Long QT syndrome type 8: novel CACNA1C mutations causing QT prolongation and variant phenotypes.

Abstract

AIMS:

CACNA1C mutations have been reported to cause LQTS type 8 (LQT8; Timothy syndrome), which exhibits severe phenotypes, although the frequency of patients with LQT8 exhibiting only QT prolongation is unknown. This study aimed to elucidate the frequency of CACNA1C mutations in patients with long QT syndrome (LQTS), except those with Timothy syndrome and investigate phenotypic variants.

METHODS AND RESULTS:

CACNA1C gene screening was performed in 278 probands negative for LQTS-related gene mutations. Functional analysis of mutant channels using a whole-cell patch-clamp technique was also performed. Using genetic screening, we identified five novel CACNA1C mutations: P381S, M456I, A582D, R858H, and G1783C in seven (2.5%) unrelated probands. Seven mutation carriers showed alternative clinical phenotypes. Biophysical assay of CACNA1C mutations revealed that the peak calcium currents were significantly larger in R858H mutant channels than those of wild-type (WT). In contrast, A582D mutant channels displayed significantly slower inactivation compared with WT. The two mutant channels exerted different gain-of-function effects on calcium currents.

CONCLUSION:

In patients with LQTS, the frequency of CACNA1C mutations was higher than reported. Even without typical phenotypes of Timothy syndrome, CACNA1C mutations may cause QT prolongation and/or fatal arrhythmia attacks.

• Authors: Megumi Fukuyama, Qi Wang, Koichi Kato, Seiko Ohno, Wei-Guang Ding, Futoshi Toyoda, Hideki Itoh, Hiromi Kimura, Takeru Makiyama, Makoto Ito, Hiroshi Matsuura, Minoru Horie
• Journal: Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology (Europace) Vol. 16 Issue 12 Pg. 1828-37 (Dec 2014) ISSN: 1532-2092 [Electronic] England
• PMID: 24728418 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: [email protected].

Chemical References

• CACNA1C protein, human
• Calcium Channels, L-Type
• Genetic Markers

Topics

• Adolescent
• Autistic Disorder
• Calcium Channels, L-Type (genetics)
• Child
• Female
• Genetic Markers (genetics)
• Genetic Predisposition to Disease (epidemiology, genetics)
• Genetic Testing (statistics & numerical data)
• Genetic Variation (genetics)
• Humans
• Incidence
• Japan (epidemiology)
• Long QT Syndrome (diagnosis, epidemiology, genetics)
• Male
• Middle Aged
• Mutation (genetics)
• Phenotype
• Polymorphism, Single Nucleotide (genetics)
• Risk Factors
• Syndactyly (diagnosis, epidemiology, genetics)