They reveal the mutations that cause one of the most frequent congenital malformations of the heart

The bicuspid aortic valve is the most common congenital malformation in humans, affecting about 1 to 2 percent of the population. It consists of the presence of two asymmetrical valves instead of three symmetrical ones. The malformation often causes valvular stenosis, endocarditis, and is associated with early calcification of the aortic valve. Currently, the only available treatment is surgical valve replacement.

But the results of a new work that has been co-led by the research group of Dr. José Luis de la Pompa from the National Center for Cardiovascular Research (CNIC) in Spain could change this scenario.

This innovative study reveals that new mutations and others previously described by this same group in the MINDBOMB1 (MIB1) gene in the academic journal Nature Medicine are the cause of bicuspid aortic valve.

This information, says Dr. De la Pompa, is expected to have important repercussions in society, helping in the future in the design of possible pharmacological and alternative therapies that lead to the reduction of surgical valve replacement, the only treatment for the bicuspid aortic valve.

For the researcher, “this is especially relevant since the aortic valve is the most common congenital malformation. In addition, it could contribute to reducing the high costs that the treatment of this disease entails for the National Health System”.

Rebeca Piñeiro-Sabarís, Marcos Siguero-Álvarez, Donald McGrogan and José Luis de la Pompa, from the research team. (Photo: CNIC)

In addition to the CNIC, Hadassah Hospital and Sheba Hospital (Israel), the Georges Pompidou European Hospital and the University of Paris (France), the University of Antwerp (Belgium), the Radboud University Medical Center (Netherlands), Harvard Medical School (USA) and the Karolinska Institute (Sweden), among others.

The research combines genome and candidate gene sequencing in a familial cohort, association study of rare variants in additional cohorts, and also association study of common variants in a third large cohort, explains Idit Tessler of Sheba Hospital in Israel. ) and who co-directed the study. In addition, the mutation analysis was performed in patients from different populations, which provides greater robustness to the study.

Subsequently, the results were validated in in vivo mouse models with the aim of analyzing the specific mechanisms by which the MIB1 gene is so important for the correct development of the heart. To do this, Rebeca Piñeiro-Sabarís from the CNIC team and co-author of the study introduced these mutations into the mouse genome using the genetic editing technique known as “CRISPR-Cas9”.

After introducing these MIB1 mutations into a partially deficient genetic background for NOTCH, the researchers observed that double heterozygous mice developed bicuspid aortic valve at a higher frequency, in contrast to what was observed in patients with the malformation with a single mutant allele. for MIB1 (heterozygous). In addition, these double mutant mice also exhibited interventricular septal defects.

This work is part of the doctoral thesis of Rebeca Piñeiro-Sabarís.

The researchers conclude that the genetic association identified in this study between the MIB1 gene and the bicuspid aortic valve (BAV) underscores the important role of the NOTCH signaling pathway in the pathophysiology of BAV and its potential as a target for the design of new diagnostic and therapeutic lines.

The study is titled “Novel Association of the NOTCH Pathway Regulator MIB1 Gene With the Development of Bicuspid Aortic Valve”. And it has been published in the academic journal JAMA Cardiology. (Source: CNIC)