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Loss-of-function variants in DUSP1 encoding dual specificity phosphatase 1 cause palmoplantar keratoderma.

Kiril Malovitski1,2, Yarden Feller1,2, Moshe Giladi2,3

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Genetic variants in Dual Specificity Phosphatase 1 (DUSP1) cause inherited palmoplantar keratoderma (PPK) by disrupting keratinocyte differentiation and cell adhesion through ERK signaling.

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Area of Science:

  • Dermatology and Genetics
  • Molecular Biology
  • Cell Biology

Background:

  • Dual Specificity Phosphatase 1 (DUSP1) is implicated in keratinocyte (KC) proliferation via ERK signaling.
  • Inherited palmoplantar keratoderma (PPK) is a group of genetic skin disorders affecting the palms and soles.

Purpose of the Study:

  • To identify the genetic cause of inherited palmoplantar keratoderma (PPK) in two families.
  • To investigate the functional impact of identified genetic variants on DUSP1 and keratinocyte behavior.

Main Methods:

  • Whole exome sequencing and direct sequencing were employed to identify genetic variants.
  • Functional studies included RT-qPCR, protein modeling, immunofluorescence, immunoblotting, and 3D skin equivalents.
  • Cellular assays assessed keratinocyte adhesion and signaling pathways.

Main Results:

  • Two pathogenic variants in the DUSP1 gene were identified in individuals with PPK.
  • These variants led to decreased DUSP1 expression, increased ERK1/2 phosphorylation, and reduced DSG1 expression in keratinocytes.
  • In vitro and ex vivo models showed disrupted cell adhesion and altered epidermal differentiation, mimicking PPK.

Conclusions:

  • DUSP1 plays a critical role in epidermal differentiation, a function previously unrecognized.
  • Genetic defects in DUSP1 expand the known spectrum of mutations causing inherited palmoplantar keratoderma.
  • Targeting ERK signaling may offer therapeutic potential for DUSP1-associated PPK.