title: Nonsense-mediated mRNA decay due to a CACNA1C splicing mutation in a patient with Brugada syndrome.
abstract: BACKGROUND
  Brugada syndrome (BrS) is an inherited cardiac arrhythmia associated with sudden death due to ventricular fibrillation. Mutations in genes related to the cardiac L-type calcium channel have been reported to be causative of BrS. Generally, the messenger RNA (mRNA) that contains a nonsense mutation is rapidly degraded via its decay pathway, which is known as nonsense-mediated mRNA decay (NMD). Previously, we reported a male patient with BrS who carried c.1896G>A (the first nucleotide of CACNA1C exon 14), which caused a synonymous mutation, p.R632R.
  
  
  OBJECTIVE
  To examine how the synonymous CACNA1C mutation p.R632R produces the phenotype of BrS, with a special emphasis on the splicing error and NMD processes.
  
  
  METHODS
  We extracted mRNA from leukocytes of the proband and his 2 children and performed reverse transcription polymerase chain reaction. Complementary DNAs were checked by using direct sequencing and quantitative analysis.
  
  
  RESULTS
  The subsequent sequence electropherogram of the complementary DNAs did not show the substitution of the nucleotide identified in the genomic DNA of the proband. In the mRNA quantification analysis, we confirmed that reduction in the CACNA1C expression level was suspected to be caused by NMD.
  
  
  CONCLUSIONS
  Mutant mRNA with a c.1896G>A substitution may be diminished by NMD, and the resultant decrease in CACNA1C message leads to a novel mechanism for inducing BrS that is distinct from that reported previously.
authors: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Shiga, Japan.
authors: Megumi
authors: M
authors: Fukuyama
authors: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Shiga, Japan.
authors: Seiko
authors: S
authors: Ohno
authors: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Shiga, Japan.
authors: Qi
authors: Q
authors: Wang
authors: Division of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors: Takeshi
authors: T
authors: Shirayama
authors: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Shiga, Japan.
authors: Hideki
authors: H
authors: Itoh
authors: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Shiga, Japan. Electronic address: horie@belle.shiga-med.ac.jp.
authors: Minoru
authors: M
authors: Horie
mesh_terms: D000328:Adult; D053840:Brugada Syndrome / Q000235:genetics*; D020746:Calcium Channels, L-Type / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D059365:Nonsense Mediated mRNA Decay / Q000235:genetics*; D012326:RNA Splicing; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type
keywords: Brugada syndrome; CACNA1C; L-type calcium channel; Nonsense-mediated mRNA decay