Gain-of-function variant in NNT causes premature diffuse familial sebaceous hyperplasia

Area of Science:

• Genetics
• Dermatology
• Cell Biology

Background:

• Premature diffuse familial sebaceous hyperplasia (PDFSH) is a rare condition with early onset, distinct facial sparing, and familial inheritance.
• The genetic basis of PDFSH has remained unknown until this study.

Purpose of the Study:

• To identify the causative gene and understand the pathogenesis of autosomal dominant PDFSH in three families.
• To investigate the molecular mechanisms underlying PDFSH.

Main Methods:

• Whole-exome sequencing and Sanger sequencing were used to identify genetic variants in PDFSH families.
• Transmission electron microscopy (TEM) analyzed sebaceous gland ultrastructure.
• Functional assays assessed antioxidant capacity, lipid peroxidation, and ferroptosis.

Main Results:

• A missense variant (c.2063T>G, p.Leu688Trp) in the NNT gene was identified in all affected individuals.
• The NNT variant led to enhanced antioxidant capacity, increased glutathione (GSH) levels, and reduced reactive oxygen species (ROS).
• Sebaceous glands showed reduced lipid peroxidation and decreased susceptibility to ferroptosis.

Conclusions:

• A gain-of-function variant in the Nicotinamide Nucleotide Transhydrogenase (NNT) gene underlies PDFSH.
• This variant mitigates oxidative stress and ferroptosis in sebaceous glands.
• The findings provide insights into the genetic and molecular basis of PDFSH.