350: OPA1 A8S in Rhesus Macaques Models Autosomal Dominant Optic Atrophy

Jaggers TN et al et al., PNAS - A spontaneous OPA1 A8S missense mutation in rhesus macaques produces retinal ganglion cell loss, RNFL thinning, optic nerve atrophy, OPA1 mislocalization, and mitochondrial abnormalities, creating a nonhuman primate model that mirrors human autosomal dominant optic atrophy. Key terms: OPA1, autosomal dominant optic atrophy, rhesus macaque, retinal ganglion cell, mitochondria.

Study Highlights:
The authors identified an OPA1 NM_015560.2:c.22G>T (p.ala8ser, A8S) variant segregating dominantly in a rhesus colony. Heterozygous macaques showed significant peripapillary RNFL thinning, temporal optic nerve head pallor, and reduced PERG amplitudes consistent with RGC dysfunction. Histology and TEM revealed RGC loss, reduced axonal mitochondrial density, dysmorphic mitochondria, myelin disruption, and OPA1 mislocalization in RNFL axons. The model displays phenotypic variability similar to human ADOA and supports use for preclinical testing of mitochondrial- and gene-targeted therapies.

Conclusion:
A spontaneous OPA1 A8S mutation in rhesus macaques recapitulates key structural, functional, and ultrastructural features of human ADOA, providing a translational NHP model for testing therapies.

Music:
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Article title:
Rhesus macaques with an OPA1 mutation demonstrate features of autosomal dominant optic atrophy

First author:
Jaggers TN et al

Journal:
PNAS

DOI:
10.1073/pnas.2509165123

Reference:
Jaggers TN et al., Rhesus macaques with an OPA1 mutation demonstrate features of autosomal dominant optic atrophy. PNAS. 2026;123:e2509165123. https://doi.org/10.1073/pnas.2509165123

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-04-25.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantive audit of the transcript sections describing the OPA1 A8S mutation, heterozygous phenotype (RNFL thinning, ONH pallor, PERG deficits), ultrastructural mitochondrial defects and OPA1 mislocalization, homozygous cases, and translational therapy implications.
- transcript topics: OPA1 A8S mutation and spontaneous nonhuman primate model; Autosomal dominant optic atrophy (ADOA) in rhesus macaques; RNFL thinning and optic nerve head pallor; PERG dysfunction in OPA1 heterozygotes; Mitochondrial abnormalities and OPA1 mislocalization; TEM findings: dysmorphic mitochondria and axon loss

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 5
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- OPA1 A8S missense mutation identified in rhesus macaques in CNPRC colony
- Mutation is dominant and linked to autosomal dominant inheritance pattern
- Heterozygotes show RNFL thinning and temporal ONH pallor; PERG amplitudes reduced
- OPA1 mislocalization and reduced axonal mitochondrial density observed in retina
- Homozygous OPA1 macaques identified; survi...

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