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 investigates the genetic basis of central centrifugal cicatricial alopecia (CCCA) in 75 patients, focusing on the PADI3 gene and its substrates. Researchers identified nine pathogenic variants in PADI3, including four new missense variants that disrupt protein function. Additionally, variants in the S100A3 and TCHH genes, which encode key substrates of PADI3, were found. These variants affect protein expression, localization, and enzymatic activity, impacting hair shaft integrity. The findings enhance understanding of CCCA's genetic mechanisms and could guide future genetic testing and therapies.

View this study on jidonline.org →

Discuss this study in the Community →

Research cited in this study

15 / 15 results

research Deimination In Epidermal Barrier And Hair Formation

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

Enzymes that change arginine to citrulline are important for skin barrier and hair formation, and their malfunction can lead to skin conditions and hair disorders.

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

May 2023 in “Archives of dermatological research”

Some factors like thyroid disease, diabetes treatment, hair dryers, natural hairstyles, and scalp conditions can affect the treatment results for a hair loss condition called CCCA.

research Variant PADI3 in Central Centrifugal Cicatricial Alopecia

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

Mutations in the PADI3 gene are linked to a higher risk of scarring hair loss in women of African descent.

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”

Early shedding of the inner root sheath in noninflamed hair follicles is a relatively specific sign of 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”

Mutations in three genes cause Uncombable Hair Syndrome, leading to frizzy hair that can't be combed flat.

research Blockade of S100A3 Activity Inhibits Murine Hair Growth

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

Stopping S100A3 activity slows down hair growth in mice.

research Dermatoscopic Features of Central Centrifugal Cicatricial Alopecia

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

Researchers found a white halo around hair in most patients with a specific type of hair loss, which helps in early diagnosis and treatment.

research The Biology of Hair Diversity

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

Hair diversity is influenced by complex genetics and environmental factors, requiring more research for practical solutions.

research Prevalence and Etiology of Central Centrifugal Cicatricial Alopecia

19 citations , August 2011 in “Archives of Dermatology”

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.

research Trichohyalin Mechanically Strengthens the Hair Follicle

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

Trichohyalin makes hair follicles stronger.

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

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

Scientists found out how a specific protein in human hair cuticles behaves and is structured.

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”

S100A3 protein is mainly found in specific parts of human hair cells.

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”

S100A3 protein is crucial for hair shaft formation in mice.

research The Fate of Trichohyalin

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

Trichohyalin is modified by enzymes to form strong structures in hair cells.

Related Community Posts Join

6 / 91 results

community I am a dermatologist with a clinical interest in alopecia. AMA

in Will treatment work for me? 3 years ago

In this conversation, 4990 discussed various treatments for hair loss, including oral minoxidil, PRP, transplan, Jak inhibitors, Dutasteride, Finasteride, Olumiant, Ketoconazole, RU58841, microneedling, baricitinib, and CCCA. They recommended scalp biopsies in unclear cases of DUPA, twice weekly to twice daily shampooing for topical minoxidil users, and two sessions spaced one month apart with follow up at month three to determine the effectiveness of PRP treatment.

community If You Have DUPA, PLEASE READ THIS: Everyone Should Be Scalp Biopsied

in Research 830 upvotes 1 year ago

Scalp biopsies are crucial for diagnosing hair loss conditions like Diffuse Unpatterned Alopecia (DUPA) and retrograde hair loss, as treatments like finasteride and dutasteride may not be effective if other conditions are present. Combining PPAR-GAMMA agonists with retinoids could improve treatments for conditions like Lichen Planopilaris.

community Wanted to say that Derma rolling and Pumpkin seed oil helped my crown out.

in Treatment 4 upvotes 6 years ago

Derma rolling, pumpkin seed oil, and daily massages helped regrow weak hairs on the crown. Nizoral shampoo and yoga also contributed to reducing scalp pain and stress.

community Finasteride doesn't work for me in 2 years and my bloodtest result just came in.

in Progress Pictures 88 upvotes 2 years ago

A user has been treating hair loss with finasteride for two years without success and is experiencing an itchy scalp with seborrhea. Despite low DHT levels, they are still losing hair, suggesting that DHT might not be the main cause of their hair loss, and they are considering other treatments or causes.

community lost my hair in a single year of treatment at 20 years old

in Finasteride/Dutasteride 89 upvotes 1 year ago

A 20-year-old lost significant hair after one year of treatment, using minoxidil, finasteride, and later dutasteride. They are considering adding RU58841 but are advised to return to finasteride and minoxidil for a year before deciding.

community Exploring Bryan Johnson's Hair Routine In Detail

in Research/Science 65 upvotes 1 year ago

Bryan Johnson uses a custom hair loss treatment that includes topical finasteride, minoxidil, azelaic acid, diclofenac, tea tree oil, rosemary oil, ginkgo biloba, biotin, and melatonin, which have shown varying degrees of effectiveness with minimal side effects. He also undergoes PRP and laser therapy, and has tried dutasteride mesotherapy.