Gene expression profiles of hiPSC-derived retinal ganglion cells in MT-ND4 mutated Leber's hereditary optic neuropathy

Lebers hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disease caused by homoplasmic mutations in complex I subunit genes, and is characterized by incomplete penetrance. The mechanism of low penetrance of complex I mutation is still largely unclear today. In this study, we created the patient-specific induced pluripotent stem cells (iPSCs) from MT-ND4 mutated LHON affected patient, asymptomatic mutation carrier and control, and differentiated them into retinal ganglion cells (RGCs) for pathogenesis survey. We observed the following phenotypic features in the LHON-specific RGCs as compared to the control: 1) enhanced mitochondrial biogenesis in affected and carriers; 2) compensatory increased mitochondrial complex I activity in carrier, but not in affected patient; 3) reduced spare respiratory activity in affected and carrier. Microarray profiling of LHON-specific RGCs revealed abundant overexpression of genes encoding components of cell cycle regulation machinery as compared to the control.

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Wu YR, Wang AG, Chen YT, Yarmishyn AA, Buddhakosai W, Yang TC, Hwang DK, Yang YP, Shen CN, Lee HC, Chiou SH, Peng CH, Chen SJ