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In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
Loss-of-function variants in EPHX3 cause nonsyndromic epidermal differentiation disorders
Kunlun Lv1,2, Karina M Forde3, Amanda T Moon4
1Dermatology Hospital, Southern Medical University, Guangzhou, China.
The British Journal of Dermatology
|May 25, 2026
Summary
New research identifies biallelic EPHX3 variants as the cause of a novel nonsyndromic epidermal differentiation disorder (nEDD). This finding highlights the crucial role of epoxide hydrolase 3 (EH3) in maintaining skin barrier lipid processing.
Area of Science:
- Genetics
- Dermatology
- Biochemistry
Background:
- Epidermal differentiation disorders (EDD) are inherited skin conditions with diverse genetic causes.
- Lipid metabolism defects contribute to some EDDs, impacting the skin's protective barrier.
- Epoxide hydrolase 3 (EPHX3) is vital for processing lipids during skin barrier formation.
Purpose of the Study:
- To identify the genetic cause of a new subtype of nonsyndromic EDD (nEDD).
- To investigate the impact of EH3 deficiency on epidermal lipid processing and skin barrier function.
Main Methods:
- Whole-exome sequencing was used to identify genetic variants in affected families.
- Skin biopsies and 3D skin equivalents were analyzed for lipid content and differentiation markers.
- EH3 activity was quantified using liquid chromatography-mass spectrometry.
Main Results:
- Biallelic loss-of-function EPHX3 variants were identified in individuals with nEDD.
- Reduced EH3 activity and altered lipid profiles were observed in affected individuals.
- 3D skin models showed disrupted stratum corneum and impaired epidermal differentiation.
Conclusions:
- Biallelic EPHX3 variants cause a newly identified subtype of nEDD.
- EH3-dependent epoxide hydrolysis is essential for proper epidermal barrier lipid processing.
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