KCNK3 – Heritable Pulmonary Arterial Hypertension

KCNK3 encodes the two-pore domain potassium channel TASK-1, which contributes to the resting membrane potential in pulmonary artery smooth muscle cells. Heterozygous variants in KCNK3 have been implicated in heritable pulmonary arterial hypertension (HPAH), an autosomal dominant disorder with incomplete penetrance characterized by progressive pulmonary vascular remodeling and right ventricular failure. The phenotype includes elevated pulmonary arterial pressure and resistance leading to right heart dysfunction (PMID:28877973). Current guidelines recommend inclusion of KCNK3 in PAH gene panels for patients with familial disease.

Genetic evidence for KCNK3-associated HPAH arises from at least three unrelated probands harboring heterozygous missense variants. Two novel variants, c.316G>C (p.Gly106Arg) and c.544G>A (p.Glu182Lys), were identified in independent familial cases (PMID:30365877; PMID:28889099). These variants segregate with disease in two small pedigrees, consistent with autosomal dominant inheritance. No large multigenerational segregation data are yet available, and carrier penetrance appears incomplete.

Case series totaling three probands revealed only missense variants affecting conserved residues. No loss-of-function truncating or splice variants have been reported to date. Allelic heterogeneity and absence of recurrent founder alleles suggest private mutations in most families. Population frequency for these variants is exceedingly low or absent in control databases.

Functional studies in heterologous systems demonstrate loss of TASK-1 current for both p.Gly106Arg and p.Glu182Lys channels. Patch-clamp electrophysiology in human pulmonary artery smooth muscle and COS-7 cells showed mutation-specific reductions in current amplitude and impaired pH and pharmacological activation with ONO-RS-082 (PMID:28889099). Structural modeling supports pore instability for the p.Gly106Arg substitution.

Animal and cellular models further corroborate KCNK3 dysfunction as a pathogenic mechanism. Kcnk3 loss-of-function rats subjected to left ventricular constriction develop exaggerated pulmonary hypertension and vascular remodeling (PMID:33483721). In kcnk3-deficient mice and patient-derived cells, altered immune responses and metabolic shifts were observed under hypoxic and inflammatory insults, suggesting a “second-hit” requirement for full disease penetrance (PMID:34065088).

Integration of genetic and functional data supports a Moderate clinical validity for the KCNK3–HPAH association. Heterozygous KCNK3 missense variants in three unrelated probands with concordant loss-of-function phenotypes provide substantial evidence, but incomplete segregation and limited numbers of families preclude a Strong classification. Inclusion of KCNK3 in diagnostic PAH panels is clinically useful for genetic counseling and early surveillance. Key take-home: Heterozygous loss-of-function KCNK3 variants cause autosomal dominant heritable PAH with incomplete penetrance and represent actionable targets for early diagnosis and potential pharmacological modulation.

References

• 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
• International Journal of Molecular Sciences • 2021 • KCNK3 Mutation Causes Altered Immune Function in Pulmonary Arterial Hypertension Patients and Mouse Models PMID:34065088
• Cardiovascular Research • 2021 • Kcnk3 dysfunction exaggerates the development of pulmonary hypertension induced by left ventricular pressure overload PMID:33483721
• European Respiratory Review • 2017 • Heritable pulmonary hypertension: from bench to bedside PMID:28877973

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