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FLASH GENE
Symbol OPA1 contributors: shn - updated : 27-08-2015
HGNC name optic atrophy 1 (autosomal dominant)
HGNC id 8140
Corresponding disease
OADOM optic atrophy, deafness, ophthalmoplegia and myopathy
OPA1 optic atrophy 1
Location 3q29      Physical location : 193.310.932 - 193.415.599
Synonym name
  • dynamin-related mitochondrial protein
  • largeG
  • mitochondrial dynamin-like GTPase
  • Synonym symbol(s) FLJ12460, KIAA0567, MSP1, NPG, NTG, MGM1
    DNA
    TYPE functioning gene
    STRUCTURE 104.21 kb     31 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    text structure
  • thirty coding exons, the last exon is not coded
  • Ex4b and Ex5b, which are vertebrate specific, define a function involved in cytochrome c release, an apoptotic process also restricted to vertebrates
  • MAPPING cloned Y linked N status provisional
    Map cen - D3S3642 - D3S3590 - OPA1 OPA1 - D3S3562 - D3S2748 - qter
    Text [OPA1 ]
    Physical map
    LOC152138 3q29 similar to PYRIN-containing APAF1-like protein 2 (NACHT-, LRR- and PYD-containing protein 2) (Nucleotide-binding site protein 1) LOC131086 3q29 similar to microtubule-associated protein 6 FGF12 3q29-qter fibroblast growth factor 12 LOC151963 3q29 similar to BcDNA:GH11415 gene product LOC285388 3q29 similar to vascular endothelial zinc finger 1 HRASLS 3q28-q29 HRAS-like suppressor DKFZp761I1011 3q29 hypothetical protein DKFZp761I1011 OPA1 3q28-q29 optic atrophy 1 (autosomal dominant) LOC389186 3 LOC389186 HES1 3q28-q29 hairy and enhancer of split 1, (Drosophila) LOC254808 3q29 hypothetical protein LOC254808 LOC285280 3q29 similar to Carboxypeptidase N 83 kDa chain (Carboxypeptidase N regulatory subunit) LRRC15 3q29 leucine rich repeat containing 15 GP5 3q29 glycoprotein V (platelet) AFURS1 3q29 ATPase family homolog up-regulated in senescence cells LOC391605 3 similar to 60S ribosomal protein L23a LOC93109 3q29 hypothetical protein BC007772 FLJ11301 3q29 hypothetical protein FLJ11301 FLJ90022 3q29 hypothetical protein FLJ90022 LOC285303 3q29 similar to MGC27169 protein FLJ35155 3q29 hypothetical protein FLJ35155 CENTB2 3q29 centaurin, beta 2 PPP1R2 3q29 protein phosphatase 1, regulatory (inhibitor) subunit 2 LOC391606 3 similar to ribosomal protein L24 LOC255812 3q29 hypothetical protein LOC255812 LOC389187 3 LOC389187
    RNA
    TRANSCRIPTS type messenger
    text eight transcript variants encoding eight isoforms resulting from alternative splicing of exons 4, 4b and 5b the presence or absence of exons 4, 4b or 5b do not alter the reading frame
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    29 splicing 6345 112 960 in the intermembrane space 2001 11810270
  • also called variant 1 or OPA1-4
  • first variant identified containing twenty eight coding exons, missing 4b and 5b (exon 4)
  • predominantly associates with the mitochondrial outer membrane
  • 28 splicing 6237 108 924 ubiquitous but weakly expressed 2001 11810270
  • also called variant 2 or OPA1-0 or OPA1S1
  • this variant is missing exons 4, 4b and 5b
  • lack a transmembrane anchor, also have important interactions with the mitochondrial inner membrane
  • robustly tubulates liposomes
  • can assemble on lipid surfaces, and this interaction dramatically activates its GTP hydrolysis activity
  • 29 splicing 6291 109 942 ubiquitous but weakly expressed 2001 11810270
  • also called variant 3 or OPA1-4b
  • this variant is missing exons 4 and 5b but contains exon 4b
  • 29 splicing 6348 112 961 ubiquitous, retina, fetal brain, heart, skeletal muscle, lung, ovary 2001 11810270
  • also called variant 4 or OPA1-5b
  • this variant is missing exons 4 and 4b but contains exon 5b
  • 30 splicing 5918 114 978 ubiquitous but slightly expressed 2001 11810270
  • also called
  • this variant is missing exon 5b but contains exons 4 and 4b
  • 30 splicing 6402 114 979 ubiquitous, kidney, liver, colon 2001 11810270
  • also called variant 6 or OPA1-4b, 5b
  • this variant is missing exon 4 but contains exons 4b and 5b
  • 30 splicing 6456 116 997 . ubiquitous, kidney, liver, colon . in the intermembrane space 2001 11810270
  • also called variant 7 or OPA1-4, 5b
  • this variant is missing exon 4b but contains exons 4 and 5b
  • associates with the mitochondrial inner membrane
  • 31 splicing 6510 118 1015 ubiquitous 2001 11810270
  • also called variant 8 or OPA1-4, 4b, 5b
  • this variant contains thirty coding exons (including exons 4, 4b and 5b) and one non coding exon
  • EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Endocrineneuroendocrinepituitary  highly
     thyroid   highly
