Phoenix Children’s Research Institute Study Identifies FOXF1 Enhancers Involved in Rare Lung Disease

Research has implications for more common pulmonary disorders

PHOENIX [June 19, 2024] – According to a study published in Nature Communications, research conducted at the Phoenix Children’s Research Institute at the University of Arizona College of Medicine — Phoenix, shows how frequent non-coding FOXF1 gene deletions that interfere with important DNA regulatory regions, called enhancers, can lead to Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV), a rare, lethal, genetic lung disease which causes respiratory failure in newborns and infants.

The FOXF1 protein is critically important in pulmonary vascular development, specifically responsible for the extension and branching of airways and blood vessels in the developing lung. 

“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,” said Vlad Kalinichenko, MD, PhD, internationally renowned lung development and regeneration researcher and director of the Phoenix Children’s Research Institute at the University of Arizona College of Medicine – Phoenix.

This study, conducted in collaboration with Cincinnati Children’s Hospital Medical Center, identified four upstream enhancers in the FOXF1 gene locus — FOXF1 Expression in the Lung 1, 2, 3 and 4. It further showed these elements stimulate cell-specific FOXF1 expression in pulmonary endothelium and stromal cells, such as fibroblasts and pericytes. Pulmonary endothelial cells are essential to the development of alveoli, the tiny branches of air tubes in the lungs responsible for the exchange of oxygen and carbon dioxide in the bloodstream. Likewise, pulmonary stromal cells are also important to lung development and are a crucial component of overall lung structure. 

Since many non-coding deletions in or near the FOXF1 gene locus cause ACDMPV, identifying specific pathogenic FOXF1 enhancers — that are critical for lung development — is important to understand and diagnose ACDMPV. This work could also enable better genetic screening for the disease, which currently relies primarily on exome DNA sequencing. 

“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,” said Dr. Kalinichenko. “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.”

The Phoenix Children's Research Institute at the University of Arizona College of Medicine –Phoenix launched in May 2023, formalizing a longstanding research collaboration between the health system and the University of Arizona College of Medicine – Phoenix. The Research Institute includes more than 700 active studies, 640 research investigators and 90 research staff members, including research scientists, associates, biostatisticians, pharmacists, nurses and coordinators. Scientists engage in research across multiple clinical disciplines, including cancer, neurology, cardiology, pulmonology and more.