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

Hermasch, Matthias A.; Janning, Helena; Perera, Roshan Priyarangana; Schnabel, Viktor; Rostam, Nadia; Ramos-Gomes, Fernanda; Muschalek, Wiebke; Bennemann, Anette; Alves, Frauke; Ralser, Damian J.; Betz, Regina C.; Schön, Michael P.; Dosch, Roland; Frank, Jorge

doi:10.1016/j.jdermsci.2022.01.001

Cited by 2 publications

(3 citation statements)

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“…A Ncstn LOF mutation induced tyrosinase leakage out of melanosomes causing the necrotic death of melanophores and mispigmentation of ZF. 40 Another recent study showed that knock down Ncstn larvae had a defect in melanophore migration, shape and number resulting in non-homogenous body pigmentation 41 as already shown for Psenen knock down larvae. 12 Note: F denotes female; M, male; NA, information is not available; +, presence of a feature; −, absence of a feature.…”

Section: Discussionmentioning

confidence: 68%

“…A Ncstn LOF mutation induced tyrosinase leakage out of melanosomes causing the necrotic death of melanophores and mis‐pigmentation of ZF 40 . Another recent study showed that knock down Ncstn larvae had a defect in melanophore migration, shape and number resulting in non‐homogenous body pigmentation 41 as already shown for Psenen knock down larvae 12 . Noteworthy, in humans, no difference in melanocytes number or tissue distribution were associated with DDD; instead, an atypical biogenesis of melanosomes in melanocytes and their subcellular distribution or retention in basal keratinocytes are key features of the disease 42,43 .…”

Section: Discussionmentioning

confidence: 99%

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A loss‐of‐function NCSTN mutation associated with familial Dowling Degos disease and hidradenitis suppurativa

de Oliveira,

de Siqueira,

Nait‐Meddour

et al. 2023

Experimental Dermatology

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Dowling Degos disease (DDD) is a rare autosomal dominant genodermatosis characterized by acquired, slowly progressive reticulated pigmented lesions primarily involving flexural skin areas. Mutations in KRT5, POGLUT‐1 and POFUT‐1 genes have been associated with DDD, and loss‐of‐function mutations in PSENEN, a subunit of the gamma‐secretase complex, were found in patients presenting with DDD or DDD comorbid with hidradenitis suppurativa (HS). A nonsense mutation in NCSTN, another subunit of the gamma‐secretase, was already described in a patient suffering from HS and DDD but whether NCSTN could be considered a novel gene for DDD is still debated. Here, we enrolled a four‐generation family with HS and DDD. Through Whole Exome Sequencing (WES) we identified a novel nonsense mutation in the NCSTN gene in all the affected family members. To study the impact of this variant, we isolated outer root sheath cells from patients' hair follicles. We showed that this variant leads to a premature stop codon, activates a nonsense‐mediated mRNA decay, and causes NCSTN haploinsufficiency in affected individuals. In fact, cells treated with gentamicin, a readthrough agent, had the NCSTN levels corrected. Moreover, we observed that this haploinsufficiency also affects other subunits of the gamma‐secretase complex, possibly causing DDD. Our findings clearly support NCSTN as a novel DDD gene and suggest carefully investigating this co‐occurrence in HS patients carrying a mutation in the NCSTN gene.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

A loss‐of‐function NCSTN mutation associated with familial Dowling Degos disease and hidradenitis suppurativa

de Oliveira,

de Siqueira,

Nait‐Meddour

et al. 2023

Experimental Dermatology

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“…Further inferred evidence for phenotypic and pathophysiological heterogeneity may be gained from investigating the genetic underpinnings of HS. The GSC, particularly nicastrin, may contribute more towards inflammation at PSU (Frew and Navrazhina, 2019;Hermasch et al, 2022), possibly through NOTCH pathways,. Other as yet unidentified genes may contribute more toward hyperkeratinization of the PSU's infundibular segment.…”

Section: Discussionmentioning

confidence: 99%

Interpreting the spectrum of gamma-secretase complex missense variation in the context of hidradenitis suppurativa—An in-silico study

2022

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Hidradenitis suppurativa (HS) is a disease of the pilosebaceous unit characterized by recurrent nodules, abscesses and draining tunnels with a predilection to intertriginous skin. The pathophysiology of HS is complex. However, it is known that inflammation and hyperkeratinization at the hair follicle play crucial roles in disease manifestation. Genetic and environmental factors are considered the main drivers of these two pathophysiological processes. Despite a considerable proportion of patients having a positive family history of disease, only a minority of patients suffering from HS have been found to harbor monogenic variants which segregate to affected kindreds. Most of these variants are in the ɣ secretase complex (GSC) protein-coding genes. In this manuscript, we set out to characterize the burden of missense pathogenic variants in healthy reference population using large scale genomic dataset thereby providing a standard for comparing genomic variation in GSC protein-coding genes in the HS patient cohort.

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

Cited by 2 publications

References 38 publications

A loss‐of‐function NCSTN mutation associated with familial Dowling Degos disease and hidradenitis suppurativa

A loss‐of‐function NCSTN mutation associated with familial Dowling Degos disease and hidradenitis suppurativa

Interpreting the spectrum of gamma-secretase complex missense variation in the context of hidradenitis suppurativa—An in-silico study

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