Rare Mutations of <i>CACNB2</i> Found in Autism Spectrum Disease-Affected Families Alter Calcium Channel Function

<div><p>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 Ca_V1.2 (<i>CACNA1C)</i> and Ca_Vβ2 (<i>CACNB2</i>) were recently identified as risk loci for psychiatric diseases. Here, we present three rare missense mutations of <i>CACNB2</i> (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 <i>CACNA1C</i> mutation causing Timothy Syndrome, a Mendelian disease presenting with ASD. In conclusion, the results of our first-time biophysical characterization of these three rare <i>CACNB2</i> missense mutations identified in ASD patients support the hypothesis that calcium channel dysfunction may contribute to autism.</p>