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Vural, S.* ; Baumgartner, M.* ; Lichtner, P. ; Eckstein, G.N. ; Hariry, H.* ; Chen, W.* ; Ruzicka, T.* ; Melnik, B.* ; Plewig, G.* ; Wagner, M. ; Giehl, K.A.*

Investigation of gamma secretase gene complex mutations in German population with Hidradenitis suppurativa designate a complex polygenic heritage.

J. Eur. Acad. Dermatol. Venereol. 35, 1386-1392 (2021)
Verlagsversion Forschungsdaten DOI
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease affecting apocrine gland-bearing skin in the axilla, groin and under the breasts. Mutations of the gamma-secretase gene complex, which is essential in the activation of Notch signalling pathways were shown in some families with HS and in a few sporadic cases. Although an imbalance in Notch signalling is implicated in the pathogenesis, the exact mechanism of HS development is yet unknown. OBJECTIVES: We aim to investigate the genetic basis of HS by determining the presence of mutations of gamma-secretase gene complex in a cohort of HS patients and by searching for a disease-causing pathogenic variant in a multi-generational HS family using parametric linkage analysis. METHODS: Thirty-eight patients clinically diagnosed with HS were included in this study. All exons and exon-intron boundaries of the genes encoding gamma-secretase complex consisting of six genes: APH1A, APH1B, PSENEN, NCSTN, PSEN1 and PSEN2 were sequenced by Sanger technique. Genetic mapping with parametric linkage analysis for the patients in the family was performed with eight affected and four healthy individuals. The logarithm of odds was calculated. RESULTS: In a sporadic patient with early-onset, severe lesions in axilla and groin, a novel single nucleotide deletion causing frameshift in exon 1 of the NCSTN gene was identified ((NM_015331.3): c.38delG, p.(Gly13Glufs*15)). The LOD score of 1.5 was never exceeded in any region of the genome, pointing towards intricate multigenic inheritance pattern within the affected family. CONCLUSIONS: The gamma-secretase gene complex mutations were rare in our cohort (3.2%). Besides, our analysis indicates a possible complex multigenic inheritance in a seemingly autosomal dominantly inherited large HS family. Genetics of both familial and sporadic HS may be complicated in most cases, and the role of other potential genes such as autoinflammatory and modifier genes as well as environmental factors may influence the pathogenesis.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Gamma Secretase ; Hidradenitis Suppurativa ; Familial ; Genetics ; Nicastrin ; Sporadic
ISSN (print) / ISBN 0926-9959
e-ISSN 1468-3083
Quellenangaben Band: 35, Heft: 6, Seiten: 1386-1392 Artikelnummer: , Supplement: ,
Verlag Wiley
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Begutachtungsstatus Peer reviewed