KCNK3 – Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy characterized by elevated pulmonary artery pressure, vascular remodeling, and right heart failure. Genetic predisposition plays a critical role in both familial and idiopathic PAH. KCNK3, encoding the TASK-1 two-pore domain potassium channel, was first implicated as a PAH gene in 2013 and has since been classified as a definitive PAH gene by ClinGen (PMID:37422716).

Initial evidence arose from a family with autosomal dominant PAH harboring a heterozygous missense variant c.608G>A (p.Gly203Asp) in KCNK3, segregating with disease in three affected members (PMID:23883380). Subsequent screening of 92 familial and 230 idiopathic PAH patients uncovered five additional damaging missense variants, supporting a recurrent channelopathy mechanism (325 probands total) (PMID:23883380).

Additional genetic studies include identification of a homozygous KCNK3 mutation in a consanguineous family with aggressive PAH, and detection of KCNK3 variants in two further PAH pedigrees during national referral and panel-based sequencing efforts, with segregation in at least 19 affected relatives overall (PMID:27649371; PMID:26699722).

The variant spectrum comprises six missense changes, including c.608G>A (p.Gly203Asp), c.23C>A (p.Thr8Lys), c.289G>A (p.Gly97Arg), c.575A>G (p.Tyr192Cys), c.544G>A (p.Glu182Lys), and c.661G>C (p.Val221Leu), all demonstrating loss of TASK-1 current in heterologous systems.

Functional assays in COS-7 cells, human pulmonary artery smooth muscle cells, and patch-clamp recordings established a loss-of-function mechanism for KCNK3 variants, with partial pharmacological rescue by the phospholipase inhibitor ONO-RS-082 and the guanylate cyclase stimulator riociguat (PMID:28889099; PMID:30365877).

A recent study identified a novel KCNK3 variant in a patient with dasatinib-associated PAH. Patch-clamp and knockdown experiments in pulmonary endothelial and smooth muscle cells confirmed channel loss-of-function, dasatinib-induced downregulation of KCNK3, impaired barrier and migratory properties, mitochondrial depolarization, and glycolytic shift, linking KCNK3 dysfunction to drug-triggered PAH (PMID:38546978).

Collectively, genetic and experimental data provide definitive evidence that heterozygous loss-of-function KCNK3 variants cause autosomal dominant PAH with incomplete penetrance. TASK-1 dysfunction underlies vasoconstriction, endothelial injury, and metabolic reprogramming, offering both diagnostic utility and a potential channel-targeted therapeutic axis.

Key Take-home: Heterozygous KCNK3 loss-of-function variants cause definitive autosomal dominant PAH, supported by robust segregation, >300 probands, and concordant functional studies, guiding genetic testing and channel-focused therapy.

References

• The New England journal of medicine • 2013 • A novel channelopathy in pulmonary arterial hypertension. PMID:23883380
• Journal of the American Heart Association • 2017 • The Impact of Heterozygous KCNK3 Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery. PMID:28889099
• The Journal of physiology • 2019 • Characterization and regulation of wild-type and mutant TASK-1 two pore domain potassium channels indicated in pulmonary arterial hypertension. PMID:30365877
• American journal of respiratory cell and molecular biology • 2024 • Role of KCNK3 Dysfunction in Dasatinib-associated Pulmonary Arterial Hypertension and Endothelial Cell Dysfunction. PMID:38546978
• Genetics in medicine : official journal of the American College of Medical Genetics • 2023 • Defining the clinical validity of genes reported to cause pulmonary arterial hypertension. PMID:37422716

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