Acute and late-onset optic atrophy due to a novel OPA1 mutation leading to a mitochondrial coupling defect

Abstract

Purpose: Autosomal dominant optic atrophy (ADOA, OMIM 165500), an inherited optic neuropathy that leads to retinal ganglion cell degeneration and reduced visual acuity during the early decades of life, is mainly associated with mutations in the OPA1 gene. Here we report a novel ADOA phenotype associated with a new pathogenic OPA1 gene mutation.

Methods: The patient, a 62-year-old woman, was referred for acute, painless, and severe visual loss in her right eye. Acute visual loss in her left eye occurred a year after initial presentation. MRI confirmed the diagnosis of isolated atrophic bilateral optic neuropathy. We performed DNA sequencing of the entire coding sequence and the exon/intron junctions of the OPA1 gene, and we searched for the mitochondrial DNA mutations responsible for Leber hereditary optic atrophy by sequencing entirely mitochondrial DNA. Mitochondrial respiratory chain complex activity and mitochondrial morphology were investigated in skin fibroblasts from the patient and controls.

Results: We identified a novel heterozygous missense mutation (c.2794C>T) in exon 27 of the OPA1 gene, resulting in an amino acid change (p.R932C) in the protein. This mutation, which affects a highly conserved amino acids, has not been previously reported, and was absent in 400 control chromosomes. Mitochondrial DNA sequence analysis did not reveal any mutation associated with Leber hereditary optic neuropathy or any pathogenic mutations. The investigation of skin fibroblasts from the patient revealed a coupling defect of oxidative phosphorylation and a larger proportion of short mitochondria than in controls.

Conclusions: The presence of an OPA1 mutation indicates that this sporadic, late-onset acute case of optic neuropathy is related to ADOA and to a mitochondrial energetic defect. This suggests that the mutational screening of the OPA1 gene would be justified in atypical cases of optic nerve atrophy with no evident cause.

Figure 1

Fundus examination. The first image represents the patient's right eye fundus examination and we observe optic disk atrophy (arrow). The second image represents left eye fundus examination, we also observe optic disk atrophy.

Figure 2

Patient 's visual evoked potentials. We observe low-amplitude potentials and increased latency in visual evoked potentials in left eye (A) and in right eye (B). It indicates defective conduction of the optic nerves.

Figure 3

Patient's electroretinograms. We show normal flicker electroretinograms (A), scotopic electroretinograms (B), and photopic electroretinograms (C).

Figure 4

Patient's encephalic MRI. MRI of the optic nerve showed severe bilateral atrophy of the optic nerve from retina to the lateral geniculate nucleus, seen on horizontal MRI section (A), including atrophy of the optic chiasma, seen on coronal MRI section (B).

Figure 5

Mitochondrial metabolic investigations in the patient and controls. A: Coupling efficiency (ATP/O): Reduced efficiency of ATP synthesis was found in the patient’s fibroblasts in comparison to controls. B: Reduced mitochondrial ATP synthesis, measured by luminescence from aliquot samples in a polarographic chamber, was found in the patient’s fibroblasts in comparison to controls. C: Maximal coupled respiration rates, i.e., ADP-stimulated oxygen consumption with malate, pyruvate, and succinate, was measured in the same polarographic chamber.

Figure 6

Quantification of mitochondrial shape showed that the patient’s fibroblasts (OPA1_R932C) contained a higher proportion of short mitochondria than controls (Appendix 3).

Figure 7

Expression of OPA1 protein in fibroblasts from the OPA1_R932C patient and from controls. Cellular extracts were analyzed by western blotting using antibodies against OPA1 and HSP60 as described in materials and methods. HSP60 was used as a mitochondrial marker and as a control for protein loading.