title: Novel long QT syndrome-associated missense mutation, L762F, in CACNA1C-encoded L-type calcium channel imparts a slower inactivation tau and increased sustained and window current.
abstract: BACKGROUND
  Mutations in the CACNA1C-encoded L-type calcium channel have been associated with Timothy syndrome (TS) with severe QT prolongation, syndactyly, facial dysmorphisms, developmental delay, and sudden death. Recently, patients hosting CACNA1C mutations with only long QT syndrome (LQTS) have been described. We sought to identify novel variants in CACNA1C associated with either TS or LQTS, and to determine the impact of the mutation on channel function.
  
  
  RESULTS
  Two probands were identified with mutations in CACNA1C, one with a TS-associated mutation, G406R, and a second with genotype-negative LQTS. Illumina HiSeq 2000 whole exome sequencing on the genotype-negative LQTS proband revealed a novel variant, CACNA1C-L762F, that co-segregated within a multi-generational family. The missense mutation localized to the DII/DIII intracellular interlinker segment of the channel in a highly conserved region in close proximity to the 6th transmembrane segment of domain II (DIIS6). Whole cell patch clamp of heterologously expressed CACNA1C-L762F in TSA201 cells demonstrated slower inactivation tau and increased sustained and window current. Comprehensive review and topological mapping of all described CACNA1C mutations revealed TS-specific hotspots localizing to the cytoplasmic aspect of 6th transmembrane segment of respective domains. Probands hosting TS mutations were associated with elevated QTc, higher prevalence of 2:1 AV block, and a younger age at presentation compared to LQTS.
  
  
  CONCLUSIONS
  The CACNA1C-L762F mutation is associated with development of LQTS through slower channel inactivation and increased sustained and window current. TS-associated mutations localize to specific areas of CACNA1C and are associated with a younger age at presentation, higher QTc, and 2:1 AV block than isolated LQTS-associated mutations.
authors.affiliation: Department of Pediatrics, The Lillie Frank Abercrombie Section of Pediatric Cardiology, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Landstrom
authors.affiliation: Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN, United States; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States.
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Boczek
authors.affiliation: Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN, United States.
authors.forename: Dan
authors.initials: D
authors.lastname: Ye
authors.affiliation: Department of Pediatrics, The Lillie Frank Abercrombie Section of Pediatric Cardiology, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Christina Y
authors.initials: CY
authors.lastname: Miyake
authors.affiliation: Department of Pediatrics, The Lillie Frank Abercrombie Section of Pediatric Cardiology, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Caridad M
authors.initials: CM
authors.lastname: De la Uz
authors.affiliation: Department of Pediatrics, The Lillie Frank Abercrombie Section of Pediatric Cardiology, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Hugh D
authors.initials: HD
authors.lastname: Allen
authors.affiliation: Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN, United States; Departments of Medicine and Pediatrics, Divisions of Cardiovascular Diseases and Pediatric Cardiology, Mayo Clinic, Rochester, MN, United States. Electronic address: ackerman.michael@mayo.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.affiliation: Department of Pediatrics, The Lillie Frank Abercrombie Section of Pediatric Cardiology, Baylor College of Medicine, Houston, TX, United States. Electronic address: jjkim@texaschildrens.org.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Kim
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D001321:Autistic Disorder / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D020746:Calcium Channels, L-Type / Q000235:genetics*; D002648:Child; D004562:Electrocardiography / Q000379:methods; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D013576:Syndactyly / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D013781:Texas / Q000453:epidemiology
chemical_list: C472073:CACNA1D protein, human; D020746:Calcium Channels, L-Type
keywords: CACNA1C; L-type calcium channel; Long QT syndrome; Mutation; Timothy syndrome