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OPA3
outer mitochondrial membrane lipid metabolism regulator OPA3
The OPA3 gene provides instructions for a protein involved in mitochondrial function, and variants in this gene are associated with inherited conditions affecting vision and neurological development. The OPA3 gene plays a role in maintaining the structure and function of mitochondria, the energy-producing organelles within cells.
OPA3 is located on the long (q) arm of chromosome 19, at band 19q13.32. Arm ratio per GRCh38 - banding schematic.
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Overview
The OPA3 gene (outer mitochondrial membrane lipid metabolism regulator OPA3) encodes a protein that localises to the mitochondria. Although its precise function is still being investigated, it is thought to contribute to the organisation of mitochondrial shape and structure, and may also be involved in programmed cell death, known as apoptosis. Pathogenic variants in the OPA3 gene are associated with several inherited conditions, primarily affecting vision and neurological function, such as Costeff syndrome and autosomal dominant optic atrophy and cataract.
What the gene does
The OPA3 protein is found within mitochondria, which are essential cellular structures responsible for energy production. While the exact molecular mechanisms remain unclear, the OPA3 protein is believed to play a part in regulating the morphology and structural integrity of mitochondria. This role is crucial for their efficient functioning and the overall energetic homeostasis of the cell. Additionally, evidence suggests OPA3 may influence apoptosis, a process of controlled cell death vital for normal development and tissue maintenance. Dysregulation of OPA3's function due to genetic variants can impair mitochondrial activity, leading to various clinical manifestations.
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Chromosome location
The OPA3 gene is situated on chromosome 19, specifically at position 19q13.32. This chromosomal location indicates where the gene resides within the human genome. The gene encodes a protein that is 179 amino acids in length.
Protein structure
The OPA3 protein contains a notable structural feature: a coiled coil domain. This coiled coil region spans amino acids 103-163 of the protein. Coiled coils are common protein motifs involved in protein-protein interactions and often contribute to the formation of stable protein structures.
Key variants
Variants within the OPA3 gene can lead to altered or non-functional protein products, impacting mitochondrial health. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions, and their specific effects can vary depending on the nature and location of the variant.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.143-1G>A | - | Pathogenic | ★★☆☆ | 3-Methylglutaconic aciduria type 3 |
c.143-1G>C | - | Pathogenic | ★★☆☆ | 3-Methylglutaconic aciduria type 3 |
c.313C>G | p.Gln105Glu | Pathogenic | ★★☆☆ | OPA3-related disorder |
g.(?_45584613)_(45584774_?)del | - | Pathogenic | ★☆☆☆ | 3-Methylglutaconic aciduria type 3 |
g.(?_46056772)_(46088022_?)del | - | Pathogenic | ★☆☆☆ | 3-Methylglutaconic aciduria type 3 |
c.103G>T | p.Glu35Ter | Pathogenic | ★☆☆☆ | 3-Methylglutaconic aciduria type 3 |
c.143-2_143-1delinsCC | - | Pathogenic | ★☆☆☆ | 3-Methylglutaconic aciduria type 3 |
c.277G>A | p.Gly93Ser | Pathogenic | - | Optic atrophy 3 |
c.322_339del | p.Gln108_Glu113del | Pathogenic | - | 3-Methylglutaconic aciduria type 3 |
c.415C>T | p.Gln139Ter | Pathogenic/Likely pathogenic | - | 3-Methylglutaconic aciduria type 3 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the OPA3 gene are associated with several inherited disorders. These include Costeff syndrome, which is characterised by optic nerve atrophy, developmental delay, and movement difficulties. Another associated condition is autosomal dominant optic atrophy and cataract, presenting with progressive vision loss that often begins in childhood, alongside cataract formation.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic OPA3 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The OPA3 gene is currently included on several NHS Genomic Medicine Service national test panels. These panels cover conditions such as Ataxia and cerebellar anomalies - childhood onset, Bilateral congenital or childhood onset cataracts (R31), Dystonia, chorea or related movement disorder, childhood onset (R57), Hereditary ataxia (including adult onset), Hereditary neuropathy (R78), Hereditary spastic paraplegia (including adult and childhood onset R61), Intellectual disability, Likely inborn error of metabolism (R98), Mitochondrial disorders (including possible mitochondrial disorder, nuclear genes R63), Optic neuropathy (R41), Parkinson Disease and Complex Parkinsonism, and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the OPA3 gene responsible for?
The OPA3 gene provides instructions for a protein located in the mitochondria, the cell's energy producers. It is believed to help organise mitochondrial structure and may also be involved in controlled cell death (apoptosis).
What conditions are associated with OPA3 gene variants?
Variants in the OPA3 gene are linked to inherited conditions such as Costeff syndrome, which causes vision loss and developmental issues, and autosomal dominant optic atrophy and cataract, primarily affecting vision.
How is OPA3 relevant to genetic screening?
The OPA3 gene is part of several NHS Genomic Medicine Service panels, indicating its importance in diagnosing inherited conditions related to neurological function, vision, and metabolic disorders, especially for carrier screening and diagnostic purposes.
References
- Li Y, Li J, Jia X. Genetic and Clinical Analyses of DOA and LHON in 304 Chinese Patients with Suspected Childhood-Onset Hereditary Optic Neuropathy. PloS one. 2017. PMID: 28081242
- Bagli E, Zikou AK, Agnantis N. Mitochondrial Membrane Dynamics and Inherited Optic Neuropathies. In vivo (Athens, Greece). 2017. PMID: 28652416
- Sergouniotis PI, Perveen R, Thiselton DL. Clinical and molecular genetic findings in autosomal dominant OPA3-related optic neuropathy. Neurogenetics. 2015. PMID: 25159689
- Grau T, Burbulla LF, Engl G. A novel heterozygous OPA3 mutation located in the mitochondrial target sequence results in altered steady-state levels and fragmented mitochondrial network. Journal of medical genetics. 2013. PMID: 24136862
- Huizing M, Dorward H, Ly L. OPA3, mutated in 3-methylglutaconic aciduria type III, encodes two transcripts targeted primarily to mitochondria. Molecular genetics and metabolism. 2010. PMID: 20350831
- Reynier P, Amati-Bonneau P, Verny C. OPA3 gene mutations responsible for autosomal dominant optic atrophy and cataract. Journal of medical genetics. 2004. PMID: 15342707
- Anikster Y, Kleta R, Shaag A. Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or Costeff optic atrophy syndrome): identification of the OPA3 gene and its founder mutation in Iraqi Jews. American journal of human genetics. 2001. PMID: 11668429