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

ABSTRACT: 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.

SUBMITTER: Frew JW

PROVIDER: S-EPMC6761225 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Frew John W JW Navrazhina Kristina K

Frontiers in medicine 20190919

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 ...[more]

PMID: 31608281

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Project description:Hidradenitis suppurativa (HS) leads to disfigurement and painful eruptions in terminal hair follicles of the intertriginous skin, mainly of axillary, genitofemoral, and perianal sites. It is associated with an excessive impairment of quality of life, psychiatric disorders, and sexual distress. Body image impairment has been linked to depression and anxiety and has been described for some dermatologic disorders but has not yet been investigated in patients with HS.To investigate whether body image is diminished in patients with HS and whether disease severity, age at onset, disease duration, obesity, depression, and anxiety are linked to body image impairment.This 12-month (August 1, 2009, to August 31, 2010) case-control study with a prospective, observational, cross-sectional design recruited 47 consecutive patients with HS entering a tertiary care center and 45 healthy control individuals matched for age, sex, and body mass index (BMI). One patient and 4 controls failed to complete the questionnaire and were excluded from the evaluation. Data analysis was performed from December 1, 2013, to February 15, 2014.The Frankfurt Body Concept Scale (FKKS) and the Hospital Anxiety and Depression Scale (HADS) were given to patients and controls. Correlations among FKKS, HADS, and disease features were calculated.Of the 46 patients and 41 controls included in the evaluation (mean [SD] age, 35.6 [1.6] years; 40 [46%] male and 47 [54%] female), HS significantly reduced body image (mean FKKS score, 234.2 [5.4] in patients and 276.9 [5.7] in controls; P < .001), even when controlled for BMI. A correlation was found for the extent of body image disruption and BMI (r = -0.589; P < .001), HADS-depression score (r = -0.619; P < .001), and HADS-anxiety score (r = -0.340; P = .03). No association was found for the body image score and the severity of HS, age at onset of disease, and duration of disease. The body contact subscale score was the only subscale score that was not different between patients with HS and controls.Patients with HS have major body image impairment, which might lead to depression and anxiety, disorders that have been largely acknowledged in HS. This study identified another element of the psychosocial burden of patients with HS and reveals that body image could potentially be used as an outcome measure in future studies of HS.

Dataset Information

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

Publications

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

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