108 citations , October 2003 in “Journal of biological chemistry/The Journal of biological chemistry”

This study documents that trichohyalin acts as a multi-functional cross-bridging protein in the inner root sheath of mouse hair follicles, enhancing mechanical strength by linking keratin filaments to the cell envelope.

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

17 citations , December 2002 in “Biochemical and biophysical research communications”

This study reports on the biochemical characteristics of S100A3 protein in human hair cuticle, notably finding its N-terminal methionine is acetylated and has a slightly lower isoelectric point compared to the recombinant version.

research Ultrastructural Localization of S100A3, a Cysteine-Rich, Calcium Binding Protein, in Human Scalp Hair Shafts Revealed by Rapid-Freezing Immunocytochemistry

40 citations , April 1999 in “Journal of Histochemistry & Cytochemistry”

In this study, the researchers identified the specific subcellular localization of the protein S100A3 in the endocuticle and cortex of human hair shafts.

research Gene Expression of Mouse S100A3, a Cysteine-Rich Calcium-Binding Protein, in Developing Hair Follicle

40 citations , November 1998 in “The journal of investigative dermatology/Journal of investigative dermatology”

This study found that the S100A3 gene is exclusively expressed in hair follicle cells differentiating into hair shaft components in mice, suggesting its important role in hair formation.

research The Fate of Trichohyalin

135 citations , October 1997 in “Journal of biological chemistry/The Journal of biological chemistry”

This study suggests that trichohyalin is modified by peptidyl-arginine deiminase before being cross-linked by TGase 3, allowing the formation of rigid structures in hair follicle cells.