|Start Date / Time||April 7, 2021 at 9:00 AM|
|End Date / Time||April 7, 2021 at 10:00 AM|
|Presenter Name||Alejandra Romero and Gabriella Robertson|
|Presentation Title||See below for titles|
|Status||This meeting has already occurred|
“Modeling the effect of Leigh
syndrome-associated mutations on
early human brain development”
Leigh syndrome (LS) is a rare, inherited neurometabolic disorder that presents with bilateral brain lesions, caused by defects in the mitochondrial respiratory chain and associated nuclear-encoded proteins. We generated iPSCs from three commercially available LS fibroblast lines and identified, by whole exome and mitochondrial sequencing, unreported mutations in pyruvate dehydrogenase (GM0372, PDH; GM13411, MT-ATP6/PDH) and dihydrolipoyl dehydrogenase (GM01503, DLD). LS-derived cerebral organoids showed defects in neural epithelial bud generation, size, and cortical architecture at 100 days. The double mutant MT-ATP6/PDH line produced organoid neural progenitor cells with abnormal mitochondrial morphology characterized by fragmentation and disorganization and showed increased generation of astrocytes. These studies aim to provide a comprehensive phenotypic characterization of available patient-derived cell lines that can be used as LS model systems.
“Examining the effect of DRP1 patient mutations on mitochondrial structure and function”
Mitochondria are dynamic signaling organelles that constantly undergoes fission (fragmentation) and fusion (elongation) to adapt its structure to the demands of the cell. DRP1 (dynamin-related protein 1) is a GTPase that plays a crucial role in mitochondrial fission. Patients with de novo heterozygous missense mutations in the gene that encodes DRP1, DNM1L, present with neurodevelopmental symptoms. To interrogate the molecular mechanisms by which DRP1 mutations cause neurodevelopmental defects, we are utilizing patient-derived fibroblasts and iPSC-derived models from patients with mutations in different domains of DRP1 who present with clinically disparate conditions.