Novel CACNA1C R511Q mutation, located in domain â
-â
¡ linker, causes non-syndromic type-8 long QT syndrome.
PLoS One
; 17(7): e0271796, 2022.
Article
en En
| MEDLINE
| ID: mdl-35862440
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)â -â ¡ 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 Dâ -â ¡ 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 Dâ -â ¡ 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<0.01). The steady-state inactivation of R511Q-ICa was weak in comparison to that of WT-ICa at higher prepulse potentials, resulting in increased window currents in R511Q-ICa. Slow component of inactivation of R511Q-ICa was significantly delayed compared to that of WT-ICa (WT-tau at +20 mV 81.3±3.3 ms, R511Q-tau 125.1±5.0 ms, P<0.01). Inactivation of R511Q-IBa was still slower than that of WT-IBa, indicating that voltage-dependent inactivation (VDI) of R511Q-ICa was predominantly delayed.CONCLUSIONS:
Delayed VDI, increased persistent currents, and increased window currents of R511Q-ICa cause nsLQT8. Our data provide novel insights into the structure-function relationships of Cav1.2 and the pathophysiological roles of the Dâ -â ¡ linker in phenotypic manifestations.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Síndrome de QT Prolongado
/
Canales de Calcio Tipo L
Tipo de estudio:
Etiology_studies
Límite:
Humans
Idioma:
En
Revista:
PLoS One
Asunto de la revista:
CIENCIA
/
MEDICINA
Año:
2022
Tipo del documento:
Article
País de afiliación:
Japón