CACNA1A loss-of-function mutations affect neurogenesis in different ways in human iPSC-derived neural models

CACNA1A encodes the pore-forming α1A subunit of CaV2.1 calcium channel, whose altered function is associated with different neurological disorders including variable forms of ataxia, epilepsy, and migraine. In this study, we generated isogenic iPSC-derived neural cultures carrying two CACNA1A loss-of-function variants differently affecting CaV2.1 isoforms. Morphological, molecular, and functional assays highlighted distinct neurodevelopmental defects. F1491S mutation, which is located in a constitutive domain of the channel, impaired neural induction at very early stages, as demonstrated by changes in migratory capacity and single-cell transcriptomic signatures in neural progenitors, and by defective polarization in neurons. Instead, cells carrying Y1854X mutation, which selectively affects the [EFa] isoform, behaved normally in terms of neural induction but showed altered neuronal network composition and lack of synchronized activity. Our findings highlighted important roles of CACNA1A in mechanisms underlying early neural induction, neuronal maturation, and neural network dynamics.