A novel nicastrin mutation in a three-generation Dutch family with hidradenitis suppurativa: a search for functional significance
| Autor: | Allard R. J. V. Vossen, J E M M de Klein, P. J. van der Spek, Andrew P. Stubbs, Deon J. Venter, K R van Straalen, H.H. van der Zee, Sigrid M.A. Swagemakers, Errol P. Prens |
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| Přispěvatelé: | Dermatology, Pathology, Clinical Genetics |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Nicastrin Dermatology medicine.disease_cause Frameshift mutation Acne Rosacea and Hidradenitis Suppurativa 030207 dermatology & venereal diseases 03 medical and health sciences symbols.namesake 0302 clinical medicine Medicine Humans Gene Genetics Sanger sequencing Mutation Splice site mutation Membrane Glycoproteins biology business.industry Microarray analysis techniques Calpain Hidradenitis Suppurativa genomic DNA 030104 developmental biology Infectious Diseases biology.protein symbols Original Article Amyloid Precursor Protein Secretases business Transcription Factors |
| Zdroj: | Journal of the European Academy of Dermatology and Venereology Journal of the European Academy of Dermatology and Venereology, 34(10), 2353-2361. Wiley-Blackwell |
| ISSN: | 1468-3083 0926-9959 |
| Popis: | Background Mutations in the γ‐secretase enzyme subunits have been described in multiple kindreds with familial hidradenitis suppurativa (HS). Objective In this study, we report a novel nicastrin (NCSTN) mutation causing HS in a Dutch family. We sought to explore the immunobiological function of NCSTN mutations using data of the Immunological Genome Project. Methods Blood samples of three affected and two unaffected family members were collected. Whole‐genome sequencing was performed using genomic DNA isolated from peripheral blood leucocytes. Sanger sequencing was done to confirm the causative NCSTN variant and the familial segregation. The microarray data set of the Immunological Genome Project was used for thorough dissection of the expression and function of wildtype NCSTN in the immune system. Results In a family consisting of 23 members, we found an autosomal dominant inheritance pattern of HS and detected a novel splice site mutation (c.1912_1915delCAGT) in the NCSTN gene resulting in a frameshift and subsequent premature stop. All affected individuals had HS lesions on non‐flexural and atypical locations. Wildtype NCSTN appears to be upregulated in myeloid cells like monocytes and macrophages, and in mesenchymal cells such as fibroblastic reticular cells and fibroblasts. In addition, within the 25 highest co‐expressed genes with NCSTN we identified CAPNS1,ARNT and PPARD. Conclusion This study reports the identification a novel NCSTN gene splice site mutation which causes familial HS. The associated immunobiological functions of NCSTN and its co‐expressed genes ARNT and PPARD link genetics to the most common environmental and metabolic HS risk factors which are smoking and obesity. |
| Databáze: | OpenAIRE |
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