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Authorde Oliveira, Ana Sofia Lima Estevao
Authorde Siqueira, Roberta Cardoso
AuthorNait-Meddour, Cécile
AuthorTricarico, Paola Maura
AuthorMoura, Ronald
AuthorAgrelli, Almerinda
Authord'Adamo, Adamo Pio
AuthorJamain, Stéphane
AuthorCrovella, Sergio
Authorde Fátima Medeiros Brito, Maria
AuthorBoniotto, Michele
AuthorBrandão, Lucas André Cavalcanti
Available date2023-09-10T08:53:11Z
Publication Date2023-01-01
Publication NameExperimental Dermatology
Identifierhttp://dx.doi.org/10.1111/exd.14919
Citationde Oliveira, ASLE, de Siqueira, RC, Nait-Meddour, C, et al. A loss-of-function NCSTN mutation associated with familial Dowling Degos disease and hidradenitis suppurativa. Exp Dermatol. 2023; 00: 1-11. doi:10.1111/exd.14919
ISSN09066705
URIhttps://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85169687384&origin=inward
URIhttp://hdl.handle.net/10576/47345
AbstractDowling Degos disease (DDD) is a rare autosomal dominant genodermatosis characterized by acquired, slowly progressive reticulated pigmented lesions primarily involving flexural skin areas. Mutations in KRT5, POGLUT-1 and POFUT-1 genes have been associated with DDD, and loss-of-function mutations in PSENEN, a subunit of the gamma-secretase complex, were found in patients presenting with DDD or DDD comorbid with hidradenitis suppurativa (HS). A nonsense mutation in NCSTN, another subunit of the gamma-secretase, was already described in a patient suffering from HS and DDD but whether NCSTN could be considered a novel gene for DDD is still debated. Here, we enrolled a four-generation family with HS and DDD. Through Whole Exome Sequencing (WES) we identified a novel nonsense mutation in the NCSTN gene in all the affected family members. To study the impact of this variant, we isolated outer root sheath cells from patients' hair follicles. We showed that this variant leads to a premature stop codon, activates a nonsense-mediated mRNA decay, and causes NCSTN haploinsufficiency in affected individuals. In fact, cells treated with gentamicin, a readthrough agent, had the NCSTN levels corrected. Moreover, we observed that this haploinsufficiency also affects other subunits of the gamma-secretase complex, possibly causing DDD. Our findings clearly support NCSTN as a novel DDD gene and suggest carefully investigating this co-occurrence in HS patients carrying a mutation in the NCSTN gene.
SponsorThis work was supported by ‘Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)’ (311415/2020-2 and 430353/2018-9), by Fondation René Touraine, by Starting Grant (SG-2019- 12369421) founded by the Italian Ministry of Health, by grants (RC16/2018 and RC03/2020) from the Institute for Maternal and Child Health IRCCS ‘Burlo Garofolo funded by the Italian Ministry of Health, and by EraPerMed 2018-17 European Community funds (JTC_2018). A.S.L.E.O is supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior–Brasil (CAPES)’–Finance Code 001, and L.A.C.B is supported by CNPq (311415/2020-2).
Languageen
PublisherWiley
SubjectDowling Degos disease
genetic mutation
gentamicin
hidradenitis suppurativa
NCSTN
TitleA loss-of-function NCSTN mutation associated with familial Dowling Degos disease and hidradenitis suppurativa
TypeArticle
ESSN1600-0625
dc.accessType Open Access


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