Key result
The CACNA1D V401L mutation identified in a patient with ASD and epilepsy resulted in a strong gain-of-function phenotype with enhanced current densities and reduced channel inactivation.
Case Report (n=1)
The V401L mutation in CACNA1D causes a strong gain-of-function phenotype, strengthening its role as an autism risk gene and suggesting potential for experimental therapy with calcium channel blockers.
May support experimental calcium channel blockade in CACNA1D-related ASD; leaves open human translation.
CACNA1D encodes the pore-forming α1-subunit of Cav1.3, an L-type voltage-gated Ca2+-channel. Despite the recent discovery of two de novo missense gain-of-function mutations in Cav1.3 in two individuals with autism spectrum disorder (ASD) and intellectual disability CACNA1D has not been considered a prominent ASD-risk gene in large scale genetic analyses, since such studies primarily focus on likely-disruptive genetic variants. Here we report the discovery and characterization of a third de novo missense mutation in CACNA1D (V401L) in a patient with ASD and epilepsy. For the functional characterization we introduced mutation V401L into two major C-terminal long and short Cav1.3 splice variants, expressed wild-type or mutant channel complexes in tsA-201 cells and performed whole-cell patch-clamp recordings. Mutation V401L, localized within the channel's activation gate, significantly enhanced current densities, shifted voltage dependence of activation and inactivation to more negative voltages and reduced channel inactivation in both Cav1.3 splice variants. Altogether, these gating changes are expected to result in enhanced Ca2+-influx through the channel, thus representing a strong gain-of-function phenotype. Additionally, we also found that mutant channels retained full sensitivity towards the clinically available Ca2+ -channel blocker isradipine. Our findings strengthen the evidence for CACNA1D as a novel candidate autism risk gene and encourage experimental therapy with available channel-blockers for this mutation. The additional presence of seizures and neurological abnormalities in our patient define a novel phenotype partially overlapping with symptoms in two individuals with PASNA (congenital primary aldosteronism, seizures and neurological abnormalities) caused by similar Cav1.3 gain-of-function mutations.
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Pinggera et al. (2017) conducted a case report in Autism spectrum disorder and epilepsy (n=1). CACNA1D V401L mutation vs. Wild-type CACNA1D was evaluated on Channel gating changes (current densities, voltage dependence of activation and inactivation). The CACNA1D V401L mutation identified in a patient with ASD and epilepsy resulted in a strong gain-of-function phenotype with enhanced current densities and reduced channel inactivation.
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