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Genetic mutation identified as a cause of PAH
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Mutations in the gene KCNK3 that affect potassium channels in the pulmonary artery have been linked to familial and idiopathic pulmonary arterial hypertension, and some of the effects may be counteracted with a phospholipase inhibitor, according to new study findings.
“The most exciting thing about our study is not that we’ve identified a new gene involved in PAH, but that we’ve found a drug that can ‘rescue’ some mutations,” researcher Wendy K. Chung, MD, assistant professor of pediatrics at Columbia University Medical Center, said in a press release.
There are many different causes of PAH, some of which are genetic, according to study background information. However, in approximately 25% of patients with genetic PAH, the cause is not known, the researchers said.
Chung and colleagues studied a family in which multiple members had PAH, but none had mutations detected in any of the genes previously known to be linked to familial PAH such as BMPR2, ALK1 or ENG. Whole-exome sequencing of their DNA was performed, and a novel mutation was found in the gene encoding potassium channel subfamily K, member 3 (KCNK3).
The results were compared with DNA samples from 92 unrelated individuals with genetic PAH and 230 with idiopathic PAH to identify other mutations and mutation carriers.
The researchers performed a functional analysis of the KCNK3 channel to evaluate the mutations. Then, using whole-cell patch-clamp procedures, they tested the expressed currents for response to various pH and pharmacologic agents.
The researchers identified a PAH-causing gene as mutation G203D in KCNK3 in the index family. They identified five other mutations of KCNK3 in the others whose DNA samples were analyzed. KCNK3 mutations were found in 3.2% of participants with genetic PAH and in 1.3% of participants with idiopathic PAH. Using in silico bioinformatic tools, the researchers predicted that all six mutations would be damaging.
Several compounds that had been shown to activate normal human KCNK3 channels were tested. One, the phospholipase A2 inhibitor ONO-RS-082, enabled recovery of potassium-channel current for some PAH-associated mutants.
“KCNK3 mutations are a rare cause of PAH, so I don’t want to oversell our findings,” Chung stated in the release. “Still, it is exciting that we’ve found a mechanism that can lead to the disease that is a new, druggable target. It’s also possible that targeting KCNK3 may be beneficial for patients who have PAH independent of their KCNK3 genetic status.”
Disclosure: The researchers report no relevant financial disclosures.
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