The utility of zebrafish cardiac arrhythmia model to predict the pathogenicity of KCNQ1 variants

Genetic testing for inherited arrhythmias and discriminating pathogenic or benign variants from variants of unknown significance (VUS) is essential for gene-based medicine. KCNQ1 is a causative gene of type 1 long QT syndrome (LQTS), and approximately 30% of the variants found in type 1 LQTS are cla...

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Bibliographic Details
Published in:Journal of molecular and cellular cardiology 2023-04, Vol.177, p.50-61
Main Authors: Cui, Shihe, Hayashi, Kenshi, Kobayashi, Isao, Hosomichi, Kazuyoshi, Nomura, Akihiro, Teramoto, Ryota, Usuda, Keisuke, Okada, Hirofumi, Deng, Yaowen, Kobayashi-Sun, Jingjing, Nishikawa, Tetsuo, Furusho, Hiroshi, Saito, Takekatsu, Hirase, Hiroaki, Ohta, Kunio, Fujimoto, Manabu, Horita, Yuki, Kusayama, Takashi, Tsuda, Toyonobu, Tada, Hayato, Kato, Takeshi, Usui, Soichiro, Sakata, Kenji, Fujino, Noboru, Tajima, Atsushi, Yamagishi, Masakazu, Takamura, Masayuki
Format: Article
Language:English
Subjects:
Action potential duration
Animals
CRISPR/Cas9
Humans
KCNQ1
KCNQ1 Potassium Channel - genetics
Long QT syndrome
Long QT Syndrome - genetics
Mutation
RNA, Complementary
Variants of unknown significance
Virulence
Zebrafish
Zebrafish - genetics
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Summary:Genetic testing for inherited arrhythmias and discriminating pathogenic or benign variants from variants of unknown significance (VUS) is essential for gene-based medicine. KCNQ1 is a causative gene of type 1 long QT syndrome (LQTS), and approximately 30% of the variants found in type 1 LQTS are classified as VUS. We studied the role of zebrafish cardiac arrhythmia model in determining the clinical significance of KCNQ1 variants. We generated homozygous kcnq1 deletion zebrafish (kcnq1del/del) using the CRISPR/Cas9 and expressed human Kv7.1/MinK channels in kcnq1del/del embryos. We dissected the hearts from the thorax at 48 h post-fertilization and measured the transmembrane potential of the ventricle in the zebrafish heart. Action potential duration was calculated as the time interval between peak maximum upstroke velocity and 90% repolarization (APD90). The APD90 of kcnq1del/del embryos was 280 ± 47 ms, which was significantly shortened by injecting KCNQ1 wild-type (WT) cRNA and KCNE1 cRNA (168 ± 26 ms, P 
ISSN:0022-2828
1095-8584
DOI:10.1016/j.yjmcc.2023.03.001