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Gene mutations may predispose women to alopecia subtype

Publish date: April 1, 2019

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Genetics of hair texture have implications for therapy

Central centrifugal cicatricial alopecia (CCCA) is characterized by hair loss with rapid, progressive, and permanent hair follicle destruction, Jouni Uitto, MD, PhD, wrote in an accompanying editorial.

The current study showed six distinct genetic mutations in PAD13, a gene that allows normal hair follicle development, in 14 of 58 women with CCCA. The researchers also found that genes involved in hair shaft formation were expressed differently in women with CCCA than in unaffected women. Dr. Uitto wrote. Thus, variants in other genes likely contribute to CCCA pathogenesis.

“The observations by Malki et al. suggest that PADI3 mutations predispose persons to CCCA, which is then clinically manifested when hairstyling practices damage the hair. Thus, in the familial setting, such practices should be discouraged in both symptomatic and asymptomatic family members.” he wrote.

Dr. Uitto also noted that uncombable hair syndrome, a rare disorder not associated with alopecia or scarring, also has been associated with mutations in PAD13. However, uncombable hair syndrome is most common in children, who usually outgrow the condition, and it appears not to be inherited. “The mutations in PADI3 in these two conditions are distinct, which suggests different pathogenic consequences of specific PADI3 variants on hair development.”

The PAD13 mutations may predispose women to CCCA, but the data do not support screening asymptomatic women, Dr. Uitto wrote.

“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,” he concluded.

Dr. Uitto is affiliated with the department of dermatology and cutaneous biology at Jefferson Medical College, Philadelphia. This is a summary of his editorial accompanying the article by Malki et al. (New Engl J Med. 2019 Feb 13. doi: 10.1056/NEJMe1900042). He reported no relevant financial disclosures.

FROM THE NEW ENGLAND JOURNAL OF MEDICINE

Mutations in the PAD13 gene were significantly more common in 58 patients with central centrifugal cicatricial alopecia, compared with 2,702 controls, in a study of women of African ancestry.

Central centrifugal cicatricial alopecia (CCCA) often runs in families, suggesting a possible genetic component, but specific genes have not been explored, wrote Liron Malki, of Tel Aviv Medical Center and his colleagues.

In a study published in the New England Journal of Medicine, the researchers used a genetic sequencing procedure to examine genes in 16 women with African ancestry with CCCA who served as a discovery set; they identified four heterozygous mutations in the PAD13 gene in 5 women, which included one splice site and three missense mutations. The PAD13 gene “is responsible for mediating the modification of proteins critical for normal hair shaft formation and shaping, such as trichohyalin, and may also play a role in interfollicular epidermal differentiation,” they wrote.

Mr. Malki and his associates then identified an additional 42 patients of African descent with CCCA and directly sequenced PADI3; they found 9 patients with genetic variations.

Overall, the researchers found six mutations in PAD13 that appeared in 14 of the 58 patients (24%) with CCCA.

In a post hoc analysis, the mutations were significantly more prevalent among CCCA patients, compared with 2,702 control women of African ancestry (P = .03 by the chi-square test and P = 0.04 by Fisher’s exact test after adjusting for relatedness of study participants).

The results were limited by several factors, including the small sample size and lack of data on individual hair grooming habits. However, the findings support data from previous studies indicating that PAD13 plays an important role in proper hair shaft formation, the researchers wrote.

“The different properties of hair among persons of African ancestry and those of European ancestry may explain, in part, the different clinical consequences of PADI3 mutations in CCCA and in the uncombable hair syndrome,” Mr. Malki and his associates wrote. “Alternatively, the distinct variants in PADI3 in each of the disorders may account for the difference in clinical outcomes.”

The study was supported in part by a grant to Eli Sprecher, MD, PhD, from the Ram Family Foundation and a grant to Dr. Sprecher and Regina C. Betz, MD, from the German-Israeli Foundation, a L’Oreal African Hair and Skin Research grant to Ncoza C. Dlova, a research grant from the Skin of Color Society to Amy McMichael, MD, and the Deutsche Forschungsgemeinschaft–funded Cluster of Excellence ImmunoSensation grant to Dr. Betz. Several other researchers – but not all – reported numerous financial disclosures from pharmaceutical and technology companies and universities and organizations.

SOURCE: Malki L et al. N Engl J Med. 2019 Feb 13. doi: 10.1056/NEJMoa1816614.

Gene mutations may predispose women to alopecia subtype

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