title: Novel calmodulin mutations associated with congenital long QT syndrome affect calcium current in human cardiomyocytes.
abstract: Calmodulin (CaM) mutations are associated with cardiac arrhythmia susceptibility including congenital long QT syndrome (LQTS).
  
  
  
  The purpose of this study was to determine the clinical, genetic, and functional features of 2 novel CaM mutations in children with life-threatening ventricular arrhythmias.
  
  
  
  The clinical and genetic features of 2 congenital arrhythmia cases associated with 2 novel CaM gene mutations were ascertained. Biochemical and functional investigations were conducted on the 2 mutations.
  
  
  
  A novel de novo CALM2 mutation (D132H) was discovered by candidate gene screening in a male infant with prenatal bradycardia born to healthy parents. Postnatal course was complicated by profound bradycardia, prolonged corrected QT interval (651 ms), 2:1 atrioventricular block, and cardiogenic shock. He was resuscitated and was treated with a cardiac device. A second novel de novo mutation in CALM1 (D132V) was discovered by clinical exome sequencing in a 3-year-old boy who suffered a witnessed cardiac arrest secondary to ventricular fibrillation. Electrocardiographic recording after successful resuscitation revealed a prolonged corrected QT interval of 574 ms. The Ca(2+) affinity of CaM-D132H and CaM-D132V revealed extremely weak binding to the C-terminal domain, with significant structural perturbations noted for D132H. Voltage-clamp recordings of human induced pluripotent stem cell-derived cardiomyocytes transiently expressing wild-type or mutant CaM demonstrated that both mutations caused impaired Ca(2+)-dependent inactivation of voltage-gated Ca(2+) current. Neither mutant affected voltage-dependent inactivation.
  
  
  
  Our findings implicate impaired Ca(2+)-dependent inactivation in human cardiomyocytes as the plausible mechanism for long QT syndrome associated with 2 novel CaM mutations. The data further expand the spectrum of genotype and phenotype associated with calmodulinopathy.
authors.affiliation: Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Pipilas
authors.affiliation: Department of Biochemistry and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Johnson
authors.affiliation: Division of Cardiology, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Gregory
authors.initials: G
authors.lastname: Webster
authors.affiliation: University Hospital Lausanne (CHUV), Lausanne, Switzerland.
authors.forename: Jurg
authors.initials: J
authors.lastname: Schlaepfer
authors.affiliation: University Hospital Lausanne (CHUV), Lausanne, Switzerland.
authors.forename: Florence
authors.initials: F
authors.lastname: Fellmann
authors.affiliation: University Hospital Lausanne (CHUV), Lausanne, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Sekarski
authors.affiliation: Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Wren
authors.affiliation: Department of Biochemistry and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Kateryna V
authors.initials: KV
authors.lastname: Ogorodnik
authors.affiliation: Department of Biochemistry and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Chazin
authors.affiliation: Department of Biochemistry and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Chazin
authors.affiliation: IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy; and Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Lia
authors.initials: L
authors.lastname: Crotti
authors.affiliation: University Hospital Lausanne (CHUV), Lausanne, Switzerland.
authors.forename: Zahurul A
authors.initials: ZA
authors.lastname: Bhuiyan
authors.affiliation: Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Electronic address: al.george@northwestern.edu.
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
mesh_terms: D000200:Action Potentials / Q000502:physiology; D002147:Calmodulin / Q000235:genetics* / Q000378:metabolism; D002675:Child, Preschool; D004562:Electrocardiography / Q000379:methods; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008133:Long QT Syndrome / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D008297:Male; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism; D013557:Switzerland
chemical_list: C488659:CALM2 protein, human; D002147:Calmodulin
keywords: Arrhythmia; Calcium channel; Calmodulin; Long QT syndrome