Purpose
To characterize a novel neurodevelopmental syndrome due to loss-of-function (LoF) variants in Ankyrin 2 (ANK2), and to explore the effects on neuronal network dynamics and homeostatic plasticity in human induced pluripotent stem cell-derived neurons.
Methods
We collected clinical and molecular data of twelve individuals with heterozygous de novo LoF variants in ANK2. We generated a heterozygous LoF allele of ANK2 using CRISPR/Cas9 in human induced pluripotent stem cells (hiPSCs). HiPSCs were differentiated towards excitatory neurons of which we measured spontaneous electrophysiological responses using micro-electrode arrays (MEAs), characterized somatodendritic morphology and axon initial segment (AIS) structure and plasticity.
Results
We found a broad neurodevelopmental disorder, comprising intellectual disability, autism spectrum disorders, and early onset epilepsy. Using MEAs, we found that hiPSC-derived neurons with heterozygous LoF of ANK2 show a hyperactive and desynchronized neuronal network. ANK2 deficient neurons also showed increased somatodendritic structures and altered AIS structure of which its plasticity is impaired upon activity-dependent modulation.
Conclusions
Phenotypic characterization of patients with de novo ANK2 LoF variants define a novel NDD with early onset epilepsy. Our functional in vitro data of ANK2-deficient human neurons show a specific neuronal phenotype in which reduced ANKB expression leads to hyperactive and desynchronized neuronal network activity, increased somatodendritic complexity and AIS structure and impaired activity-dependent plasticity of the AIS.
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