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 individuals that features progressive loss in visual acuity leading, in many cases, to legal blindness. Phenotypic variations and loss of retinal ganglion cells, as found in Leber hereditary optic neuropathy (LHON), have suggested possible mitochondrial impairment. The OPA1 gene has been localized to 3q28-q29 (refs 13-19). 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.

OPA1 alternate splicing uncouples an evolutionary conserved function in mitochondrial fusion from a vertebrate restricted function in apoptosis

“…To gain insight into the identification of OPA1 variant expression, we performed quantitative polymerase chain reaction (Q-PCR) on cDNA from HeLa cells, using couples of oligonucleotides specific of each of the eight mRNA variants. The OPA1-Ex4 mRNA variant #1 was arbitrarily chosen as reference, as it was the first OPA1 sequence identified (AB011139), 28 and since then selected in most reported OPA1 ectopic expression experiments. Our Q-PCR data suggest that four OPA1 mRNA variants predominate: Ex4, Ex4 þ Ex4b, Ex4 þ Ex5b and Ex4 þ Ex4b þ Ex5b, the other four being 25-40 times less abundant than OPA1-Ex4 mRNA ( Figure 1a and Supplementary Table 1).…”

The Eutherian Armcx genes regulate mitochondrial trafficking in neurons and interact with Miro and Trak2

“…Mitochondrial transport is essential for neuronal viability 18,19,34,35 . To address whether Alex3 is involved in mitochondrial transport in axons, we used live-imaging techniques.…”

Mitochondrial dynamics in the regulation of neuronal cell death

“…The third GTPase required for mitochondrial fusion is localized to the intermembrane space and is called Opa1 [86][87][88][89]. Opa1 (Optical Atrophy 1) is imported into the mitochondrial inner membrane where it undergoes a regulated cleavage event to release a soluble shorter form of the protein into the intermembrane space.…”

“…Opa1 (Optical Atrophy 1) is imported into the mitochondrial inner membrane where it undergoes a regulated cleavage event to release a soluble shorter form of the protein into the intermembrane space. Mutations in Opa1 are causal for autosomal dominant optical atrophy, characterized by degeneration of the retinal ganglial cells in the eye resulting in blindness [90,91]. There are 8 splice variants of Opa1 in humans, and the ratio of these isoforms and their cleavage products has complicated the progress to determine the precise function of Opa1.…”