Abstract
Here we describe two families with retinitis pigmentosa, a hereditary neurodegeneration of rod and cone photoreceptors in the retina. Affected family members were homozygous for loss-of-function mutations in IDH3B, encoding the β-subunit of NAD-specific isocitrate dehydrogenase (NAD-IDH, or IDH3), which is believed to catalyze the oxidation of isocitrate to α-ketoglutarate in the citric acid cycle. Cells from affected individuals had a substantial reduction of NAD-IDH activity, with about a 300-fold increase in the Km for NAD. NADP-specific isocitrate dehydrogenase (NADP-IDH, or IDH2), an enzyme that catalyzes the same reaction, was normal in affected individuals, and they had no health problems associated with the enzyme deficiency except for retinitis pigmentosa. These findings support the hypothesis that mitochondrial NADP-IDH, rather than NAD-IDH, serves as the main catalyst for this reaction in the citric acid cycle outside the retina, and that the retina has a particular requirement for NAD-IDH.
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Acknowledgements
This work was supported by the Foundation Fighting Blindness and the US National Institutes of Health (NIH-EY00169, NIH-EY08683, NIH-HL67774 and P30-EY014104). The microarray analyses were carried out at the Microarray Core Facility at Dana-Farber Cancer Institute.
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D.T.H., T.L.M. and T.P.D. designed and conducted the molecular genetic analyses. E.L.B. clinically evaluated, selected and recruited affected individuals and their family members and helped design the study. M.D. and R.F.C. designed and conducted the enzyme assays. All authors discussed and interpreted the results and wrote the manuscript.
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All authors declare that there is no conflict of interest. T.P.D. may appear to have a conflict of interest because he currently works for Novartis, a publicly traded pharmaceutical company. He is also still a faculty member at Harvard Medical School (part time). T.P.D. affirms that his position at Novartis does not entail any conflict of interest with the manuscript. His contributions to this study were mostly carried out before beginning his position at Novartis, and the entire body of research is unrelated to his employment at Novartis, was not sponsored by Novartis, and has no bearing on research or clinical programs at Novartis.
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Hartong, D., Dange, M., McGee, T. et al. Insights from retinitis pigmentosa into the roles of isocitrate dehydrogenases in the Krebs cycle. Nat Genet 40, 1230–1234 (2008). https://doi.org/10.1038/ng.223
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DOI: https://doi.org/10.1038/ng.223
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