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. 2023 Nov 14;148(20):1598-1601.
doi: 10.1161/CIRCULATIONAHA.122.061864. Epub 2023 Nov 13.

Studying Long QT Syndrome Caused by NAA10 Genetic Variants Using Patient-Derived Induced Pluripotent Stem Cells

Nadjet Belbachir  1   2 , Yiyang Wu  3   4 , Mengcheng Shen  1   2 , Sophia L Zhang  1   2 , Joe Z Zhang  1   2 , Chun Liu  1   2   5 , Bjorn C Knollmann  6 , Gholson J Lyon  3   7   8 , Ning Ma  1   2   9   10 , Joseph C Wu  1   2   11   5
Affiliations

Studying Long QT Syndrome Caused by NAA10 Genetic Variants Using Patient-Derived Induced Pluripotent Stem Cells

Nadjet Belbachir et al. Circulation. .
No abstract available

Keywords: Cav1.2 calcium channel; NAA10; iPSC; long QT; rare disease.

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Conflict of interest statement

Disclosures J.C.W. is a cofounder and scientific advisory board member of Greenstone Biosciences. The other authors report no conflicts.

Figures

Figure.
Figure.
Studying N-α-acetyltransferase 10 variants using patient-derived induced pluripotent stem cells. A, iPSCs were reprogrammed from 2 patients carrying mutations on the NAA10 gene (p.S37P and p.Y43S),, and corresponding clustered regularly interspaced short palindromic repeats (CRISPR)-corrected isogenic control iPSC lines were generated and then differentiated into iPSC-CMs. A full electrophysiology investigation was conducted, including patch clamp both in perforated and whole cell configurations and multielectrode array (MEA) measurements. B, Representative action potential recordings of iPSC-CMs from patient lines (NAA10p.Y43S and NAA10p.S37P) and isogenic CRISPR-corrected lines (NAA10p.Y43Scor, NAA10p.S37Pcor) by patch clamp. C, Early after depolarization observed in action potential recordings from mutated and corrected isogenic iPSC-CMs (NAA10_Y43S: n=9 vs Y43Scor: n=14 and S37P: n=12 vs S37Pcor: n=10). D, Action potential durations (APDs) of patient lines and corrected isogenic lines. **P<0.01, ***P<0.001 by Mann-Whitney test. E, L-type calcium current (ICaL) current-voltage relationship of maximum current density (NAA10_Y43S: n=9 vs Y43Scor: n=9 and S37P: n=14 vs S37Pcor: n=11). **P<0.01, ***P<0.001, ****P<0.0001 by 2-way ANOVA combined with multiple comparison test comparing mutated lines vs corrected lines at each voltage regardless of row and column. F, Representative ICaL records of NAA10 variant lines (p.Y43S and p.S37P) and corresponding corrected isogenic lines using patch clamp. Inset, Voltage-clamp protocol. G, Overlap of ICaL activation (G/Gmax) and inactivation (I/Imax) plots, both fitted using the Boltzmann equation. Inset, ICaL window current (NAA10_Y43S: n=9 vs Y43Scor: n=9 and S37P: n=16 vs S37Pcor: n=9). *P<0.05, **P<0.01, ***P<0.001 by 2-way ANOVA with multiple comparison between corrected and mutated lines at each voltage point. H, Representative MEA recordings of NAA10 variants (p.Y43S and p.S37P) and corresponding corrected isogenic lines before and after acute treatment with ICaL inhibitors nifedipine (blue) and verapamil (green). Red arrows indicate arrhythmic events. I, Field-potential duration measurements of NAA10p.Y43S, NAA10p.Y43Scor, NAA10p.S37P, and NAA10p.S37Pcor iPSC-CMs before and after acute nifedipine and verapamil treatment. ***P<0.001, **** P<0.0001 (2-way ANOVA statistical analysis combined with multiple comparison test comparing baseline vs dose for each line). CM indicates cardiomyocyte; FPDc, corrected field potential duration; iPSC, induced pluripotent stem cell; iPSC-CM, induced pluripotent stem cell–derived cardiomyocyte; and NAA10, N-α-acetyltransferase 10.
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References

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