Key result
KCNJ5 W101C mutation slows cardiomyocyte pacing by ~25%, which is rescued by IK,ACh inhibition.
Why the study?
KCNJ5 mutations have recently been linked to inherited sinus node dysfunction, but the pathogenic mechanism of the W101C KCNJ5 mutation underlying sinus bradycardia remained to be investigated.
Does the W101C KCNJ5 mutation cause constitutive activation of IK,ACh channels leading to slower pacing, and can it be rescued by channel blockade in hiPSC-derived cardiomyocytes?
Does the W101C KCNJ5 mutation cause constitutive activation of IK,ACh channels leading to slower pacing, and can it be rescued by channel blockade in hiPSC-derived cardiomyocytes?
Absolute Event Rate: 1.5% vs 2%
p-value: p=<0.05
The W101C KCNJ5 mutation causes sinus node dysfunction by constitutively activating GIRK channels, and blocking these channels rescues the bradycardic phenotype in a human cellular model.
Supports GIRK blockade for KCNJ5-related bradycardia in cellular models; hypothesis-generating, should not yet change practice.
Mutations in the KCNJ5 gene, encoding one of the major subunits of cardiac G-protein-gated inwardly rectifying K+ (GIRK) channels, have been recently linked to inherited forms of sinus node dysfunction. Here, the pathogenic mechanism of the W101C KCNJ5 mutation underlying sinus bradycardia in a patient-derived cellular disease model of sinus node dysfunction (SND) was investigated. A human-induced pluripotent stem cell (hiPSCs) line of a mutation carrier was generated, and CRISPR/Cas9-based gene targeting was used to correct the familial mutation as a control line. Both cell lines were further differentiated into cardiomyocytes (hiPSC-CMs) that robustly expressed GIRK channels which underly the acetylcholine-regulated K+ current (IK,ACh). hiPSC-CMs with the W101C KCNJ5 mutation (hiPSCW101C-CM) had a constitutively active IK,ACh under baseline conditions; the application of carbachol was able to increase IK,ACh, further indicating that not all available cardiac GIRK channels were open at baseline. Additionally, hiPSCW101C-CM had a more negative maximal diastolic potential (MDP) and a slower pacing frequency confirming the bradycardic phenotype. Of note, the blockade of the constitutively active GIRK channel with XAF-1407 rescued the phenotype. These results provide further mechanistic insights and may pave the way for the treatment of SND patients with GIRK channel dysfunction.
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Kayser et al. (2023) studied Sinus node dysfunction (SND). W101C KCNJ5 mutation vs. CRISPR/Cas9-corrected isogenic control hiPSC-CMs was evaluated on Spontaneous action potential frequency (pacemaking activity) (p=<0.05). The W101C KCNJ5 mutation induced a slower spontaneous pacing frequency in hiPSC-derived cardiomyocytes (1.5 Hz vs 2.0 Hz in controls) due to constitutively active GIRK channels, which was rescued by the IK,ACh blocker XAF-1407.
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