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

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.