γ-Secretase Mutations in Hidradenitis Suppurativa: New Insights into Disease Pathogenesis

Pink, Andrew E.; Simpson, Michael A.; Desai, Nemesha; Trembath, Richard C.; Barker, Jonathan

doi:10.1038/jid.2012.372

Cited by 146 publications

(128 citation statements)

References 56 publications

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“…The γ-secretase complex comprises four integral membrane proteins: presenilin, nicastrin, anterior pharynx defective and PEN-2, which are encoded by PSEN1 or PSEN2 , NCSTN , APH1A or APH1B, and PEN-2 , respectively. The protease complex cleaves transmembrane proteins such as amyloid precursor protein, Notch receptors, N-cadherin and E-cadherin [5,6,7]. …”

Section: Discussionmentioning

confidence: 99%

A Frameshift Mutation in PEN-2 Causes Familial Comedones Syndrome

Panmontha¹,

Rerknimitr

Yeetong³

et al. 2015

Dermatology

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Background: Familial comedones without dyskeratosis are a rare autosomal dominant skin disorder, characterized by the occurrence of comedones that are distributed all over the body with specific features. We have previously reported two Thai families with familial comedones with expanded phenotypic spectrum. However, its genetic defect and pathogenesis remain unknown. Objective: To explore the molecular defect causing familial comedones. Methods: Whole-genome linkage analysis and whole-exome sequencing in family I were performed. Results: We identified a heterozygous one-base pair insertion, c.84_85insT (p. L28FfsX93) in PEN-2, located within the linked region on chromosome 19. PCR-Sanger sequencing confirmed the identified mutation. The mutation segregated with the disease phenotype in family I and was fully penetrant. This similar mutation was also present in the unrelated affected individual from family II. Quantitative PCR revealed increased mRNA expression of PEN-2 in leukocytes of affected individuals. Conclusion: We for the first time identify PEN-2 as the causative gene of familial comedones.

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Section: Discussionmentioning

confidence: 99%

A Frameshift Mutation in PEN-2 Causes Familial Comedones Syndrome

Panmontha¹,

Rerknimitr

Yeetong³

et al. 2015

Dermatology

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“…This unique role may be caused by γ-secretase-independent activities of PS that are more relevant to AD pathogenesis, by a higher intrinsic mutation rate of the human PSEN genes than of the other γ-secretase subunit genes, or by PS forming the catalytic core of the γ-secretase complex. Interestingly, recent human genetic studies identified large numbers of loss-of-function mutations in the Nct (17) and Pen-2 (3) genes that are associated with familial acne inversa or hidradenitis suppurativa (27)(28)(29)(30)(31). The lack of mutations identified in the Aph-1A and Aph-1B genes may reflect the genetic redundancy of the Aph-1 family; however, one mutation was reported in the PSEN1 gene despite the presence of its family member PSEN2 (27).…”

Section: Discussionmentioning

confidence: 99%

Synaptic function of nicastrin in hippocampal neurons

Lee

Sharma

Südhof

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Synaptic dysfunction is widely thought to play a key role in the pathogenesis of Alzheimer's disease (AD). Presenilins, the major gene products involved in familial AD, are essential for short-and long-term synaptic plasticity in mature neurons as well as for the survival of cortical neurons during aging. Presenilin and nicastrin are both indispensable components of the γ-secretase complex, but it remains unknown whether presenilin regulates synaptic function in a γ-secretase-dependent or γ-secretase-independent manner and whether nicastrin plays similar roles in central synapses. In the current study, we address these questions using an electrophysiological approach to analyze nicastrin conditional knockout (cKO) mice in the hippocampal Schaffer collateral pathway. In these mice, we found that, even at 2 mo of age, deletion of nicastrin in excitatory neurons of the postnatal forebrain using Cre recombinase expressed under the control of the αCaMKII promoter led to deficits in presynaptic short-term plasticity including paired-pulse facilitation and frequency facilitation. Depletion of Ca 2+ in the endoplasmic reticulum mimics and occludes the presynaptic facilitation deficits in nicastrin cKO mice, suggesting that disrupted intracellular Ca 2+ homeostasis underlies the presynaptic deficits. In addition, NMDA receptor-mediated responses and long-term potentiation induced by theta-burst stimulation were decreased in nicastrin cKO mice at 3 mo but not at 2 mo of age. Together, these findings show that, similar to presenilins, nicastrin plays essential roles in the regulation of short-and longterm synaptic plasticity, highlighting the importance of γ-secretase in the function of mature synapses.A lzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and cognitive decline. The majority of familial AD cases are caused by missense mutations in genes encoding presenilin 1 (PS1) and presenilin 2, which are crucial components of the γ-secretase complex responsible for intramembrane cleavages of type I membrane proteins such as Notch. In addition to presenilin (PS), nicastrin (Nct), presenilin enhancer 2 (Pen-2), and anterior pharynx defective 1 (Aph-1) also are required to form the active γ-secretase complex. Nct is a type-1 transmembrane glycoprotein that originally was identified by its ability to form high molecular weight complexes with PS (1). Nct −/− mice die by embryonic day 10.5 and exhibit patterning defects similar to those in embryos lacking PS or Notch (2-7).In the adult brain, genetic studies using conditional genetargeting approaches demonstrated that both PS and Nct are essential for long-term memory and age-dependent neuronal survival (8-12). These findings highlight the importance of γ-secretase in memory and neuronal survival (13), even though γ-secretase-independent activities of PS have been reported also (14). However, Notch is unlikely to be the key mediator of γ-secretase in the adult brain, because Notch1 and Notch2 conditional knockout (cKO)...

