Somatic mutations reveal hyperactive Notch signaling in prurigo nodularis.

Area of Science:

• Dermatology
• Genetics
• Molecular Biology

Background:

• Prurigo nodularis (PN) is a chronic inflammatory skin condition with unknown causes.
• Somatic genetic alterations are increasingly recognized in inflammatory diseases.
• Understanding the genetic landscape of PN is crucial for identifying pathogenic mechanisms.

Purpose of the Study:

• To investigate somatic genetic mutations in lesional skin of patients with Prurigo nodularis.
• To compare the genetic profile of PN lesions with adjacent nonlesional skin and atopic dermatitis.
• To explore the role of Notch signaling in PN pathogenesis.

Main Methods:

• Whole-exome sequencing of lesional and nonlesional skin biopsies from PN patients.
• Comparison with biopsies from atopic dermatitis patients.
• Somatic mutational and copy-number analysis, followed by immunofluorescence validation.

Main Results:

• Recurrent somatic mutations in fibrotic, neurotropic, and cancer-associated genes were identified in PN lesional skin.
• NOTCH1 mutations and altered Notch signaling were prominent in PN lesions but absent in atopic dermatitis.
• Deleted and downregulated genes related to axonal guidance were found in PN lesional skin.

Conclusions:

• The study identifies a distinct somatic genetic landscape in Prurigo nodularis lesions.
• NOTCH1 pathway dysregulation is implicated in the pathogenesis and fibrosis of PN.
• These findings suggest potential therapeutic targets for Prurigo nodularis.