Letter abstract
Nature Genetics 40, 1230 - 1234 (2008)
Published online: 21 September 2008 | doi:10.1038/ng.223
Insights from retinitis pigmentosa into the roles of isocitrate dehydrogenases in the Krebs cycle
Dyonne T Hartong1,4,5, Mayura Dange2,5, Terri L McGee1, Eliot L Berson3, Thaddeus P Dryja1 & Roberta F Colman2
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 
-subunit of NAD-specific isocitrate dehydrogenase (NAD-IDH, or IDH3), which is believed to catalyze the oxidation of isocitrate to 
-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.
- Ocular Molecular Genetics Institute, Harvard Medical School, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, Massachusetts 02114, USA.
- Department of Chemistry and Biochemistry, University of Delaware, Academy Street, Newark, Delaware 19716, USA.
- The Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, Massachusetts 02114, USA.
- Present address: Department of Ophthalmology, University Medical Center Groningen, Groningen, The Netherlands.
- These authors contributed equally to this work.
Correspondence to: Thaddeus P Dryja1 e-mail: thaddeus.dryja@novartis.com
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