Novel CACNA1C R511Q mutation, located in domain Ⅰ-Ⅱ linker, causes non-syndromic type-8 long QT syndrome

Tadashi Nakajima, Reika Kawabata-Iwakawa, Shuntaro Tamura, Hiroshi Hasegawa, Takashi Kobari, Hideki Itoh, Minoru Horie, Masahiko Nishiyama, Masahiko Kurabayashi, Yoshiaki Kaneko and Hideki Ishii

PLOS ONE, 2022, vol. 17, issue 7, 1-15

Abstract: Background: Gain-of-function mutations in CACNA1C encoding Cav1.2 cause syndromic or non-syndromic type-8 long QT syndrome (LQTS) (sLQT8 or nsLQT8). The cytoplasmic domain (D)Ⅰ-Ⅱ linker in Cav1.2 plays a pivotal role in calcium channel inactivation, and mutations in this site have been associated with sLQT8 (such as Timothy syndrome) but not nsLQT8. Objective: Since we identified a novel CACNA1C mutation, located in the DⅠ-Ⅱ linker, associated with nsLQTS, we sought to reveal its biophysical defects. Methods: Target panel sequencing was employed in 24 genotype-negative nsLQTS probands (after Sanger sequencing) and three family members. Wild-type (WT) or R511Q Cav1.2 was transiently expressed in tsA201 cells, then whole-cell Ca2+ or Ba2+ currents (ICa or IBa) were recorded using whole-cell patch-clamp techniques. Results: We identified two CACNA1C mutations, a previously reported R858H mutation and a novel R511Q mutation located in the DⅠ-Ⅱ linker. Four members of one nsLQTS family harbored the CACNA1C R511Q mutation. The current density and steady-state activation were comparable to those of WT-ICa. However, persistent currents in R511Q-ICa were significantly larger than those of WT-ICa (WT at +20 mV: 3.3±0.3%, R511Q: 10.8±0.8%, P

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pone00:0271796

DOI: 10.1371/journal.pone.0271796

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