Somatic Mutations in NEK9 Cause Nevus Comedonicus.

Area of Science:

• Genetics
• Dermatology
• Molecular Biology

Background:

• Acne vulgaris (AV) is common in adolescents, with 20% experiencing moderate to severe forms.
• Comedones, key to AV pathogenesis, are follicular plugs of keratinocytes and sebum.
• Genetic factors for AV are not fully understood despite high heritability.

Observation:

• Nevus comedonicus (NC), a rare disorder with comedones and acne cysts, was studied using whole-exome sequencing (WES).
• Somatic NEK9 mutations were identified in affected tissue of all three NC subjects.
• These mutations affect conserved residues in NEK9's kinase or RCC1 domains.

Findings:

• All identified NEK9 mutations were gain-of-function, increasing phosphorylation at Thr210, indicating kinase activation.
• Comedo formation in NC showed loss of follicular differentiation markers.
• Keratin-15-positive cells expanded, and ectopic keratin 10 expression occurred in follicles.

Implications:

• NEK9 mutations in NC disrupt normal follicular differentiation processes.
• NEK9 is identified as a potential regulator of follicular homeostasis.
• This research provides a potential genetic target for understanding and treating acne vulgaris.