Somatic Mutations in NEK9 Cause Nevus Comedonicus.

TitleSomatic Mutations in NEK9 Cause Nevus Comedonicus.
Publication TypeJournal Article
Year of Publication2016
AuthorsLevinsohn, JL, Sugarman, JL, McNiff, JM, Antaya, RJ, Choate, KA
Corporate AuthorsYale Center for Mendelian Genomics
JournalAm J Hum Genet
Date Published2016 May 05
KeywordsAdolescent, Adult, Child, Female, Fluorescent Antibody Technique, High-Throughput Nucleotide Sequencing, Humans, Male, Mutation, Nevus, NIMA-Related Kinases, Prognosis, Skin Neoplasms, Young Adult

Acne vulgaris (AV) affects most adolescents, and of those affected, moderate to severe disease occurs in 20%. Comedones, follicular plugs consisting of desquamated keratinocytes and sebum, are central to its pathogenesis. Despite high heritability in first-degree relatives, AV genetic determinants remain incompletely understood. We therefore employed whole-exome sequencing (WES) in nevus comedonicus (NC), a rare disorder that features comedones and inflammatory acne cysts in localized, linear configurations. WES identified somatic NEK9 mutations, each affecting highly conserved residues within its kinase or RCC1 domains, in affected tissue of three out of three NC-affected subjects. All mutations are gain of function, resulting in increased phosphorylation at Thr210, a hallmark of NEK9 kinase activation. We found that comedo formation in NC is marked by loss of follicular differentiation markers, expansion of keratin-15-positive cells from localization within the bulge to the entire sub-bulge follicle and cyst, and ectopic expression of keratin 10, a marker of interfollicular differentiation not present in normal follicles. These findings suggest that NEK9 mutations in NC disrupt normal follicular differentiation and identify NEK9 as a potential regulator of follicular homeostasis.

Alternate JournalAm. J. Hum. Genet.
PubMed ID27153399
PubMed Central IDPMC4863661
Grant ListT32 GM007205 / GM / NIGMS NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States