Key result
The novel CaVβ1b_R296C variant identified in an ASD patient significantly decreased L-type calcium channel whole-cell current density compared to wild-type (11.7 vs 21.0 pA/pF, p=0.003).
Why the study?
Voltage-gated calcium channel subunits are genetically associated with autism spectrum disorders, prompting functional characterization of a novel CaVbeta1b variant identified in a patient.
Absolute Event Rate: 11.7% vs 21%
p-value: p=0.003
The novel CaVβ1b_R296C variant identified in an ASD patient acts as a loss-of-function mutation, inhibiting L- and N-type voltage-gated calcium channels, contrasting with previously described gain-of-function CaVβ2 variants in ASD.
Loss-of-function CaVβ1 effects merit ASD model studies; leaves open cardiac or clinical relevance pending in vivo confirmation.
Voltage-gated calcium channel (VGCC) subunits have been genetically associated with autism spectrum disorders (ASD). The properties of the pore-forming VGCC subunit are modulated by auxiliary β-subunits, which exist in four isoforms (Ca V β 1-4 ). Our previous findings suggested that activation of L-type VGCCs is a common feature of Ca V β 2 subunit mutations found in ASD patients. In the current study, we functionally characterized a novel Ca V β 1b variant (p.R296C) identified in an ASD patient. We used whole-cell and single-channel patch clamp to study the effect of Ca V β 1b_R296C on the function of L- and N-type VGCCs. Furthermore, we used co-immunoprecipitation followed by Western blot to evaluate the interaction of the Ca V β 1b -subunits with the RGK-protein Gem. Our data obtained at both, whole-cell and single-channel levels, show that compared to a wild-type Ca V β 1b , the Ca V β 1b_R296C variant inhibits L- and N-type VGCCs. Interaction with and modulation by the RGK-protein Gem seems to be intact. Our findings indicate functional effects of the Ca V β 1b_R296C variant differing from that attributed to Ca V β 2 variants found in ASD patients. Further studies have to detail the effects on different VGCC subtypes and on VGCC expression.
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Despang et al. (2022) studied Autism spectrum disorder. CaVβ1b_R296C variant vs. Wild-type CaVβ1b was evaluated on Whole-cell current density of CaV1.2 at 0 mV (p=0.003). The novel CaVβ1b_R296C variant identified in an ASD patient significantly decreased L-type calcium channel whole-cell current density compared to wild-type (11.7 vs 21.0 pA/pF, p=0.003).
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