Mutation in Potassium Channel Gene Linked to Rare Form of Pulmonary Hypertension
By LabMedica International staff writers
Posted on 08 Aug 2013
A mutation in a gene that encodes a potassium channel protein has been linked to development of the rare disease idiopathic pulmonary arterial hypertension (PAH).Posted on 08 Aug 2013
PAH, a rare fatal disease with an incidence of about two to three cases per million of population per year, is characterized by high blood pressure in the lungs that eventually leads to coronary hypertrophy and death. Current there is no cure or effective treatment for PAH, and most PAH patients die within five to seven years of diagnosis.
Image: Cross section of a potassium channel in a smooth muscle cell of the pulmonary artery. A recent study has identified six new mutations in a gene called KCNK3 that can interfere with the function of potassium channels and lead to pulmonary hypertension. The mutations are depicted in color at the locations where they exert their effects (Photo courtesy of Columbia University Medical Center).
To gain a better understanding for the underlying genetic cause behind PAH, investigators at the Columbia University Medical Center (New York, NY, USA) studied a family in which multiple members had PAH without identifiable mutations in any of the genes known to be associated with the disease, including BMPR2, ALK1, ENG, SMAD9, and CAV1. Three family members were studied with whole-exome sequencing. Additional patients with familial or idiopathic PAH were screened for the mutations in the gene that was identified on whole-exome sequencing.
The investigators reported in the July 15, 2013, online edition of the New England Journal of Medicine (NEJM) that they had identified a novel heterozygous missense variant in KCNK3 (the gene encoding potassium channel subfamily K, member 3) as a disease-causing candidate gene in the family. Five additional heterozygous missense variants in KCNK3 were independently identified in 92 unrelated patients with familial PAH and 230 patients with idiopathic PAH.
Computer models predicted that all six novel variants would be damaging to channel protein function, and these predictions were confirmed by electrophysiological studies of the channel that showed that all the missense mutations resulted in loss of function. The reduction in potassium-channel current caused by the mutations in KCNK3 could be reversed in cell cultures by treatment with a phospholipase inhibitor, the candidate drug ONO-RS-082.
“We were surprised to learn that KCNK3 appears to play a role in the function of potassium channels in the pulmonary artery,” said senior author Dr. Wendy K. Chung, associate professor of pediatrics and medicine at Columbia University Medical Center. “No one had suspected that this mechanism might be associated with PAH. The most exciting thing about our study is not that we have identified a new gene involved in pulmonary hypertension, but that we have found a drug that can rescue some mutations. In genetics, it is common to identify a gene that is the source of a disease. However, it is relatively rare to find potential treatments for genetic diseases.”
“KCNK3 mutations are a rare cause of PAH, so I do not want to oversell our findings,” said Dr. Chung. “Still, it is exciting that we have found a mechanism that can lead to the disease that is a new, druggable target. It is also possible that targeting KCNK3 may be beneficial for patients who have PAH independent of their KCNK3 genetic status.”
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Columbia University Medical Center