Scrotal Dowling–Degos disease caused by a novel frameshift variant in gamma‐secretase subunit presenile enhancer gene

Ren, Jun; Zeng, Liyue

doi:10.1111/ajd.13316

Cited by 4 publications

(9 citation statements)

References 11 publications

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“…A distinctive subtype of Dowling-Degos with HS (HS-DDD) is defined by heterozygous variants in PSENEN (OMIM # 613736) on 19q13. Patients having underlying PSENEN variants but suffering from DDD exclusively have been described ( Ralser et al, 2017 ; Ren and Zeng, 2020 ). Interestingly, only obese family members harboring the pathogenic PSENEN c.62-1G > C splice variant manifested HS + DDD, whilst their lean, non-smoking relative who also harbored the same mutation manifested DDD exclusively ( Ralser et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

“…Non-smoking, lean patients from another family having PSENEN 84_85insT variant manifested DDD without HS ( Ralser et al, 2017 ). On the other hand, the c.216delC PSENEN variant was described in non-smoking, lean patients from two separate families manifesting DDD exclusively but also in an unrelated patient with DDD-HS, whose smoking history and weight were not documented ( Ralser et al, 2017 ; Ren and Zeng, 2020 ; Theut Riis et al, 2020 ). This suggests that in the context of HS, PSENEN pathogenic variants exhibit incomplete penetrance and variable expressivity, and possibly only manifest disease in the setting of specific triggers such as obesity.…”

Section: Discussionmentioning

confidence: 99%

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The Genomic Architecture of Hidradenitis Suppurativa—A Systematic Review

2022

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Hidradenitis suppurativa is a chronic, suppurative condition of the pilosebaceous unit manifesting as painful nodules, abscesses, and sinus tracts mostly in, but not limited to, intertriginous skin. Great strides have been made at elucidating the pathophysiology of hidradenitis suppurativa, which appears to be the product of hyperkeratinization and inflammation brought about by environmental factors and a genetic predisposition. The identification of familial hidradenitis suppurativa has sparked research aimed at identifying underlying pathogenic variants in patients who harbor them. The objective of this review is to provide a broad overview of the role of genetics in various aspects of hidradenitis suppurativa, specifically the pathophysiology, diagnosis, and clinical application.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Genomic Architecture of Hidradenitis Suppurativa—A Systematic Review

2022

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“…24 There was also no sign of DDD in these patients, a progressive disease that is acquired over the years . 1 In order to evaluate the impact of this SNV, ORS cells were isolated from plucked hairs of subjects II-3 (healthy control), III-2, III-5 and IV-2 (cases). A significant decrease in both NCSTN mRNA and protein level was observed by qPCR and western-blot assays in subjects carrying the heterozygous premature stop codon when compared with the unmutated individual (Figure 3).…”

Section: Identification Of a Novel Variant Associated With Ddd And Hsmentioning

confidence: 99%

“…Dowling-Degos disease (DDD) (ORPHA:79145) is a rare autosomal dominant genodermatosis characterized by slowly progressive reticulated pigmented lesions in flexural skin areas. 1 The first gene associated with DDD was KRT5. 2 Mutations in the head region of keratin 5 (KRT5) protein are found in ~1/3 of DDD patients, usually presenting an acantholytic variant named Galli-Galli Disease (GGD).…”

Section: Introductionmentioning

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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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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“…Both POGLUT1 and POFUT1 play a critical role in Notch signaling, which is essential in regulating melanocyte and keratinocyte proliferation and differentiation 10,11 . Finally, PSENEN gene mutations, which also affect the Notch signaling pathway by modifying an enhancer gene that encodes a component of γ‐secretase protein complex, have recently been identified in a DDD variant associated with hidradenitis suppurativa and with DDD localized to the scrotum 14 …”

Section: Geneticsmentioning

confidence: 99%

Dowling‐Degos disease: a review

2020

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Dowling‐Degos disease is a rare autosomal dominant genodermatosis. It is characterized by acquired reticulate hyperpigmentation over the flexures, comedone‐like follicular papules, and pitted perioral scars that usually develop during adulthood. Mutations in genes affecting melanosome transfer, and melanocyte and keratinocyte differentiation have been implicated in the pathogenesis of this disease. These genes include KRT5, POFUT1, POGLUT1 and, most recently, PSENEN. Dowling‐Degos disease can be found in isolation or with other associated findings, most notably hidradenitis suppurativa. This condition belongs to a spectrum of conditions that all result in reticulate hyperpigmentation that at times are hard to distinguish from each other. The most closely linked entity is Galli‐Galli, which is clinically indistinguishable from Dowling‐Degos disease and can only be distinguished by the presence of acantholysis on microscopy. Unfortunately, Dowling‐Degos disease is generally progressive and recalcitrant to treatment.

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Scrotal Dowling–Degos disease caused by a novel frameshift variant in gamma‐secretase subunit presenile enhancer gene

Cited by 4 publications

References 11 publications

The Genomic Architecture of Hidradenitis Suppurativa—A Systematic Review

The Genomic Architecture of Hidradenitis Suppurativa—A Systematic Review

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

Dowling‐Degos disease: a review

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