Arizona College of Medicine’s Phoenix Children’s Research Institute, in collaboration with Cincinnati Children’s Hospital Medical Center, has identified critical enhancers in the FOXF1 gene.

According to the Phoenix Children’s Research Institute, these enhancers play a pivotal role in the development of alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV).

ACDMPV is a rare and often fatal genetic lung disease affecting newborns and infants.

Published in Nature Communications, the study highlights how frequent deletions in non-coding regions of the FOXF1 gene disrupt enhancers, which are DNA segments crucial for regulating gene activity.

These disruptions interfere with FOXF1 protein production, which is essential for proper pulmonary vascular development, including the extension and branching of airways and blood vessels in the lungs.

Phoenix Children’s Research Institute director Vlad Kalinichenko said: “Prior to this study, we knew deletions and mutations in the FOXF1 gene locus can result in ACDMPV, so our goal was to identify FOXF1 enhancers associated with the disease so we can diagnose it more precisely in newborn babies.”

ACDMPV leads to respiratory failure due to abnormalities in the alveolar capillary structure, impairing the exchange of oxygen and carbon dioxide in the bloodstream.

By identifying four specific enhancers, FOXF1 Expression in the Lung 1, 2, 3, and 4, the research demonstrated their role in stimulating FOXF1 expression in pulmonary endothelial and stromal cells, such as fibroblasts and pericytes. These cells are critical for alveolar development and overall lung structure.

The findings are said to underscore the importance of understanding these enhancers in diagnosing ACDMPV and potentially improving genetic screening methods.

Current diagnostic approaches heavily rely on exome DNA sequencing, but the identification of pathogenic FOXF1 enhancers could enhance accuracy and effectiveness in diagnosing this type of lung disease.

Kalinichenko said: “This study demonstrates four specific FOXF1 enhancers play critical roles in the development of ACDMPV and resolves an important clinical question regarding why frequent non-coding FOXF1 deletions that interfere with endothelial and mesenchymal enhancers can lead to this lethal disease.

“Identifying mutations in the FOXF1 gene locus sooner will be critical for accurate genetic diagnosis of this severe congenital disease.

“As we continue to gain additional insight into how genes work, it will improve our capabilities to implement effective therapeutic interventions in more common pulmonary disorders of newborns and infants, such as bronchopulmonary dysplasia and congenital diaphragmatic hernia.”