A Novel CNTNAP2 Mutation Results in Abnormal Neuronal E/I Balance

CNTNAP2 (coding for protein Caspr2), a member of the neurexin family, plays an important role in the balance of excitatory and inhibitory post-synaptic currents (E/I balance). Here, we describe a novel pathogenic missense mutation in an infant with spontaneous recurrent seizures (SRSs) and intellectual disability. Genetic testing revealed a missense mutation, c.2329 C>G (p. R777G), in the CNTNAP2 gene. To explore the effect of this novel mutation, primary cultured neurons were transfected with wild type homo CNTNAP2 or R777G mutation and the morphology and function of neurons were evaluated. When compared with the vehicle control group or wild type group, the neurites and the membrane currents, including spontaneous excitatory post-synaptic currents (sEPSCs) and inhibitory post-synaptic currents (sIPSCs), in CNTNAP2 R777G mutation group were all decreased or weakened. Moreover, the action potentials (APs) were also impaired in CNTNAP2 R777G group. Therefore, CNTNAP2 R777G may lead to the imbalance of excitatory and inhibitory post-synaptic currents in neural network contributing to SRSs.

Automated summary

A novel pathogenic missense mutation in the CNTNAP2 gene was found in an infant with spontaneous recurrent seizures and intellectual disability. This mutation led to changes in neuron morphology and function, causing an imbalance in excitatory and inhibitory post-synaptic currents in the neural network, potentially contributing to the occurrence of SRSs.