Rare mutations of CACNB2 found in autism spectrum disease-affected families alter calcium channel function.

Alexandra F S Breitenkamp,Peter Nürnberg,Jan Matthes,Stefan Herzig,Judith Sinzig,Robert Daniel Nass,Gerd Lehmkuhl,Michael Edward Zwick

doi:10.1371/journal.pone.0095579

Alexandra F S Breitenkamp, Peter Nürnberg + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0095579

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Journal: PloS one	Publication Date: Apr 21, 2014
Citations: 75	License type: CC BY 4.0

Affiliation: University of Cologne, LVR-Klinik Bonn

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.

Highlights

Autism spectrum disorder (ASD) is defined by dysfunction of social interaction and communication, stereotypic behavior and sensory integration problems
A first hint to unravel pathophysiological pathway of ASD came from the identification of the mutation p.G406R found in the L-type calcium channel pore-forming subunit (CaV1.2) gene CACNA1C in patients with Timothy Syndrome (TS) [2]
For the first time, we present three missense mutations located in conserved regions of the calcium channel CACNB2 gene found in three families affected by ASD

Summary

Introduction

Autism spectrum disorder (ASD) is defined by dysfunction of social interaction and communication, stereotypic behavior and sensory integration problems. The activity and kinetics of several pore-forming subunits of L-type (CaV1.1–1.4) and Non-Ltype (CaV2.1–2.3) channels [2,12,13,16] are regulated by CaVbsubunits They are involved in various signaling pathways [2,17,18], all of which have been linked to ASD pathophysiology previously. Based on our previous studies showing that current and gating kinetics profoundly depend on the particular CaVb-subunit isoform or splice variant associated with the channel pore [8,9], we hypothesized that CaVb-subunit mutations might lead to electrophysiological phenotypes similar to that observed in TS. Though our data do not prove an association between these CACNB2 mutations and ASD, our findings support the idea of Cavb variants being of functional relevance for ASD pathophysiology

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