title: Long QT syndrome type 8: novel CACNA1C mutations causing QT prolongation and variant phenotypes.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga 520-2192, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Fukuyama
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga 520-2192, Japan.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga 520-2192, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kato
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga 520-2192, Japan Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.affiliation: Department of Physiology, Shiga University of Medical Science, Shiga 520-2192, Japan.
authors.forename: Wei-Guang
authors.initials: WG
authors.lastname: Ding
authors.affiliation: Department of Physiology, Shiga University of Medical Science, Shiga 520-2192, Japan.
authors.forename: Futoshi
authors.initials: F
authors.lastname: Toyoda
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga 520-2192, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Itoh
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga 520-2192, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Makiyama
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga 520-2192, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ito
authors.affiliation: Department of Physiology, Shiga University of Medical Science, Shiga 520-2192, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuura
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu, Shiga 520-2192, Japan horie@belle.shiga-med.ac.jp.
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
mesh_terms: D000293:Adolescent; D001321:Autistic Disorder; D020746:Calcium Channels, L-Type / Q000235:genetics*; D002648:Child; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000235:genetics*; D005820:Genetic Testing / Q000706:statistics & numerical data; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D015994:Incidence; D007564:Japan / Q000453:epidemiology; D008133:Long QT Syndrome / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D013576:Syndactyly / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*
chemical_list: C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type; D005819:Genetic Markers
keywords: Arrhythmia; Genetics; L-type calcium channels; L-type calcium current; Long QT syndrome