Mitochondrial DNA variant found in normal-tension glaucoma patients

Image: PD

1. Three mitochondrial genes were found to have significantly different variants among normal-tension glaucoma (NTG) patients compared to control patients: COX3, ND2, and CYTB (56.5 vs. 44.4%, p=0.02; 28.4 vs. 15.3%, p=0.002; 3.1 vs. 0.0%, p=0.03 respectively).

2. Normal-tension glaucoma patients with thymine (T) at position 4883 within the ND2 gene had a significantly worse progression of visual field loss compared to those with cytosine (C) at that position (p=0.009).

Evidence Rating Level: 1 (Excellent)

Study Rundown: This study seems to suggest that mitochondrial dysfunction may be a potential etiology of one form of glaucoma referred to as normal-tension glaucoma (NTG). NTG represents glaucomatous disease amongst patients with normal intraocular pressure (IOP) readings. By examining the mitochondrial DNA (mtDNA) of NTG patients and controls using next-generation sequencing, the authors were able to identify significant changes in genotype frequencies between the two groups. While variants within three genes were found to have significantly different frequencies between the groups, the change of one base at position 4883 in the protein ND2 withstood all statistical analyses. ND2 is known to be part of the oxidative phosphorylation complex, seeming to suggest that mitochondrial dysfunction due to abnormal ATP production may be involved in NTG pathogenesis. Strengths of the study include the relatively large sample size and rigorous statistical analyses. However, the major limitation of the study is its restriction to one ethnicity; all patients were Korean. NTG is much more prevalent in East Asia, which may confound these results. It would be valuable to assess whether similar results are discovered among other ethnic groups.

Click to read the study in Investigative Ophthalmology and Visual Sciences

Relevant Reading: Mitochondrial abnormalities in patients with primary open-angle glaucoma

In-Depth [genomic study]: This study attempted to identify any significant variations in mtDNA in patients with NTG by completing next-generation sequencing using NTG and control patients’ blood. NTG patients were identified as having normal IOP with optic disc cupping and visual field defects. Initially, 20 NTG patients were used for the discovery screen. Approximately 150 different mtDNA sequence changes were identified in this group, of which 21 had a frequency greater than 15%. A validation study with a larger cohort of NTG and control patients was then completed for disease-gene association. Three particular genes were found to have significant variants among NTG patients compared to controls – COX3, ND2, and CYTB (56.5 vs. 44.4%, p=0.02; 28.4 vs. 15.3%, p=0.002; 3.1 vs. 0.0%, p=0.03 respectively). After additional statistical analyses, only the ND2 variant (specifically a change from cytosine to thymine at position 4883) remained significant. In addition, the authors discovered a phenotypic effect; NTG patients with thymine at that position had a significantly worse progression of visual field loss compared to those with cytosine at that site (p=0.009). These data appear to suggest that mitochondrial dysfunction may be involved in one type of glaucoma pathogenesis.

By Swarup Swaminathan and Andrew Bishara

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