NEW YORK (GenomeWeb News) – A team led by researchers at Columbia University Medical Center uncovered a new gene linked with pulmonary arterial hypertension, and as the group reported in The New England Journal of Medicine this week, the effects of some mutations in this gene may be mitigated by drug treatment.
Pulmonary arterial hypertension is a rare, progressive, and fatal disorder marked by increased pulmonary artery pressure, which leads to decreased blood flow from the heart to the lungs. And while a number of genes have been linked to familial and idiopathic PAH, the genetic cause of about a quarter of familial cases of the disease is unknown.
Through whole-exome sequencing of a family with multiple members affected by PAH, the researchers homed in on a variant in KCNK3 that appeared to be disease-causing. KCNK3, the researchers noted, encodes part of a potassium channel that is thought to be involved in resting membrane potential and pulmonary vascular tone. By expanding their search to other families as well as to idiopathic PAH cases, the researchers uncovered multiple KCNK3 variants linked to the disease.
"The most exciting thing about our study is not that we've identified a new gene involved in pulmonary hypertension, but that we've found a drug that can 'rescue' some mutations," said Wendy Chung, an associate professor of pediatrics and medicine at Columbia and a co-senior author of the paper, in a statement. "In genetics, it's common to identify a gene that is the source of a disease. However, it's relatively rare to find potential treatments for genetic diseases."
To search for the genetic root of PAH in an affected family lacking known disease mutations, Chung and her colleagues performed whole-exome sequencing of three family members with the disease to a 78.7x average depth of coverage. By filtering out common variants, ones that did not adhere to the autosomal dominant mode of inheritance suggested by a pedigree study, and ones that had predicted benign effects, the researchers narrowed their focus down to 19 SNVs and five indels.
Of those, the G203D missense variant in KCNK3 stood out to the researchers as a strong disease-causing variant as the gene encodes a potassium channel. Using Sanger sequencing, the investigators confirmed that all affected family members carried the variant. Interestingly, one unaffected family member also had the variant, which the researchers said could suggest incomplete penetrance or late onset of the disease.
The investigators also hunted for additional KCNK3 variants in 92 unrelated patients with familial PAH and 230 patients with the idiopathic form of the disease. They found, and confirmed, an additional five variants: G97R, V221L, T8K, E182K, and Y192C. All were predicted to be deleterious.
Through electrophysiological studies of mutant KCNK3 potassium channels, the researchers found that all six variants led to changes to the channel and a loss of its function. For example, the T8K mutation affects the N-terminal, which is the part of the channel involved in membrane transport and interacting with other proteins.
To try to rescue the effects of these mutations, Chung and her colleagues turned to a phospholipase A2 inhibitor that had previously been shown to activate non-mutant KCNK3 channels. In cell cultures, they found that the application of phospholipase A2 inhibitor ONO-RS-082 could increase the current density of two of the three mutant channels tested to non-mutant levels, suggesting a possible therapeutic for some PAH patients.
"KCNK3 mutations are a rare cause of PAH, so I don't want to oversell our findings," Chung noted. "Still, it's exciting that we've found a mechanism that can lead to the disease that is a new, druggable target."