Neuronal migration defects, including pachygyria, are among the most severe developmental brain defects in humans. Using human genetics approaches, we recently identified bi-allelic truncating mutations in CTNNA2, encoding αN-catenin, in patients with a phenotypically distinct recessive form of pachygyria. Interestingly, two mouse lines harboring nonsense mutations of the ortholog to human CTNNA2 (Catna2) have been characterized, but failed to recapitulate the human cortical lamination phenotype observed in our patients. Therefore, to investigate neuronal phenotypes in a human model, we developed stem cell-derived neuronal assays to assess neuron morphology as well as define the molecular disease mechanism. I will highlight the need for human cell-based models for neocortical gyration disorders as well as discuss the advantages of using stem cell based systems to discover pathogenic mechanisms and novel insight into human brain development, with this case as an example.
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