Novel PA-Hypertension Gene Variants Identified, Treatment Approach Hinted

July 26, 2013

BOSTON, Massachusetts — Several variants of a gene related to potassium-ion channels that appear to mediate pulmonary vascular function have been identified in families of patients with pulmonary artery (PA) hypertension, according to a report in the July 25, 2013 issue of the New England Journal of Medicine [1].

Neither the specific gene involved, KCNK3, nor the potassium channelopathies associated with its variants had been previously linked to PA hypertension, so they represent a "mechanistically novel cause" of the disorder, write the authors, led by Dr Lijiang Ma (Columbia University Medical Center, New York, NY).

Several members of a family with multiple cases of PA hypertension, but lacking mutations already associated with the disorder, were studied using whole-exome sequencing. A novel variant on KCNK3 emerged as a possible genetic cause of the family's disease and was subsequently identified in many members of the extended family.

Five more variants on the same gene were separately identified in 92 other patients with familial PA hypertension and in 230 patients with PA hypertension that had been considered idiopathic. Upon electrophysiologic testing, they were found to be loss-of-function mutations affecting potassium channels.

In vitro application of ONO-RS-082 (2-[p-amylcinnamoyl]amino-4-chlorobenzoic acid), an investigational drug that is, among other things, a phospholipase A2 inhibitor, led to a "robust increase" in ion channels related to nonmutant-containing KCNK3 and recovery of function of channels associated with two out of three tested KCNK3 mutations.

Identification of asymptomatic carriers of KCNK3 variants, the group writes, "provides a potential opportunity for early intervention and treatment if an effective therapy is available."

The study was supported by grants from the National Institutes of Health and Vanderbilt University.


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