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Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis

Lihi Atzmony1, Keith A Choate2

  • 1Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

The Journal of Investigative Dermatology
|November 23, 2019
PubMed

Insights

Porokeratosis skin lesions arise from distinct genetic events in keratinocytes. Familial and sporadic cases link to mevalonate pathway gene mutations, with linear porokeratosis originating prenatally and disseminated superficial actinic porokeratosis postnatally.

Area of Science:

  • Dermatology
  • Genetics
  • Molecular Biology

Background:

  • Porokeratosis, a group of keratinization disorders, is linked to germline mutations in mevalonate pathway genes.
  • Both familial and sporadic forms of porokeratosis share this genetic association.

Purpose of the Study:

  • To investigate the clonal origin and genetic events underlying different types of porokeratosis.
  • To elucidate the specific genetic hits that lead to the development of skin lesions in porokeratosis.

Main Methods:

  • Analysis of keratinocyte clones from porokeratosis lesions.
  • Genetic sequencing to identify somatic mutations in the wild-type allele of mevalonate pathway genes.

Main Results:

  • Each lesion of disseminated superficial actinic porokeratosis originates from a unique postnatal keratinocyte clone.
  • These clones acquire distinct second-hit genetic events in the wild-type allele of relevant genes.
  • Linear porokeratosis is confirmed to arise from a single prenatal keratinocyte clone with a second-hit genetic event.

Conclusions:

  • Porokeratosis development involves distinct somatic genetic events in specific keratinocyte clones.
  • The timing of the second-hit event (prenatal vs. postnatal) differentiates linear from disseminated superficial actinic porokeratosis.

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