Altered Notch Signaling in Dowling-Degos Disease: Additional Mutations in POGLUT1 and Further Insights into Disease Pathogenesis

Ralser, Damian J.; Takeuchi, Hideyuki; Fritz, Günter; Basmanav, Fitnat Buket; Effern, Maike; Sivalingam, Sugirthan; El-Shabrawi-Caelen, Laila; Değirmentepe, Ece Nur; Kocatürk, Emek; Singh, Manuraj; Booken, Nina; Spierings, Natalia M.K.; Schnabel, Viktor; Heineke, Andre; Knuever, Jana; Wolf, Sabrina; Wehner, Maria; Tronnier, Michael; Leverkus, Martin; Tantcheva‐Poór, Iliana; Wenzel, Jörg; Oji, Vinzenz; Has, Cristina; Hölzel, Michael; Frank, Jorge; Haltiwanger, Robert S.; Betz, Regina C.

doi:10.1016/j.jid.2018.10.030

Cited by 16 publications

(18 citation statements)

References 17 publications

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“…The heterozygous mutation c.1051C>T (p.Gln351*) in patient B resulting in a preliminary stop codon with a shortened protein has recently been described by us . Similarly, molecular genetic analyses of DNA from patients C and D revealed heterozygous mutations in POGLUT1 [c.1080dupG (p.Asn361Glufs*5) and c.835C>T (p.R279W), respectively] as previously described by us . These patients show a more disseminated pattern of reticulate hyperpigmentation and lentigines.…”

supporting

confidence: 70%

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Mast cell activation in Dowling–Degos disease

et al. 2019

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supporting

confidence: 70%

“…Patients A and D who had severe pruritus had more extensively degranulated mast cells than patients B and C who showed less pronounced pruritus. Mutations in KRT5 and POGLUT1 are implicated in Notch signalling, which might influence inflammatory mediators in the mast cells, leading to degranulation and attracting further mast cells to the tissue.…”

mentioning

confidence: 99%

Mast cell activation in Dowling–Degos disease

et al. 2019

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“…Reticulate hyperpigmentation similar to that observed in Dowling–Degos disease has also been reported together with HS in patients with PSENEN mutations (MIM 613736) . Additional gene defects in the Notch signalling pathway could also be important for HS and Dowling–Degos disease, such as the recently reported mutations in POFUT1 and POGLUT1 …”

Section: Human Disorders That Cause Acne‐like Phenotypesmentioning

confidence: 63%

“…[102][103][104] Additional gene defects in the Notch signalling pathway could also be important for HS and Dowling-Degos disease, such as the recently reported mutations in POFUT1 and POGLUT1. [105][106][107][108][109] Mutations in genes from the c-secretase complex result in haploinsufficiency, which is predicted to decrease activity of Notch signalling in the skin. 101 c-Secretase is an enzyme complex of four proteins that cleaves the intracellular domain of Notch, allowing translocation to the nucleus and activation of Notch target genes.…”

Section: Hidradenitis Suppurativa (Mim 142690)mentioning

confidence: 99%

What does acne genetics teach us about disease pathogenesis?

2019

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Summary Background Acne vulgaris is a highly prevalent inflammatory skin disorder with a complex pathogenesis, characterized by comedones, papules, pustules and nodules. Familial preponderance clearly indicates a genetic basis for acne vulgaris, but until recently solid genetic associations were lacking. Results The advent of high‐resolution genotyping array technologies has allowed for large‐scale studies with both family‐based and cross‐sectional designs. These studies have revealed genetic loci encompassing genes that could be active in biological pathways and processes underlying acne vulgaris. However, specific functional consequences of those variants remain elusive. In parallel, investigations into rare disorders and syndromes that incorporate features of acne or acne‐like lesions have recently accelerated our understanding of disease pathogenesis. The genes revealed by these rare disorders highlight mechanisms cardinal for pilosebaceous biology and therefore anchor our insights from genetic association studies for acne vulgaris. Conclusions The next phase of research will require more in‐depth mechanistic investigations of loci and genes implicated in acne phenotypes to define the key molecular players driving the disorder. Concurrently, new treatments for acne vulgaris could be developed by dissecting the candidate molecular pathways to identify druggable targets.

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“…Knockdown of POFUT1 reduces the expression of NOTCH1, NOTCH2, a Notch downstream target, HES1, and KRT5 in human keratinocyte HaCaT cells(Li et al, 2013). More recently, 12 novel heterozygous mutations in POGLUT1 including three missense mutations (p.Val328Gly, p.Arg279Gln, and p.Arg-218Gln) were reported(Ralser et al, 2019). More recently, 12 novel heterozygous mutations in POGLUT1 including three missense mutations (p.Val328Gly, p.Arg279Gln, and p.Arg-218Gln) were reported(Ralser et al, 2019).…”

mentioning

confidence: 99%

Effects of Notch glycosylation on health and diseases

Urata

Takeuchi

2019

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Notch signaling is an evolutionarily conserved signaling pathway and is essential for cell-fate specification in metazoans. Dysregulation of Notch signaling results in various human diseases, including cardiovascular defects and cancer. In 2000, Fringe, a known regulator of Notch signaling, was discovered as a Notch-modifying glycosyltransferase. Since then, glycosylation-a post-translational modification involving literal sugars-on the Notch extracellular domain has been noted as a critical mechanism for the regulation of Notch signaling. Additionally, the presence of diverse Oglycans decorating Notch receptors has been revealed in the extracellular domain epidermal growth factor-like (EGF) repeats. Here, we concisely summarize the recent studies in the human diseases associated with aberrant Notch glycosylation. K E Y W O R D S

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Altered Notch Signaling in Dowling-Degos Disease: Additional Mutations in POGLUT1 and Further Insights into Disease Pathogenesis

Cited by 16 publications

References 17 publications

Mast cell activation in Dowling–Degos disease

Mast cell activation in Dowling–Degos disease

What does acne genetics teach us about disease pathogenesis?

Effects of Notch glycosylation on health and diseases

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