Nicastrin Mutation Research Articles

Discovery and Potential Functional Characterization of Long Noncoding RNAs Associated with Familial Acne Inversa with NCSTN Mutation

Background: Long noncoding RNAs (lncRNAs) are associated with many dermatologic diseases. However, little is known about the regulatory function of lncRNAs in familial acne inversa (AI) patients with nicastrin (NCSTN) mutation. Objectives: The aim of this study was to explore the regulatory function of lncRNAs in familial AI patients with NCSTN mutation. Methods: The expression profiles of lncRNAs and mRNAs in skin tissues from familial AI patients with NCSTN mutation and healthy individuals were analysed in this study via RNA sequencing (RNA-seq). Results: In total, 359 lncRNAs and 1,863 mRNAs were differentially expressed between the two groups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the dysregulated mRNAs targeted by lncRNAs were mainly associated with the immune regulation, Staphylococcus aureus infection and B cell receptor signalling pathways. The lncRNA-miRNA-mRNA coexpression network contained 265 network pairs comprising 55 dysregulated lncRNAs, 11 miRNAs, and 74 mRNAs. Conservation analysis of the differentially expressed lncRNAs between familial AI patients with NCSTN mutation and Ncstn keratinocyte-specific knockout (Ncstn^ΔKC) mice identified 6 lncRNAs with sequence conservation; these lncRNAs may participate in apoptosis, proliferation, and skin barrier function. Conclusions: These findings provide a direction for exploring the regulatory mechanisms underlying the progression of familial AI patients with NCSTN mutation.

Evolutionary distinct roles of γ-secretase subunit nicastrin in zebrafish and humans

BackgroundMutations in the genes that encode the human γ-secretase subunits Presenilin-1, Presenilin Enhancer Protein 2, and Nicastrin (NCSTN) are associated with familial hidradenitis suppurativa (HS); and, regarding Presenilin Enhancer Protein 2, also with comorbidity for the hereditary pigmentation disorder Dowling-Degos disease. ObjectiveHere, the consequences of targeted inactivation of ncstn, the zebrafish homologue of human NCSTN, were studied. MethodsAfter morpholino (MO)-mediated ncstn-knockdown, the possibilities of phenotype rescue through co-injection of ncstn-MO with wildtype zebrafish ncstn or human NCSTN mRNA were investigated. Further, the effects of the co-injection of a human missense, nonsense, splice-site, and frameshift mutation were studied. ResultsMO-mediated ncstn-knockdown resulted in a significant reduction in melanophore morphology, size and number; and alterations in their patterns of migration and distribution. This phenotype was rescued by co-injection of zebrafish ncstn RNA, human NCSTN RNA, or a construct encoding the human NCSTN missense mutation p.P211R. ConclusionHuman NCSTN mutations encoding null alleles confer loss-of-function regarding pigmentation homeostasis in zebrafisch. In contrast, the human missense mutation p.P211R was less harmful, asserting sufficient residual ncstn activity to maintain pigmentation in zebrafish. Since fish lack the anatomical structures affected by HS, our data suggest that the zebrafish ncstn gene and the human NCSTN gene have probably acquired different functions during evolution. In fish, one major role of ncstn is the maintenance of pigmentation homeostasis. In contrast, one of the roles of NCSTN in humans is the prevention of inflammatory processes in the adnexal structures of the skin, as seen in familial HS.

A novel nicastrin mutation in a three‐generation Dutch family with hidradenitis suppurativa: a search for functional significance

BackgroundMutations in the γ‐secretase enzyme subunits have been described in multiple kindreds with familial hidradenitis suppurativa (HS).ObjectiveIn 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.MethodsBlood 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.ResultsIn 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.ConclusionThis 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.

Nicastrin/miR-30a-3p/RAB31 Axis Regulates Keratinocyte Differentiation by Impairing EGFR Signaling in Familial Acne Inversa

Nicastrin (NCSTN) mutations are associated with familial acne inversa (AI), and emerging evidence suggests that microRNAs (miRNAs) are involved in various skin diseases. However, whether NCSTN mutations affect miRNA levels and their subsequent signaling pathways in familial AI patients has not been studied. We aimed to elucidate the relationship between NCSTN mutations and familial AI pathogenesis by investigating differential miRNA expression and their related pathways. Combined with miRNA microarray data from familial AI patients, Ncstn keratinocyte-specific-knockout (NcstnΔKC) mice and bioinformatics predictions showed that NCSTN mutations led to decreased miR-30a-3p levels, which negatively regulated RAB31 expression. Moreover, enhanced RAB31 levels accelerated degradation of activated EGFR, leading to abnormal differentiation in keratinocytes. The impaired EGFR signaling and its effects on epidermal differentiation were also observed in familial AI patients and NcstnΔKC mice. Thus, our study showed that miR-30a-3p/RAB31/EGFR signaling pathway may play a key role in the pathogenesis of familial AI with NCSTN mutations.

A novel nicastrin mutation in a large Chinese family with hidradenitis suppurativa

A novel nicastrin mutation in a large Chinese family with hidradenitis suppurativa

Acne inversa (Hidradenitis suppurativa): A review with a focus on pathogenesis and treatment

Acne inversa (AI) is a disabilitating chronic inflammatory disease with major negative impact on quality of life and significant co-morbidities. This is an important link to insights into immune dysfunction, which stimulated therapeutic approaches like tumor necrosis-α inhibitor therapy. This new off-label drug treatment is particularly beneficial when used in combination with wide excision of inflamed skin and subcutaneous tissue. Retinoids have been reported to be helpful in secondary prevention. The standard of therapy in advanced cases is surgery with wide excisions and healing by secondary intention. This treatment results in significant reduction of complaints and achieves satisfactory body contouring.

P4-136 Nicastrin mutation (N417Y) is a risk factor in Alzheimer's disease

P4-136 Nicastrin mutation (N417Y) is a risk factor in Alzheimer's disease