Currently, the only effective treatment for congenital heart defects is valve replacement surgery.

The prevalence of bicuspid aortic valve, the most common congenital defect in humans, affects approximately 1% to 2% of the population. Instead of the typical three symmetrical leaflets, individuals with this condition have two asymmetrical valve leaflets. It often leads to aortic stenosis, endocarditis, and early calcification of the aortic valve. At present, the only effective treatment is valve replacement surgery.

However, the outcome of a recent study conducted by an international team, co-led by Dr. José Luis de la Pompa, a group leader at CNIC, has the potential to change this situation.

The groundbreaking multicenter study, published in JAMA Cardiology, reveals that mutations in the MINDBOMB1 gene (MIB1) are responsible for causing bicuspid aortic valve.

Some of these mutations were newly identified in the study, while others had been previously reported by the same research group in an earlier article published in Nature Medicine.

Dr. de la Pompa is hopeful that these discoveries will have a significant impact, enabling the development of pharmacological treatments as alternatives to valve replacement surgery in the future.

He emphasized the importance of this prospect since bicuspid aortic valve is the most prevalent congenital defect. In addition to benefiting patients, non-surgical alternatives could alleviate the financial burden on healthcare systems.

For the study, the CNIC team partnered with, among other centers, Hadassah and Sheba Hospitals in Israel, Georges Pompidou European Hospital and the University of Paris in France, the University of Antwerp in Belgium,  (Bélgica), Radboud University Medical Center in The Netherlands, Harvard University Medical School in the USA, and the Karolinska Institute in Sweden.

The study involved collaboration between the CNIC team and various institutions, including Hadassah and Sheba Hospitals in Israel, Georges Pompidou European Hospital and the University of Paris in France, the University of Antwerp in Belgium, Radboud University Medical Center in the Netherlands, Harvard University Medical School in the USA, and the Karolinska Institute in Sweden.

To investigate the specific mechanisms by which MIB1 ensures proper heart development, Dr. Rebeca Piñeiro-Sabarís from the CNIC team, co-first author of the study and part of Dr. José Luis de la Pompa’s team, employed CRISPR-Cas9 gene editing.

This approach involved introducing the identified mutations into the genome of mice already carrying one mutant allele for the NOTCH receptor. The mice only developed bicuspid aortic valve at a high rate when they possessed both mutations (double heterozygotes), contrasting with human patients who developed the heart defect with a single mutation in one MIB1 allele (single heterozygotes).

Furthermore, the mice with both mutations exhibited defects in the interventricular septum.

This study forms part of Dr. Rebeca Piñeiro-Sabarís’ doctoral thesis.

The researchers conclude that the discovered association between MIB1 and bicuspid aortic valve underscores the significant role of the NOTCH signaling pathway in this congenital defect. It also highlights the potential of targeting NOTCH pathway components for the development of new diagnostic and therapeutic strategies.

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