ABCC8 – Pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive vasculopathy characterized by elevated pulmonary artery pressure and vascular resistance, leading to right heart failure. Genetic studies have recently implicated rare variants in the ABCC8 gene, encoding the SUR1 subunit of the ATP-sensitive potassium (K_ATP) channel, in a subset of PAH patients. Loss-of-function mutations in ABCC8 disrupt channel activity, suggesting a novel channelopathy mechanism in PAH.

Genetic Evidence

Heterozygous rare ABCC8 variants were identified in 12 unrelated PAH probands through exome sequencing of 233 pediatric and adult cases, including a de novo c.2873G>A (p.Arg958His) variant in an idiopathic PAH child ([PMID:30354297]). A second cohort of 680 adult‐onset PAH patients yielded 11 additional heterozygous predicted damaging missense variants ([PMID:30354297]). In a Spanish registry of 624 PAH patients, 11 rare ABCC8 variants—several affecting canonical splice sites—were confirmed by hybrid minigene assays ([PMID:32934261]).

Variant Spectrum and Inheritance

All reported ABCC8 PAH variants are heterozygous and predominantly missense, with one premature termination change. Variants cluster across transmembrane and nucleotide-binding domains with no clear founder alleles reported. De novo occurrence and absence in population databases support pathogenicity.

Functional Evidence

Patch-clamp and rubidium flux analyses in COS cells demonstrated loss of ATP-sensitive K^+ current for all PAH-associated SUR1 variants, which was pharmacologically rescued by the SUR1 activator diazoxide ([PMID:30354297]). Hybrid minigene splicing assays verified aberrant exon usage for predicted splice variants ([PMID:32934261]). These data confirm that ABCC8 variants produce loss of K_ATP channel function in vitro.

Mechanism and Clinical Implications

ABCC8 loss-of-function allele carriers have impaired SUR1 regulation of pulmonary vascular tone, contributing to increased vascular resistance in PAH. ABCC8 variants account for ~2.7% of PAH cases across multiple cohorts ([PMID:35204766]). This channelopathy insight suggests SUR1 activators as potential targeted therapies and informs genetic screening in PAH.

Key Take-home: Heterozygous loss-of-function ABCC8 variants cause a novel SUR1 channelopathy in ~2.7% of PAH patients, with direct implications for diagnosis and pharmacological rescue.

References

• Circulation. Genomic and precision medicine • 2018 • Loss-of-Function ABCC8 Mutations in Pulmonary Arterial Hypertension PMID:30354297
• Scientific Reports • 2020 • Characterization of rare ABCC8 variants identified in Spanish pulmonary arterial hypertension patients PMID:32934261
• Biomolecules • 2022 • Channelopathy Genes in Pulmonary Arterial Hypertension PMID:35204766

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