A gene dysfunction module reveals the underlying pathogenesis of hidradenitis suppurativa: An update

Li, Xueli; Jiang, Lei; Huang, Yong; Z, Ren; Liang, Xiaoqin; Wang, Peng

doi:10.1111/ajd.13107

Cited by 13 publications

(11 citation statements)

References 28 publications

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“…Indeed, enhanced keratinocyte proliferation and/or reduced cell death in the isthmus/ infundibulum region of the hair follicle has been proposed as one of the earliest abnormalities in HS skin (27,60). In addition, genetic alterations, including gamma-secretase mutations, have been reported in HS patients, which may lead to inappropriate Notch signaling and disruption of normal hair follicle biology (26,61,62). Rupture of follicular cysts in HS patients results in a heterogenous immune cell infiltrate composed initially of predominantly myeloid cells followed by T cells and B cells (63,64).…”

Section: Discussionmentioning

confidence: 99%

Immunopathogenesis of hidradenitis suppurativa and response to anti–TNF-α therapy

Lowe¹,

Naik²,

Clancy³

et al. 2020

JCI Insight

102

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Section: Discussionmentioning

confidence: 99%

Immunopathogenesis of hidradenitis suppurativa and response to anti–TNF-α therapy

Lowe¹,

Naik²,

Clancy³

et al. 2020

JCI Insight

102

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“…The clinical validity of this work is supported by the fact that all assessed sequence variants are those deemed pathogenic through established criteria as published in our previous review (11), although a limitation to our study is that no external validation of functional confirmation has been undertaken to confirm these in silico findings. We note with interest that Notch was not identified as a HS-specific GSC substrate, despite the evidence from the published literature (19, 20) regarding alterations in Notch signaling and POGLUT1 (20), an endoplasmic reticulum O-glucosyltransferase involved in Notch signaling. This may indicate that Notch is not a HS- specific substrate and alterations in Notch and subsequent Notch-associated loci (21) may also be shared with AlzD.…”

Section: Discussionmentioning

confidence: 95%

In silico Analysis of Gamma-Secretase-Complex Mutations in Hidradenitis Suppurativa Demonstrates Disease-Specific Substrate Recognition and Cleavage Alterations

Frew

Navrazhina

2019

Front. Med.

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Background: Familial Hidradenitis Suppurativa and Familial Alzheimer's Disease are both associated with Gamma-Secretase Complex mutations; however, the two diseases are not epidemiologically associated. Understanding the molecular differences between the two diseases may aid in the development of hypotheses for differing pathogenesis and ultimately, targets for detection.Aims: To characterize the in silico structural and functional alterations to the Gamma Secretase Complex in documented mutations in Familial Hidradenitis Suppurativa, along with comparison of downstream substrate recognition and cleavage.Methods: In silico analysis of publicly available genomic data, assessment of protein structure and binding affinity using Swiss-model and Dynamut was undertaken. Differential Expression was expressed using Log Fold Change using the general framework for linear models in R. Differentially expressed genes (DEGs) were defined by FCH ≥1.5 or ≤−1.5 and false discovery rate (FDR ≤ 0.05).Results: Twenty three of 39 mutations in HS are degraded via nonsense mediated decay with altered substrate and binding affinity of substrates identified in the remaining mutations. Significant differential expression of ErbB4, SCNB1, and Tie1 in lesional skin was specific to Hidradenitis Suppurativa and EphB2, EPHB4, KCNE1, LRP6, MUSK, SDC3, Sortilin1 in blood specific to Familial Alzheimer's Disease.Discussion and Conclusions: We present the first in silico evidence as to the impact of documented mutations in Familial Hidradenitis Suppurativa. We also demonstrate unique substrate recognition and cleavage between Hidradenitis Suppurativa and Familial Alzheimer's Disease, providing a potential explanation as to why the two diseases do not occur within the same pedigree. These proteomic signatures may be a first step in identifying reliable biomarkers for Familial Hidradenitis Suppurativa.

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“…Predominantly loss‐of‐function mutations have been reported in genes of the γ‐secretase complex, namely NCSTN, PSEN1, PSENEN and PSTPIP1 6–8 . To date, the highest number of reported mutations was found in the NCSTN gene encoding nicastrin, which is important for the regulation of the γ‐secretase activity 9,10 …”

Section: Introductionmentioning

confidence: 99%

Increased expression profile of NCSTN, Notch and PI3K/AKT3 in hidradenitis suppurativa

Hessam

Gambichler

Skrygan

et al. 2020

Acad Dermatol Venereol

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BackgroundIn a small number of kindreds with familial hidradenitis suppurativa (HS) different mutations of NCSTN (nicastrin) have been identified. Blocking of NCSTN leads to impairment of the Notch and PI3K/AKT signalling pathway, which is assumed to play a pathogenic role in HS. However, very limited data are available concerning expression levels of these pathway components in HS skin.ObjectivesTo analyse the mRNA and protein expression of NCSTN, Notch1–3, PIK3R3 and AKT3 in HS.MethodsSkin samples from healthy controls, lesional and perilesional skin of HS patients with and without a positive family history were analysed by quantitative real‐time RT‐PCR and immunohistochemistry. Univariate statistical analyses were conducted regarding association between expression levels and patient's characteristics.ResultsExpression levels of all investigated genes showed significantly higher levels in lesional HS skin compared with healthy controls. Univariate analysis showed no association between a positive family history and mRNA expression levels. Perilesional HS skin of patients with mild disease severity (Hurley I) showed significant higher mRNA expression levels of the investigated pathway components compared to moderate (Hurley II) and severe disease (Hurley III).ConclusionWe found no evidence for diminished expression levels of the Notch signalling. In contrast, the NCSTN, Notch and PI3K/AKT signalling components are overexpressed in HS. Future research is needed to investigate a possible pathogenetic role or to reveal a coactivation of these overexpressed components during inflammatory response in HS.

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A gene dysfunction module reveals the underlying pathogenesis of hidradenitis suppurativa: An update

Cited by 13 publications

References 28 publications

Immunopathogenesis of hidradenitis suppurativa and response to anti–TNF-α therapy

Immunopathogenesis of hidradenitis suppurativa and response to anti–TNF-α therapy

In silico Analysis of Gamma-Secretase-Complex Mutations in Hidradenitis Suppurativa Demonstrates Disease-Specific Substrate Recognition and Cleavage Alterations

Increased expression profile of NCSTN, Notch and PI3K/AKT3 in hidradenitis suppurativa

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