Loss of RhoE Function in Dermatofibroma Promotes Disorganized Dermal Fibroblast Extracellular Matrix and Increased...

Area of Science:

• Dermatology
• Genetics
• Molecular Biology

Background:

• Dermatofibromas (DFs) are common benign skin tumors, often solitary but sometimes multiple and familial.
• The underlying mechanisms for multiple familial DFs remain unclear.

Purpose of the Study:

• To investigate the genetic basis of autosomal dominant multiple familial dermatofibromas.
• To elucidate the molecular mechanisms involving RhoE and PLOD2 in DF pathogenesis.

Main Methods:

• Exome sequencing to identify genetic variants in affected families.
• CRISPR-Cas9 for RhoE depletion in human dermal fibroblasts.
• Analysis of RhoE-PLOD2 interactions and their effect on extracellular matrix.
• Immunohistochemical analysis of DF skin samples.

Main Results:

• A heterozygous variant (c.692C>T, p.T231M) in RND3, encoding RhoE, was identified in a family with multiple DFs.
• Mutant T231M-RhoE or RhoE depletion increased fibroblast proliferation and extracellular matrix adhesion via enhanced β1 integrin activation.
• PLOD2 was identified as a RhoE binding partner, and this interaction was disrupted by T231M-RhoE.
• DF skin samples showed reduced RhoE and increased PLOD2 expression compared to controls.

Conclusions:

• Loss of RhoE function due to RND3 variants contributes to DF development.
• Increased PLOD2 activation, enhanced integrin signaling, and extracellular matrix disorganization are key mechanisms in DF pathogenesis.