In vivo characterization of a patient CACNA1A variant reveals paradoxical synaptic effects

Channelopathies are a class of neurodevelopmental disorders with often devastating consequences, and effective therapies depend on understanding how patient variants alter channel function. These effects are typically assessed by biophysical characterization in heterologous expression systems. Mutations in CACNA1A, which encodes the P/Q-type calcium channel CaV2.1, underlie a spectrum of neurological disorders in which symptoms are generally classified as loss-of-function (LoF) or gain-of-function (GoF). However, some patients present with overlapping phenotypes that defy this binary framework. Here we describe a CACNA1A variant for which heterologous assays fail to capture a key in vivo fun