    Nervousbrainforebraincerebral cortexfrontal cortex 
     brainhindbraincerebellumcerebellar cortex 
    Reproductivefemale systemovary   
     male systemtestis   
    Visualeyeretina  highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / hematopoieticbone marrow  highly
    Connectivebone  highly
    Muscularstriatumcardiac  
    Muscularstriatumskeletal  
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousastrocyte
    NervousPurkinje cell
    Visualcone photoreceptor
    Visualganglion cell
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N terminal highly basic region (~ 100 amino acid long) required for mitochondrial localization, unique among the dynamin family, is critical to specify functional and regulatory mechanisms
  • a transmembran domain
  • a region containing coiled-coil structures
  • a GTPase domain
  • a central dynamin domain
  • a C terminal coiled-coil domain
  • HOMOLOGY
    interspecies ortholog to Opa1, Mus musculus
    ortholog to Opa1, Rattus norvegicus
    ortholog to opa1, Danio rerio
    ortholog to OPA1, Pan troglodytes
    Homologene
    FAMILY
  • dynamin family
  • CATEGORY structural protein
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria,inner
    intracellular,cytoplasm,organelle,mitochondria,outer
    intracellular,cytoplasm,organelle,mitochondria,interspace
    intracellular,cytoplasm,organelle,membrane
    text
  • associated with the mitochondrial inner membrane
  • direct link between OPA1 on the inner mitochondrial membrane and the apoptotic machinery on the outer membrane that modulates fusion and cristae structure by separate mechanisms
  • basic FUNCTION
  • playing a role in mitochondrial membrane formation and integrity and inducing mitochondrial tubulation
  • participating in a fission/fragmentation pathway or in the maintenance of the structural integrity of the mitochondrial reticulum
  • having an important and specific function, not only in the optic nerve forming ganglion cells but also in the intrinsic signal processing of the inner retina
  • involved in mitochondrial fission and fusion as well as in maintenance of mitochondrial DNA
  • might be involved in the functioning of the mitochondria that are present in both inner and outer retinal neurons
  • crucial role in maintaining dendrites and their synapses
  • required for fusion of mitochondria and proteolytic processing of OPA1 links mitochondrial dysfunction to alterations in mitochondrial morphology
  • importance of OPA1 in mtDNA maintenance
  • essential for the fusion of the inner mitochondrial membranes
  • can promote the protrusion of lipid tubules from the surface of cardiolipin-containing liposomes
  • significance of OPA1 in the control of mitochondrial Ca2+ metabolism (
  • a dual-specificity A-kinase anchoring protein associated with lipid droplets (
  • essential for retinal ganglion cell synaptic architecture and connectivity (
  • role in Ca2+ homeostasis
  • protects against neuronal degeneration
  • role in synaptic maturation and dendritic growth through maintenance of proper mitochondrial oxidative metabolism and distribution
  • requirement for vertebrate development
  • OPA1 processing is dispensable for fusion but coordinates the dynamic behavior of mitochondria and is crucial for mitochondrial integrity and quality control
  • CELLULAR PROCESS cell organization/biogenesis
    PHYSIOLOGICAL PROCESS
    text implicated in the formation and maintenance of the mitochondrial network
    PATHWAY
    metabolism
    signaling sensory transduction/vision
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • requiring MFN1 to induce mitochondrial fusion (but not MFN2)
  • directly interacts with subunits of complexes I, II and III, but not IV and with apoptosis inducing factor
  • a subset of OPA1 isoforms is constitutively cleaved by YME1L1
  • interacts with BNIP3, leading to mitochondrial fragmentation and apoptosis
  • organizes a supramolecular complex containing both PKA and perilipin (
  • can associate with dynamin-like GTPase Optic Atrophy-1 (OPA1) and contribute to the maintenance of mitochondrial morphology
  • Higd-1a
  • stress-induced OPA1 processing by OMA1 converts OPA1 completely into short isoforms, inhibits fusion, and triggers mitochondrial fragmentation
  • OMA1 is a critical regulator of neuronal survival, demonstrating that stress-induced OPA1 processing by OMA1 promotes neuronal death and neuroinflammatory responses
  • differential degradation of YME1L1 and OMA1 alters their proteolytic processing of the dynamin-like GTPase OPA1, a critical regulator of mitochondrial inner membrane morphology, which influences the recovery of tubular mitochondria following membrane-depolarization-induced fragmentation
