With the advancement of genomics and genome sequencing, it has become possible for researchers to study diseases down to their very blueprints. “Brand name” diseases like cancer have used this to enormous effect, while rarer diseases have been left in the dust (relatively speaking). However, efforts are being made to bring them up to speed.
Pulmonary arterial hypertension is a rare cardiovascular disease where the blood vessels of the pulmonary arteries change and make it harder for blood to pass through them. This type of disease usually causes heart failure if not treated in time. From a genetic standpoint, studies already have several genes that are commonly mutated in pulmonary arterial hypertension. A new gene, ABCC8, has recently been added to that list, and a team from the Universidade de Vigo in Spain decided to investigate more.
ABCC8 is a gene encoding a subunit of an ion channel associated with type 2 diabetes. Pulmonary arterial hypertension can also be characterized as a “channelopathy” due to mutations in other ion channels present in the disease. Finally, diabetes, in general, is linked to cardiovascular disease, so it stood to reason that ABCC8 may be linked to pulmonary arterial hypertension in some way. The team examined data from 624 pulmonary arterial hypertension patients from a Spanish registry to identify any with ABCC8 mutations. They then studied those mutations to determine if any were unique or disease-causing.
The initial screening of the 624 patients found that only 11 had ABCC8 mutations. Of these mutations, five were associated with diabetes in some way. Genetic analysis showed all but four of the mutation sites were essential (based on gene conservation). None of the mutations were predicted to destabilize the final protein in a significant way. While this may not translate well into real-world results, details such as these are how we begin to understand how a protein works at a base level.
The team notes that while none of the mutations were predicted to destabilize the protein as a whole, two were located near the active site, causing problems with the protein’s activity. Final analysis of the mutations indicated two were pathogenic (disease-causing), and six were likely to be pathogenic. A more extensive study would be needed to confirm these results. However, as pulmonary arterial hypertension is a rare disease, it would be challenging to meet those requirements.
This study identified eight possible ABCC8 mutations that might be pathogenic for pulmonary arterial hypertension. They also studied the mutations in question and generated useful data for more high-level studies.
The study concludes, “we report eleven novel changes in ABCC8 gene found in PAH patients. Thanks to in vitro biochemical analyses and in silico tools we were able to classify them according to ACMG: two as pathogenic, six as likely pathogenic and three as VUS.”