title: Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome.
abstract: Gain-of-function mutations in CACNA1C, encoding the L-type Ca(2+) channel Cav1.2, cause Timothy syndrome (TS), a multi-systemic disorder with dysmorphic features, long-QT syndrome (LQTS) and autism spectrum disorders. TS patients have heterozygous mutations (G402S and G406R) located in the alternatively spliced exon 8, causing a gain-of-function by reduced voltage-dependence of inactivation. Screening 540 unrelated patients with non-syndromic forms of LQTS, we identified six functional relevant CACNA1C mutations in different regions of the channel. All these mutations caused a gain-of-function combining different mechanisms, including changes in current amplitude, rate of inactivation and voltage-dependence of activation or inactivation, similar as in TS. Computer simulations support the theory that the novel CACNA1C mutations prolong action potential duration. We conclude that genotype-negative LQTS patients should be investigated for mutations in CACNA1C, as a gain-of-function in Cav1.2 is likely to cause LQTS and only specific and rare mutations, i.e. in exon 8, cause the multi-systemic TS.
authors: Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Deutschhausstr. 1-2, 35037 Marburg, Germany.
authors: Konstantin
authors: K
authors: Wemhöner
authors: Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, Domagkstr. 3, 48149 Münster, Germany.
authors: Corinna
authors: C
authors: Friedrich
authors: Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, Domagkstr. 3, 48149 Münster, Germany.
authors: Birgit
authors: B
authors: Stallmeyer
authors: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors: Alison J
authors: AJ
authors: Coffey
authors: Department of Biochemistry, University of Cambridge, Hopkins Building, Tennis Court Road, Cambridge CB2 1QW, UK; Papworth Hospital, Cambridge CB23 3RE, UK.
authors: Andrew
authors: A
authors: Grace
authors: Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, Domagkstr. 3, 48149 Münster, Germany.
authors: Sven
authors: S
authors: Zumhagen
authors: Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, Domagkstr. 3, 48149 Münster, Germany.
authors: Guiscard
authors: G
authors: Seebohm
authors: Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Deutschhausstr. 1-2, 35037 Marburg, Germany.
authors: Beatriz
authors: B
authors: Ortiz-Bonnin
authors: Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Deutschhausstr. 1-2, 35037 Marburg, Germany.
authors: Susanne
authors: S
authors: Rinné
authors: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, 95 South 2000 East, Salt Lake City, UT 84112, USA; Department of Bioengineering, James LeVoy Sorenson Molecular Biotechnology Building, 36 S. Wasatch Drive, Salt Lake City, UT 84112, USA.
authors: Frank B
authors: FB
authors: Sachse
authors: Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, Domagkstr. 3, 48149 Münster, Germany.
authors: Eric
authors: E
authors: Schulze-Bahr
authors: Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Deutschhausstr. 1-2, 35037 Marburg, Germany. Electronic address: decher@staff.uni-marburg.de.
authors: Niels
authors: N
authors: Decher
mesh_terms: D000200:Action Potentials; D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D001321:Autistic Disorder / Q000235:genetics; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020013:Calcium Signaling; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005260:Female; D015870:Gene Expression; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D008133:Long QT Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D054730:Protein Interaction Domains and Motifs; D013576:Syndactyly / Q000235:genetics; D055815:Young Adult
chemical_list: C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type
keywords: Arrhythmia; Cav1.2; Gain-of-function; LQT8; Timothy syndrome