Skip to main content
Premium Trial:

Request an Annual Quote

Hair Shaft Formation Gene Associated With Alopecia in Women of African Ancestry

NEW YORK (GenomeWeb) – An international team led by investigators at Tel Aviv University has identified mutations associated with a form of scarring alopecia called central centrifugal cicatricial alopecia (CCCA), which is particularly common in women with African ancestry.

Using exome sequencing, the researchers searched for potential CCCA culprits in 16 affected South African women, narrowing in on five individuals with splice site or heterozygous missense mutations in PADI3, a gene coding for a peptidyl arginine deiminase type III enzyme involved in hair shaft formation via post-translational modification. They subsequently verified ties between PADI3 mutations and CCCA with targeted gene sequencing on another 42 patients.

As reported yesterday in the New England Journal of Medicine, the team went on to explore the consequences of these alterations with the help of RNA sequencing, immunofluorescence staining, and quantitative rtPCR on scalp skin biopsy samples from PADI3 mutation-positive patients and unaffected controls. Findings from those and other experiments, including human keratinocyte cell line transfection experiments, pointed to a dip in PADI3 expression, coinciding with altered localization and lower-than-usual activity by the resulting enzyme, the investigators reported.

"Taken together, these data predict that decreased expression, diminished activity, or misfolding of PADI3 is likely to exert a deleterious effect on hair shaft formation and hair follicle development, which may underlie the disease phenotype seen in CCCA," corresponding author Eli Sprecher, a dermatology researcher at Tel Aviv Medical Center and a human molecular genetics and biochemistry researcher at Tel Aviv University, and his colleagues wrote.

CCCA is marked by symptoms ranging from hair breakage to thinning and progressive hair loss, often as a result of hair grooming, the team explained, noting that the condition earned the nickname 'hot comb alopecia' in the 1960s when it was documented in some African American women who straightened their hair with a hot comb and petrolatum products. Prior analyses hinted that CCCA may involve lymphocytic inflammation, fibrosis, and degeneration of the hair follicle, even though it may not appear to involve inflammatory processes from the outside.

For the first stage of their study, the researchers focused on 16 women with CCCA, including one individual who appeared to have a familial form of the disease, using exome sequencing data that was generated at Fulgent Genetics or BGI. Based on disease prevalence, predicted variant effect, and functional analyses, they focused in on four suspicious PADI3 mutations — one splice site change and three missense mutations at conserved sites in the gene — that were found in five CCCA patients.

Autosomal recessive mutations in PADI3 were previously implicated in a condition called "uncombable hair syndrome," the team noted.

When the investigators incorporated targeted gene sequencing on 42 additional patients, they saw PADI3 coding mutations in 14 individuals, or nearly one-quarter of the cases considered. Through a series of follow-up experiments, they not only shored up associations between the loss-of-function PADI3 mutations and CCCA but also explored the basis of this relationship.

For example, the team noted that PADI3 mutations were significantly more frequent in the group of CCCA patients of African ancestry than they were in African population controls from the gnomAD exome database.

"A post hoc analysis of the combined data sets showed that the prevalence of PADI3 mutation was higher among patients with CCCA than in a control cohort of African ancestry," the authors reported, consistent with the notion that mutations in the gene contribute to CCCA risk by altering hair shaft formation and related processes.

In a related editorial in NEJM, Jouni Uitto, a researcher at the Sidney Kimmel Medical College, noted that it is "unlikely that PADI3 variants are solely responsible for the disease" and cautioned against screening for PADI3 mutations in unaffected women based on the information available so far.

Even so, Uitto concluded that the "presence of variants in PADI3 in both CCCA and uncombable hair syndrome suggests that this gene has a pleiotropic effect on the determination of hair texture, and the finding holds implications for future development of therapy, such as the restoration of PADI3 activity."