Bioinformatics Researchers Identify Twenty Potentially Pathogenic Mutations in Gene Associated with Pulmonary Arterial Hypertension
Researchers at HSE University, in collaboration with colleagues from other Russian institutions, have identified which mutations in the ACVRL1 gene may be pathogenic in patients with pulmonary arterial hypertension. The team modelled how genetic variations affect ATP binding to the protein—a process essential for transmitting signals required for normal vascular function. The researchers found that 20 of the 32 variants studied can disrupt signal transmission and are therefore likely to cause disease. The findings have been published in the Journal of Structural Biology.
Pulmonary arterial hypertension (PAH) is a rare chronic disease in which blood vessels of the lungs become narrowed or stiffened, increasing pressure in the pulmonary arteries and making it harder for the heart to pump blood through the lungs. Over time, this places excessive strain on the right side of the heart and can lead to heart failure. PAH can arise from a variety of causes, and identifying the underlying cause is not always straightforward. The disease may be hereditary, triggered by exposure to certain drugs or toxins, or associated with less obvious environmental factors. In some patients, PAH develops as a result of genetic mutations that impair normal vascular function.
Researchers from the HSE Faculty of Computer Science, in collaboration with colleagues from Moscow State University and Moscow's Bauman City Clinical Hospital No. 29, identified which mutations in the ACVRL1 gene can disrupt the normal functioning of vascular cells.
Maria Poptsova
'We had clinical data from two patients with pulmonary arterial hypertension. Standard genetic testing did not identify the cause of the disease, as no known pathogenic variants were detected. However, both patients carried mutations in the ACVRL1 gene near the ATP-binding site. This prompted us to investigate which changes in this gene might be associated with PAH,' explains study co-author Maria Poptsova, Director of the Centre for Biomedical Research and Technologies at the AI and Digital Science Institute, HSE Faculty of Computer Science.
The ACVRL1 gene contains the instructions for assembling the ALK1 receptor protein. Located on the surface of vascular cells, this protein helps transmit signals that are essential for the development and proper functioning of blood vessels. For signal transmission to occur, an adenosine triphosphate (ATP) molecule must bind to the ATP-binding pocket—a small cavity within the protein's structure. If a mutation alters the shape or chemical properties of this pocket, ATP may bind either too weakly or too strongly. In both cases, signal transmission is disrupted: the protein must not only bind ATP but also release it at the right time for the next step in the signalling pathway.
The researchers examined how amino acid substitutions in the ALK1 protein influence the structure of the ATP-binding pocket. To do this, they used molecular dynamics, a computational simulation method making it possible to track how protein atoms and associated molecules behave over time.
The authors emphasize that these findings are fundamental in nature and do not have direct biological implications.
First, the researchers validated the effectiveness of their approach using ACVRL1 variants that were already known to be pathogenic or likely pathogenic. They then analysed all ACVRL1 variants reported in genetic databases that remained of uncertain diagnostic significance. In 20 of the 32 variants studied, ATP binding was disrupted, leading the authors to propose reclassifying them as likely pathogenic. In addition, the researchers examined mutations that have not yet been observed in databases but could theoretically occur in patients. Among the variants that standard prediction algorithms could not confidently classify, 9 out of 12 were also suggested to be likely pathogenic.
