title: Rare mutations of CACNB2 found in autism spectrum disease-affected families alter calcium channel function.
abstract: Autism Spectrum Disorders (ASD) are complex neurodevelopmental diseases clinically defined by dysfunction of social interaction. Dysregulation of cellular calcium homeostasis might be involved in ASD pathogenesis, and genes coding for the L-type calcium channel subunits CaV1.2 (CACNA1C) and CaVβ2 (CACNB2) were recently identified as risk loci for psychiatric diseases. Here, we present three rare missense mutations of CACNB2 (G167S, S197F, and F240L) found in ASD-affected families, two of them described here for the first time (G167S and F240L). All these mutations affect highly conserved regions while being absent in a sample of ethnically matched controls. We suggest the mutations to be of physiological relevance since they modulate whole-cell Ba2+ currents through calcium channels when expressed in a recombinant system (HEK-293 cells). Two mutations displayed significantly decelerated time-dependent inactivation as well as increased sensitivity of voltage-dependent inactivation. In contrast, the third mutation (F240L) showed significantly accelerated time-dependent inactivation. By altering the kinetic parameters, the mutations are reminiscent of the CACNA1C mutation causing Timothy Syndrome, a Mendelian disease presenting with ASD. In conclusion, the results of our first-time biophysical characterization of these three rare CACNB2 missense mutations identified in ASD patients support the hypothesis that calcium channel dysfunction may contribute to autism.
authors.affiliation: Department of Pharmacology, University of Cologne, Cologne, Germany.
authors.forename: Alexandra F S
authors.initials: AF
authors.lastname: Breitenkamp
authors.affiliation: Department of Pharmacology, University of Cologne, Cologne, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Matthes
authors.affiliation: Department of Pharmacology, University of Cologne, Cologne, Germany.
authors.forename: Robert Daniel
authors.initials: RD
authors.lastname: Nass
authors.affiliation: Department of Child and Adolescent Psychiatry and Psychotherapy, LVR-Klinik Bonn, Bonn, Germany; Department of Child and Adolescent Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Sinzig
authors.affiliation: Department of Child and Adolescent Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Lehmkuhl
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Department of Pharmacology, University of Cologne, Cologne, Germany; Center for Molecular Medicine, University of Cologne, Cologne, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Herzig
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000235:genetics*; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000503:physiopathology*; D005190:Family; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating; D008969:Molecular Sequence Data; D017354:Point Mutation / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics; D013997:Time Factors
chemical_list: C107597:CACNB2 protein, human; D020746:Calcium Channels, L-Type
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