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Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy

Abstract

Optic atrophy type 1 (OPA1, MIM 165500) is a dominantly inherited optic neuropathy occurring in 1 in 50,000 individuals1,2,3 that features progressive loss in visual acuity leading, in many cases, to legal blindness4,5,6,7,8. Phenotypic variations5 and loss of retinal ganglion cells9,10, as found in Leber hereditary optic neuropathy (LHON), have suggested possible mitochondrial impairment11,12. The OPA1 gene has been localized to 3q28–q29 (refs 1319). We describe here a nuclear gene, OPA1, that maps within the candidate region and encodes a dynamin-related protein localized to mitochondria. We found four different OPA1 mutations, including frameshift and missense mutations, to segregate with the disease, demonstrating a role for mitochondria in retinal ganglion cell pathophysiology.

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Figure 1: OPA1 structure and mapping by FISH.
Figure 2: OPA1 belongs to the mitochondrial network and is expressed ubiquitously.
Figure 3: Identification of four OPA1 mutations in six unrelated families with DOA.
Figure 4: Mitochondrial network is disorganized in OPA1 mutants.
Figure 5: Fundus photograph of right eye of 29-year-old patient II-5 from family MT2 showing the macular area and the optic disc with retinal vessels converging to it.

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Acknowledgements

We thank the patients and their families for support; M. Roux, A. Dumas and J. Aimé for encouragement; P. Roustan for help; T. Nagase for providing clone HH2110 (human OPA1 cDNA); and P. Gaudray for help in gene localization. This work was supported by Association Française contre les Myopathies, CHU de Montpellier, Fondation pour la Recherche Médicale, Information Recherche sur les Rétinites Pigmentaires, Retina France and SOS Rétinite, France (C.D. is a recipient of a SOS Rétinite fellowship).

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Correspondence to Bernard Ducommun or Christian P. Hamel.

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Delettre, C., Lenaers, G., Griffoin, JM. et al. Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet 26, 207–210 (2000). https://doi.org/10.1038/79936

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