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

• DOI: 10.1093/europace/euu063
• Publication Date: 2014-04-13T00:54:25Z
• 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
• Keywords: Prolongation

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 elucidate in long syndrome (LQTS), except those and investigate phenotypic variants.CACNA1C gene screening was performed 278 probands negative for LQTS-related mutations. Functional analysis mutant channels using a whole-cell patch-clamp technique also performed. Using genetic screening, we identified five novel mutations: P381S, M456I, A582D, R858H, G1783C seven (2.5%) unrelated probands. Seven mutation carriers showed alternative clinical phenotypes. Biophysical assay revealed that peak calcium currents were significantly larger R858H than wild-type (WT). In contrast, A582D displayed slower inactivation compared WT. The two exerted different gain-of-function effects on currents.In LQTS, higher reported. Even without typical phenotypes syndrome, may and/or fatal arrhythmia attacks.