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N Engl J Med. 2019 Feb 28;380(9):833-841. doi: 10.1056/NEJMoa1816614. Epub 2019 Feb 13.

Variant PADI3 in Central Centrifugal Cicatricial Alopecia.

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From the Department of Dermatology (L.M., O.S., A.P., M.P., E.W., L.S., V.B., J.M., E.S.) and the Institute of Pathology (A.G.), Tel Aviv Medical Center, the Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine (L.M., A.P., J.M., E.S.), and the Department of Cell and Developmental Biology (O.I., T.R., N.S.), Tel Aviv University, Tel Aviv, and the Schulich Faculty of Chemistry, Technion, Haifa (N.A.) - all in Israel; the Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany (M.-T.R., R.C.B.); L'Unité Différenciation Epitheliale et Autoimmunité Rhumatoïde (UDEAR), INSERM, Université Paul Sabatier, Université de Toulouse Midi-Pyrénées, Toulouse, France (M.-C.M., M.S.); the Department of Dermatology, Wake Forest Baptist Medical Center, Winston-Salem, NC (L.U., A.M.); and the Dermatology Department, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa (N.C.D).



Central centrifugal cicatricial alopecia (CCCA) is the most common form of scarring alopecia among women of African ancestry. The disease is occasionally observed to affect women in families in a manner that suggests an autosomal dominant trait and usually manifests clinically after intense hair grooming. We sought to determine whether there exists a genetic basis of CCCA and, if so, what it is.


We used exome sequencing in a group of women with alopecia (discovery set), compared the results with those in a public repository, and applied other filtering criteria to identify candidate genes. We then performed direct sequencing to identify disease-associated DNA variations and RNA sequencing, protein modeling, immunofluorescence staining, immunoblotting, and an enzymatic assay to evaluate the consequences of potential etiologic mutations. We used a replication set that consisted of women with CCCA to confirm the data obtained with the discovery set.


In the discovery set, which included 16 patients, we identified one splice site and three heterozygous missense mutations in PADI3 in 5 patients (31%). (The approximate prevalence of the disease is up to 5.6%.) PADI3 encodes peptidyl arginine deiminase, type III (PADI3), an enzyme that post-translationally modifies other proteins that are essential to hair-shaft formation. All three CCCA-associated missense mutations in PADI3 affect highly conserved residues and are predicted to be pathogenic; protein modeling suggests that they result in protein misfolding. These mutations were found to result in reduced PADI3 expression, abnormal intracellular localization of the protein, and decreased enzymatic activity - findings that support their pathogenicity. Immunofluorescence staining showed decreased expression of PADI3 in biopsy samples of scalp skin obtained from patients with CCCA. We then directly sequenced PADI3 in an additional 42 patients (replication set) and observed genetic variants in 9 of them. 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 women of African ancestry (P = 0.002 by the chi-square test; P = 0.006 by Fisher's exact test; and after adjustment for relatedness of persons, P = 0.03 and P = 0.04, respectively).


Mutations in PADI3, which encodes a protein that is essential to proper hair-shaft formation, were associated with CCCA. (Funded by the Ram Family Foundation and others.).

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