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T. M. Bosley, K. K. Abu-Amero; Genome-Wide Transcription Profile in Leukocytes of LHON Patients With the 11778 Mutation. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3468.
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We evaluated gene expression in leukocytes of four patients with the 11778 mitochondrial DNA mutation and bilateral optic neuropathy consistent with Leber hereditary optic neuropathy (LHON) and three age, sex, and ethnicity matched controls in order to examine the altered expression of mitochondrial and nuclear genes associated directly or indirectly with mitochondria or the oxidative phosphorylation machinery and to see if a unique gene expression profile could be obtained for LHON.
RNA was extracted from leukocytes and cDNA reverse transcribed and hybridized to Affymetrix Gene Chips. Principle component analysis and the Rate Monotonic Algorithm were performed and further analysis applied to genes with a 2-fold expression difference and p < 0.005 between patients and controls.
The gene expression profile of patients with the 11778 mtDNA mutation was significantly different from controls. With the aid of the Gene Ontology Database, the most commonly up-regulated genes (n = 137) were found to be related to the cellular transport (13.8%; 19/137) and transcription (12.4%; 17/137). Similarly, the most commonly down-regulated genes (n = 152) were also related to the cellular transport (17.8%; 27/152) and transcription (18.4%; 28/152). Surprisingly, none of the 13 mitochondrial coded genes and no structural mitochondrial nuclear-encoded genes were differentially expressed. The OPA1 gene was down-regulated, but no other non-structural nuclear-encoded mitochondrial gene was differentially expressed.
The presence of the 11778 mtDNA mutation resulted in a unique gene expression profile compared to controls together with changes in transcription of specific genes that may provide information about LHON disease mechanisms. In particular, down-regulation of OPA1 could be integral to the mitochondria-induced apoptosis that is likely the pathologic process in LHON.
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