OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28
Abstract
Autosomal dominant optic atrophy (ADOA) is the most prevalent hereditary optic neuropathy resulting in progressive loss of visual acuity, centrocoecal scotoma and bilateral temporal atrophy of the optic nerve with an onset within the first two decades of life. The predominant locus for this disorder (OPA1; MIM 165500) has been mapped to a 1.4-cM interval on chromosome 3q28-q29 flanked by markers D3S3669 and D3S3562 (ref. 3). We established a PAC contig covering the entire OPA1 candidate region of approximately 1 Mb and a sequence skimming approach allowed us to identify a gene encoding a polypeptide of 960 amino acids with homology to dynamin-related GTPases. The gene comprises 28 coding exons and spans more than 40 kb of genomic sequence. Upon sequence analysis, we identified mutations in seven independent families with ADOA. The mutations include missense and nonsense alterations, deletions and insertions, which all segregate with the disease in these families. Because most mutations probably represent null alleles, dominant inheritance of the disease may result from haploinsufficiency of OPA1. OPA1 is widely expressed and is most abundant in the retina. The presence of consensus signal peptide sequences suggests that the product of the gene OPA1 is targeted to mitochondria and may exert its function in mitochondrial biogenesis and stabilization of mitochondrial membrane integrity.
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Loss-of-function mutations in MFN2 and OPA1 genes cause Charcot-Marie-Tooth type 2A (CMT2A) and dominant optic atrophy (DOA), respectively.
“Loss-of-function mutations in MFN2 and OPA1 genes cause two neurodegenerative diseases, Charcot–Marie–Tooth type 2A (CMT2A) [179] and dominant optic atrophy (DOA) [180, 181], respectively.”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [180]
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- Authors
- Alexander, C., Votruba, M., Pesch, U. E. A., Thiselton, D. L., Mayer, S., Moore, A., Rodriguez, M., Kellner, U., Leo-Kottler, B., Auburger, G., Bhattacharya, S. S., & Wissinger, B.
- Affiliations
- University College London (GB)
- Moorfields Eye Hospital (GB)
- Universitätsklinikum Tübingen (DE)
- Düsseldorf University Hospital (DE)
- Corresponding author
- Bhattacharya, Shomi S.
- Wissinger, Bernd
- ORCID
- Venue
- Nature Genetics
- Published
- 2000-10
- Volume
- 26
- Issue
- 2
- Pages
- 211-215
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1967445833
- Cited by
- 1,330
- References
- 27
- Citations by year
- 2026: 23 · 2025: 43 · 2024: 45 · 2023: 42 · 2022: 45 · 2021: 64 · 2020: 56 · 2019: 50 · 2018: 50 · 2017: 62 · 2016: 56 · 2015: 57 · 2014: 59 · 2013: 58 · 2012: 86
- FWCI
- 8.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Health Sciences › Medicine › Ophthalmology › Glaucoma and retinal disorders
- Keywords
- OPA1, autosomal dominant optic atrophy, dynamin-related GTPase, hereditary optic neuropathy, gene mapping, missense mutations, nonsense mutation, haploinsufficiency, mitochondrial biogenesis, mitochondrial membrane integrity, retinal gene expression, null alleles
- MeSH terms
- Amino Acid Sequence, Animals, Chromosome Mapping, Chromosomes, Human, Pair 3, DNA Mutational Analysis, Drosophila, Exons, Female, Genes, Dominant, Genetic Markers, Humans, Introns, Genetic Linkage, Male, Molecular Sequence Data, Mutation, Optic Atrophy, Pedigree, Saccharomyces cerevisiae, Salmon, Sequence Alignment, Sequence Homology, Amino Acid, GTP Phosphohydrolases, Dynamins
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