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“…[3,8,15,26,27]. The importance of genetic factors is highlighted by studies showing that 30-40% of HS patients reported a family history of HS [28,29] as well as 5% of HS patients presenting with a familial form with mutations in subunits of the γ-secretase proteins [30,31]. Originally, when first described, HS was thought to be a disease of the apocrine gland because it most commonly occurs in apocrine gland-rich intertriginous areas.…”

Section: Pathogenesismentioning

confidence: 99%

“…Indeed, Melnik and Plewig eloquently described the concept of HS as an autoinflammatory disease with dysregulation of the γ-secretase/notch pathway [40]. Particularly, mutations of the γ-secretase-notch pathway have already been shown to be involved in the molecular pathogenesis of familial HS among Chinese, British, Japanese, and French families [30,31]. Moreover, deficient notch signaling is able to switch the fate of outer root sheath cells, resulting in the conversion of hair follicles to keratin-enriched epidermal cysts, and compromise apocrine gland homoeostasis also leading to stimulation of toll-like receptor (TLR)-mediated innate immunity by damage-associated molecular pattern molecules released by either ruptured epidermal cysts exposing keratin fibers or altered structural components of less maintained apocrine glands, supporting and maintaining chronic inflammation.…”

Section: Pathogenesismentioning

confidence: 99%

Medical and Surgical Treatment of Hidradenitis Suppurativa: A Review

Scuderi

Monfrecola

Dessy

et al. 2017

Skin Appendage Disord

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Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease presenting with painful nodules, abscesses, sinus tracts, and scarring primarily affecting apocrine gland-rich intertriginous areas. HS prevalence ranges from 0.05 to 1%. The central pathogenic event in HS is believed to be the occlusion of the upper part of the folliculopilosebaceous unit, leading to the rupture of the sebofollicular canal with the consequent development of perifollicular lymphohistiocytic inflammation. The HS treatment choices are influenced by disease severity and its individual subjective impact, involving both medical and surgical interventions. However, given the chronic nature of HS, its destructive impact on social, working, and daily life of patients, its management is often frustrating for both the patient and physician. Hence, prompt and effective management strategies are urgently needed and a multidisciplinary approach is advocated. Therefore, in this article, we highlighted the main features of HS (clinical aspects, epidemiology, pathogenesis, diagnostic criteria, classifications, comorbidities, and treatments), so that awareness of this disease might be heightened in primary care physicians and surgeons, who may be the first health care providers to see patients with this disease owing to its characteristic clinical presentation (inflammatory nodules, abscesses, sinus tract, etc.).

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γ-Secretase Mutations in Hidradenitis Suppurativa: New Insights into Disease Pathogenesis

Cited by 146 publications

References 56 publications

A Frameshift Mutation in <b><i>PEN-2</i></b> Causes Familial Comedones Syndrome

A Frameshift Mutation in <b><i>PEN-2</i></b> Causes Familial Comedones Syndrome

Synaptic function of nicastrin in hippocampal neurons

Medical and Surgical Treatment of Hidradenitis Suppurativa: A Review

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