Impairment of Notch 1 Signaling Is a Common Defect in Lesions From Patients With Hidradenitis Suppurativa

The study investigated the impact of gamma-secretase complex gene mutations on notch signaling in patients with hidradenitis suppurativa (HS). A new mutation in the NCSTN gene was identified in a family with autosomal dominant HS, leading to reduced levels of mutated NCSTN transcripts in lesional skin, keratinocytes, and monocytes. Notch-1 protein showed an abnormal membrane pattern in lesions of 5 mutated patients, unlike the normal cytoplasmic expression in 12 healthy individuals. Notch-2 protein expression was also reduced. A significant decrease in notch1-induced gene expression was observed in 5 mutated patients compared to 10 healthy individuals. The study found that haploinsufficiency, rather than a dominant negative effect, accounted for gamma-secretase impairment. In 10 HS cases without GS gene mutations, a similar ectopic notch1 pattern and reduced notch-1-related gene transcripts were observed. The findings demonstrated that notch1 signaling was severely impaired in HS, affecting keratinocytes and hair follicle cells, regardless of NCSTN or other GS gene mutations, highlighting the canonical nature of this defect.