  • cell & other
  • interaction of OPA1 with membranes can stimulate higher order assembly, enhance GTP hydrolysis and lead to membrane deformation into tubules
  • REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) OPA1 , OADOM
    related resource Retinal Information Network
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    found in Huntington disease patients relative to the controls
    Susceptibility
  • glaucoma (high tension glaucoma)
  • to transient ischemic attacks and non-cardioembolic infarction at younger onset
  • decreased OPA1 expression in primary open angle glaucoma patients (
  • Variant & Polymorphism SNP , other T54 allele susceptibility marker for transient ischemic attacks and non-cardioembolic infarction at younger onset
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurosensorialvisualdegenerative
    overexpression of superoxide dismutase 1, Vitamin E, and human SOD1 is able to reverse the glossy eye phenotype of dOPA1 mutant large clones in drosophilia
    ANIMAL & CELL MODELS
  • mouse homozygous for a Opa1 gene splice site mutation (c.1065 + 5G>A) die in utero during embryogenesis with first notable developmental delay at E8.5 while heterozygous mice are viable but exhibit an age-dependent loss of retinal ganglion cells progressesing to a severe degeneration of the ganglion cell and nerve fibre layer whose axones display an abnormal shape, disorganized mitochondrial cristae structures
  • ENU-induced mutant mouse carrying a protein-truncating nonsense mutation in opa1 display 50% reduction in opa1 protein in retina and all tissues on western analysis, alteration in morphology, with an increase in mitochondrial fission and fragmentation, a slow onset of degeneration in the optic nerve and a functional reduction in visual function
  • Mouse Opa1 homozygous mutation is embryonic lethal by 13.5 days post coitum
  • Heterozygous mutation of dOpa1 by a P-element or transposon insertions causes no discernable eye phenotype in Drosophila while homozygous mutation results in embryonic lethality
  • somatic homozygous mutation of dOpa1 in the Drosophila eyes caused rough (mispatterning) due to the loss of hexagonal lattice cells in developing eyes, and glossy (decreased lens and pigment deposition) eye phenotypes in adult flies
  • in adult flies, the dOpa1 mutation caused an increase in reactive oxygen species production as well as mitochondrial fragmentation associated with loss and damage of the cone and pigment cells
  • heterozygous dOpa1 mutation caused shortened lifespan, increased susceptibility to oxidative stress and elevated production of ROS in the whole Drosophila
  • homozygous mutant drosophila for OPA1 developed a rough and glossy eye phenotype due to the loss of hexagonal lattice cells, with decreased lens and pigment deposition
  • heterozygous B6;C3-Opa1(Q285STOP) mice display retinal ganglion cell dendropathy
  • Opa1(+/-) mutant mice (B6;C3-Opa1) have a marked reduction in retinal ganglion cell synaptic, decreased levels of postsynaptic density protein 95 and glutamatergic synaptic sites, increased synaptic vesicle number in bipolar cell terminal, retraction of mitochondria towards the soma of retinal ganglion cells and mitochondrial fragmentation, preceding dendritic loss
  • OPA1 knockdown retinal ganglion cells results in profound cristae depletion and loss of crista junctions, and defective Ca(2+) homeostasis
  • Opa1 mouse model carrying the recurrent Opa1(delTTAG) mutation displays a multi-systemic poly-degenerative phenotype: visual failure, deafness, encephalomyopathy, peripheral neuropathy, ataxia and cardiomyopathy, premature age-related axonal and myelin degenerations, increased autophagy and mitophagy and mitochondrial supercomplex instability preceding degeneration and cell death
  • downregulation of the OPA1 protein in rodent cortical primary neurons leads to fragmented mitochondria that become less abundant along the dendrites, reduced expression of mitochondrial respiratory complexe, reduction of mitochondrial DNA, decreased mitochondrial membrane potential, diminished reactive oxygen species levels, and a major restriction of dendritic growth, together with reduction of synaptic proteins
  • depletion of Opa1 in zebrafish embryos leads to mitochondrial morphology disruption, abnormal blood circulation and heart defects, small eyes, small pectoral fin buds and impairment of locomotor activity
  • Ablation of OPA1 in HeLa cells and 143b cells specifically abrogated pH flashes and reduced the propagation of matrix photoactivated GFP