The human gene OPA1 is implicated in multiple diseases with a broad range of neurologic phenotypes (MIM:605290); common phenotypes include optic atrophy, other vision problems, hearing loss, and ataxia. The OPA1 gene encodes a protein that localizes to the inner mitochondrial membrane and that impacts mitochondrial fusion, apoptosis, reactive oxygen species production and ATP production. It has been postulated that retinal ganglion cells may be particularly vulnerable to mitochondrial dysfunction (Yu-Wai-Man et al., 2009; pubmed:19001017). There is a single orthologous gene in Drosophila, Dmel\Opa1, for which RNAi-targeting constructs and hypomorphic alleles caused by insertional mutagenesis have been generated.
Multiple UAS constructs of the human Hsap\OPA1 gene, including wild-type and variants implicated in disease, have been introduced into flies. See the 'Disease-Implicated Variants' table below. Partial heterologous rescue (functional complementation) has been demonstrated. Variants of Hsap\OPA1 implicated in disease fail to rescue or exhibit a lower degree of rescue. More severe mutations are associated with optic atrophy plus syndrome (FBhh0000645) and less severe with optic atrophy 1 (FBhh0000644); this analysis allows quantitative evaluation of loss-of-function severity by comparing the rescue capabilities of known or newly identified variants, thus allowing rapid determination of the disease subtype.
Animals homozygous for loss-of-functions mutations of Dmel\Opa1 die in the larval stage. Heterozygotes exhibit visual abnormalities and defects in mitochondrial morphology in muscle; degeneration of the optic nerve is observed. When targeted loss of function is effected by RNAi, fragmented mitochondria are frequently observed in the targeted tissue. Somatic clones, especially in the eye, have been used to further characterize loss-of-function phenotypes. Phenotypes of somatic clones and in heterozygous animals have been used to assess therapeutic candidates.
[updated Oct. 2024 by FlyBase; FBrf0222196]
The OPA1 gene encodes a protein that localizes to the inner mitochondrial membrane and regulates several important cellular processes including stability of the mitochondrial network, mitochondrial bioenergetic output, and sequestration of proapoptotic cytochrome c oxidase molecules within the mitochondrial cristae spaces (summary by Yu-Wai-Man et al., 2010; pubmed:). [from MIM:605290; 2017.10.02]
One to one (1 human to 1 Drosophila).
High-scoring ortholog of human OPA1 (1 Drosophila to 1 human). Dmel\Opa1 shares 52% identity and 69% similarity with the human gene.
