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Nicastrin haploinsufficiency alters expression of type I interferon-stimulated genes: the relationship to familial hidradenitis suppurativa.

ABSTRACT: BACKGROUND:Hidradenitis suppurativa (HS), also called acne inversa, is a chronic skin disease. The symptoms can be severe, and include intensely painful nodules and abscesses in apocrine-gland rich inverse skin, such as the buttocks, under the arms and in the groin. Autosomal dominant forms of HS exist, but are rare. Some of these kindred have heterozygous loss-of-function rare variants in the ?-secretase complex component nicastrin (NCSTN). AIM:To investigate the effect of NCSTN haploinsufficiency on human keratinocytes and assess potential mechanisms for lesion development. METHODS:NCSTN was knocked down using a small hairpin RNA construct in both a keratinocyte cell line (HEK001) and an embryonic kidney cell line (HEK293), and differential gene expression was assessed using RNA microarray. Using the HEK293 line, a heterozygous deletion of NCSTN was created with CRISPR/Cas9 genome editing, and nuclear factor kappa B activity was assessed using a luciferase reporter. RESULTS:Compared with controls, the keratinocyte NCSTN knockdown cell line showed a significantly increased expression of genes related to the type I interferon response pathway. Both HEK001 and HEK293 knockdowns demonstrated evidence of altered growth. There was a small but significant increase in nuclear factor kappa B signalling in response to tumour necrosis factor treatment in HEK293 cells genome-edited for reduced NCSTN. CONCLUSIONS:Our data suggest a role for increased keratinocyte inflammatory responsiveness in familial HS. Confirming this phenotype and characterizing additional effects in different cell types will require study beyond cell lines, such as in primary cells and tissues.

SUBMITTER: Cao L

PROVIDER: S-EPMC7029778 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Nicastrin haploinsufficiency alters expression of type I interferon-stimulated genes: the relationship to familial hidradenitis suppurativa.

Cao L L Morales-Heil D J DJ Roberson E D O EDO

Clinical and experimental dermatology 20190117 4

<h4>Background</h4>Hidradenitis suppurativa (HS), also called acne inversa, is a chronic skin disease. The symptoms can be severe, and include intensely painful nodules and abscesses in apocrine-gland rich inverse skin, such as the buttocks, under the arms and in the groin. Autosomal dominant forms of HS exist, but are rare. Some of these kindred have heterozygous loss-of-function rare variants in the γ-secretase complex component nicastrin (NCSTN).<h4>Aim</h4>To investigate the effect of NCSTN ...[more]

PMID: 30656721

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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.

Project description:BackgroundAccumulating evidence suggests that alterations in gut microbiota composition are associated with the hidradenitis suppurativa (HS). However, the causal association between gut microbiota and HS remain undetermined.MethodsWe performed a bidirectional two-sample Mendelian randomization (MR) analysis using genome-wide association study summary data of gut microbiota and hidradenitis suppurativa from the MiBioGen consortium which concluded 18,340 individuals analyzed by the MiBioGen Consortium, comprising 211 gut microbiota. HS data were acquired from strictly defined HS data collected by FinnGenbiobank analysis, which included 211,548 European ancestors (409 HS patients, 211,139 controls). The inverse variance weighted method (IVW), weighted median (WME), simple model, weighted model, weighted median, and MR-Egger were used to determine the changes of HS pathogenic bacterial taxa, followed by sensitivity analysis including horizontal pleiotropy analysis. The MR Steiger test evaluated the strength of a causal association and the leave-one-out method assessed the reliability of the results. Additionally, a reverse MR analysis was carried out to seek for possible reverse causality.ResultsBy combining the findings of all the MR steps, we identified four causal bacterial taxa, namely, Family XI, Porphyromonadaceae, Clostridium innocuum group and Lachnospira. The risk of HS might be positively associated with a high relative abundance of Clostridium innocuum group (Odds ratio, OR 2.17, p = 0.00038) and Lachnospira (OR 2.45, p = 0.017) but negatively associated with Family XI (OR 0.67, p = 0.049) and Porphyromonadaceae (OR 0.29, p = 0.014). There were no noticeable outliers, horizontal pleiotropy, or heterogeneity. Furthermore, there was no proof of reverse causation found in the reverse MR study.ConclusionThis study indicates that Clostridium innocuum group and Lachnospira might have anti-protective effect on HS, whereas Family XI and Porphyromonadaceae might have a protective effect on HS. Our study reveals that there exists a beneficial or detrimental causal effect of gut microbiota composition on HS and offers potentially beneficial methods for therapy and avoidance of HS.

Dataset Information

Nicastrin haploinsufficiency alters expression of type I interferon-stimulated genes: the relationship to familial hidradenitis suppurativa.

Publications

Nicastrin haploinsufficiency alters expression of type I interferon-stimulated genes: the relationship to familial hidradenitis suppurativa.

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