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Human iPSC-derived cerebral organoids model features of Leigh syndrome and
reveal abnormal corticogenesis.
Romero-Morales AI, Robertson GL, Rastogi A, Rasmussen ML, Temuri H, McElroy GS,
Chakrabarty RP, Hsu L, Almonacid PM, Millis BA, Chandel NS, Cartailler JP, Gama
Submitted Externally on 10/5/2022
Development (Cambridge, England)
Volume : Pages
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 human induced
pluripotent stem cells (iPSCs) from three LS patient-derived fibroblast lines.
Using whole-exome and mitochondrial sequencing, we identified unreported
mutations in pyruvate dehydrogenase (GM0372, PDH; GM13411, MT-ATP6/PDH) and
dihydrolipoyl dehydrogenase (GM01503, DLD). These LS patient-derived iPSC lines
were viable and capable of differentiating into progenitor populations, but we
identified several abnormalities in three-dimensional differentiation models of
brain development. LS patient-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 precursor cells with
abnormal mitochondrial morphology, characterized by fragmentation and
disorganization, and showed an increased generation of astrocytes. These studies
aim to provide a comprehensive phenotypic characterization of available
patient-derived cell lines that can be used to study Leigh syndrome.
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Financial support for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (National MMPC, RRID:SCR_008997,
) under the MICROMouse Program, grants DK076169.
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