The disorder is caused by mutations in a gene on the X-chromosome called Protocadherin 19 (PCDH19). The random inactivation of one of the two X chromosomes in each of the patient’s brain cells leads to a mosaic of healthy and unhealthy cells.
PhD student Claire Homan at the University of Adelaide (UoA) used two different models to learn how the mutant gene affects brain development. She first extracted neural stem cells from the cortex of a mouse lacking the Pcdh19 gene. These experiments found that Pcdh19 helps developing nerve cells move to the right place in the brain and then to turn into the appropriate types of brain cells.
Ms Homan then established a human model of PCDH19-GCE. She extracted skin cells from patients with the disorder and reprogrammed them into induced pluripotent stem cells (iPSCs). She then compared normal iPSCs with those from the PCDH19-GCE patients in a cell culture model of human cortical brain development. Immunofluorescence microscopy in the AMMRF (now Microscopy Australia) at the UoA was used to identify and measure morphological and gene activity changes in the two cell types as they developed into brain-like structures.
Data showed that when the PCDH19 protein is absent, cells cannot form correctly oriented structures during early brain development. This could cause long-term changes to brain architecture and contribute to the disorder’s pathogenesis.