A neurodevelopmental disorder caused by a dysfunctional CACNA1A allele.

P/Q-type Ca2+ flux into nerve terminals via CaV2.1 channels is essential for neurotransmitter release at neuromuscular junctions and nearly all central synapses. Mutations in CACNA1A, the gene encoding CaV2.1, cause a spectrum of pediatric neurological disorders. We have identified a patient harboring an autosomal-dominant de novo frameshift-causing nucleotide duplication in CACNA1A (c.5018dupG). The duplicated guanine precipitated 43 residues of altered amino acid sequence beginning with a glutamine to serine substitution in CaV2.1 at position 1674 ending with a premature stop codon (CaV2.1 p.Gln1674Serfs*43). The patient presented with episodic downbeat vertical nystagmus, hypotonia, ataxia, developmental delay and febrile seizures. In patch-clamp experiments, no Ba2+ current was observed in tsA-201 cells expressing CaV2.1 p.Gln1674Serfs*43 with β4 and α2δ-1 auxiliary subunits. The ablation of divalent flux in response to depolarization was likely attributable to the inability of CaV2.1 p.Gln1674Serfs*43 to form a complete channel pore. Our results suggest that the pathology resulting from this frameshift-inducing nucleotide duplication is a consequence of an effective haploinsufficiency.