In:
PLOS ONE, Public Library of Science (PLoS), Vol. 17, No. 7 ( 2022-7-21), p. e0271796-
Kurzfassung:
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 Ca 2+ or Ba 2+ currents (I Ca or I Ba ) 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-I Ca . However, persistent currents in R511Q-I Ca were significantly larger than those of WT-I Ca (WT at +20 mV: 3.3±0.3%, R511Q: 10.8±0.8%, P 〈 0.01). The steady-state inactivation of R511Q-I Ca was weak in comparison to that of WT-I Ca at higher prepulse potentials, resulting in increased window currents in R511Q-I Ca . Slow component of inactivation of R511Q-I Ca was significantly delayed compared to that of WT-I Ca (WT-tau at +20 mV: 81.3±3.3 ms, R511Q-tau: 125.1±5.0 ms, P 〈 0.01). Inactivation of R511Q-I Ba was still slower than that of WT-I Ba , indicating that voltage-dependent inactivation (VDI) of R511Q-I Ca was predominantly delayed. Conclusions Delayed VDI, increased persistent currents, and increased window currents of R511Q-I Ca cause nsLQT8. Our data provide novel insights into the structure-function relationships of Cav1.2 and the pathophysiological roles of the DⅠ-Ⅱ linker in phenotypic manifestations.
Materialart:
Online-Ressource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0271796
DOI:
10.1371/journal.pone.0271796.g001
DOI:
10.1371/journal.pone.0271796.g002
DOI:
10.1371/journal.pone.0271796.g003
DOI:
10.1371/journal.pone.0271796.t001
DOI:
10.1371/journal.pone.0271796.t002
DOI:
10.1371/journal.pone.0271796.t003
DOI:
10.1371/journal.pone.0271796.t004
Sprache:
Englisch
Verlag:
Public Library of Science (PLoS)
Publikationsdatum:
2022
ZDB Id:
2267670-3