NR2F2 loss‑of‑function mutation is responsible for congenital bicuspid aortic valve

Area of Science:

• Cardiovascular Genetics
• Developmental Biology
• Human Genetics

Background:

• Bicuspid aortic valve (BAV) is the most common congenital heart defect, affecting up to 2% of the population.
• BAV significantly increases the risk of severe cardiovascular complications like valvulopathy and aortopathy.
• While the genetic basis of BAV is recognized, the specific genes involved in most cases remain unknown.

Purpose of the Study:

• To investigate the genetic underpinnings of congenital bicuspid aortic valve (BAV).
• To identify novel genes and mutations contributing to the pathogenesis of BAV.
• To elucidate the functional consequences of identified genetic variations on cardiovascular development.

Main Methods:

• Sequencing of the nuclear receptor subfamily 2 group F member 2 (NR2F2) gene in 176 unrelated BAV cases.
• Genotyping of NR2F2 in family members and 280 healthy controls.
• Functional characterization of NR2F2 mutations using a dual-luciferase reporter assay.

Main Results:

• A novel heterozygous NR2F2 mutation (c.288C>A; p.(Cys96*)) was identified in a BAV family, inherited in an autosomal dominant manner.
• The identified nonsense mutation was absent in 560 control chromosomes.
• Functional assays revealed the mutant NR2F2 protein lacked transcriptional activity and impaired synergistic activation with GATA-4.

Conclusions:

• NR2F2 is identified as a novel susceptibility gene for human congenital bicuspid aortic valve (BAV).
• The findings reveal a new molecular mechanism contributing to BAV development.
• This research deepens our understanding of the genetic etiology of BAV and associated cardiovascular diseases.