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Pathogenic variants affecting peptidyl arginine deiminase 3 and its major substrates underlie central centrifugal cicatricial alopecia

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dc.contributor.authorKeller-Rosenthal, Noy
dc.contributor.authorSarig, Ofer
dc.contributor.authorMalovitski, Kiril
dc.contributor.authorRubinstein, Rotem
dc.contributor.authorHaitin, Yoni
dc.contributor.authorLarrondo Gálvez, Jorge Felipe
dc.contributor.authorLenzy, Yolanda
dc.contributor.authorDlova, Ncoza
dc.contributor.authorMcMichael, Amy
dc.contributor.authorSprecher, Eli
dc.date.accessioned2026-08-03T22:19:14Z
dc.date.available2026-08-03T22:19:14Z
dc.date.issued2026
dc.description.abstractCentral centrifugal cicatricial alopecia (CCCA) is the most common form of primary scarring alopecia in women of African descent, typically characterized by progressive hair loss originating at the vertex of the scalp. Although genetic susceptibility has been implicated in the pathogenesis of CCCA, only 1 gene (PADI3, encoding peptidyl arginine deiminase 3) has been thus far associated with CCCA. This study aimed to broaden our understanding of the genetic basis of CCCA by analyzing whole-exome sequences from 75 patients with clinically and histologically confirmed CCCA. We identified 9 pathogenic heterozygous variants in PADI3, including, to our knowledge, 4 previously unreported missense variants, all predicted to disrupt protein function. Functional analyses revealed reduced expression, abnormal intracellular localization, and diminished enzymatic activity in cells transfected with constructs expressing the PADI3 variants. More interestingly, pathogenic variants were identified in 2 additional genes, S100A3 and TCHH, which encode the main substrates of PADI3, S100 calcium-binding protein A3 and trichohyalin. Both proteins play critical roles in hair shaft integrity. The S100A3 variant was found to cause reduced citrullination by PADI3, whereas TCHH variants altered intracellular localization and resulted in significantly reduced expression of the protein. These findings provide further insights into disease mechanisms and may inform future strategies for genetic testing and targeted therapies.
dc.description.versionVersión Publicada
dc.identifier.citationKeller-Rosenthal N, Sarig O, Giladi M, Malovitski K, Rubinstein R, Haitin Y, Larrondo J, Lenzy Y, Dlova N, McMichael A, Sprecher E. Pathogenic variants affecting peptidyl arginine deiminase 3 and its major substrates underlie central centrifugal cicatricial alopecia. J Invest Dermatol. 2026 Jun;146(6):1596-1604.e2. doi: 10.1016/j.jid.2025.10.609
dc.identifier.doihttps://doi.org/10.1016/j.jid.2025.10.609
dc.identifier.urihttps://hdl.handle.net/11447/10949
dc.language.isoen
dc.subjectCCCA
dc.subjectPADI3
dc.subjectS100A3
dc.subjectScarring alopecia
dc.subjectTrichohyalin
dc.titlePathogenic variants affecting peptidyl arginine deiminase 3 and its major substrates underlie central centrifugal cicatricial alopecia
dc.typeArticle
dcterms.accessRightsAcceso Abierto
dcterms.sourceThe Journal of investigative dermatology
dspace.entity.typePublication
relation.isAuthorOfPublication9b443012-c26a-4fef-a86b-70f2301189bc
relation.isAuthorOfPublication.latestForDiscovery9b443012-c26a-4fef-a86b-70f2301189bc

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