Massively parallel sequencing of mitochondrial genome in primary open angle glaucoma identifies somatically acquired mitochondrial mutations in ocular tissue

Glaucoma is a sight threatening neurodegenerative condition of the optic nerve head associated with ageing and marked by the loss of retinal ganglion cells. Mitochondrial dysfunction plays a crucial role in the pathogenesis of neurodegeneration in the most prevalent type of glaucoma: primary open an...

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Bibliographic Details
Published in:Scientific reports Vol. 14; no. 1; pp. 26324 - 12
Main Authors: Vallabh, Neeru Amrita, Lane, Brian, Simpson, David, Fuchs, Marc, Choudhary, Anshoo, Criddle, David, Cheeseman, Robert, Willoughby, Colin
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01.11.2024
Nature Publishing Group
Nature Portfolio
Subjects:
631/208
631/208/2489
692/699/3161/3169
692/699/3161/3172
Aged
DNA biosynthesis
DNA damage
DNA sequencing
DNA, Mitochondrial - genetics
Eye diseases
Female
Fibroblasts
Fibroblasts - metabolism
Fibroblasts - pathology
Genome, Mitochondrial
Genomes
Glaucoma
Glaucoma, Open-Angle - genetics
Heteroplasmy
High-Throughput Nucleotide Sequencing
Humanities and Social Sciences
Humans
Leukocytes
Male
Massively parallel sequencing
Middle Aged
Mitochondria - genetics
Mitochondrial DNA
Mitochondrial genome
multidisciplinary
Mutation
Neurodegeneration
Optic nerve
Pathogenesis
Peripheral blood
Retinal ganglion cells
Science
Science (multidisciplinary)
Somatic mutations
Tenon’s fibroblasts
Whole genome sequencing
Tenon’s fibroblasts
Glaucoma
Massively parallel sequencing
Mitochondrial DNA
Somatic mutations
Mitochondrial genome
ISSN:2045-2322, 2045-2322
Online Access:Get full text
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Summary:Glaucoma is a sight threatening neurodegenerative condition of the optic nerve head associated with ageing and marked by the loss of retinal ganglion cells. Mitochondrial dysfunction plays a crucial role in the pathogenesis of neurodegeneration in the most prevalent type of glaucoma: primary open angle glaucoma (POAG). All previous mitochondrial genome sequencing studies in POAG analyzed mitochondrial DNA (mtDNA) isolated from peripheral blood leukocytes and have not evaluated cells derived from ocular tissue, which better represent the glaucomatous disease context. In this study, we evaluated mitochondrial genome variation and heteroplasmy using massively parallel sequencing of mtDNA in a cohort of patients with POAG, and in a subset assess the role of somatic mitochondrial genome mutations in disease pathogenesis using paired samples of peripheral blood leukocytes and ocular tissue (Tenon’s ocular fibroblasts). An enrichment of potentially pathogenic nonsynonymous mtDNA variants was identified in Tenon’s ocular fibroblasts from participants with POAG. The absence of oxidative DNA damage and predominance of transition variants support the concept that errors in mtDNA replication represent the predominant mutation mechanism in Tenon’s ocular fibroblasts from patients with POAG. Pathogenic somatic mitochondrial genome mutations were observed in people with POAG. This supports the role of somatic mitochondrial genome variants in the etiology of glaucoma.
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-024-72684-6