Mitochondrial DNA Variant Discovery in Normal-Tension Glaucoma Patients by Next-Generation Sequencing

Mitochondrial DNA Variant Discovery in Normal-Tension Glaucoma Patients by Next-Generation Sequencing

Background:

The authors of this study seem to have identified a genetic variant that is a risk factor for the development of normal tension glaucoma (NTG). It is a mitochondrial DNA variant. Mitochondria are the energy factories of our cells -- they are located in every cell. Mitochondrial DNA is inherited from the mother only, unlike the 23 chromosomes in the cell nucleus (which come from both parents). Results of this study may improve our understanding of normal tension glaucoma and allow us to construct a new disease prediction model of NTG.

PURPOSE:

Normal-tension glaucoma (NTG) is a disease of late onset, complex trait with multiple risk factors. In this study, we discovered a mitochondrial DNA variant in normal tension glaucoma patients using next-generation sequencing (NGS).

METHODS:

The DNA was extracted from the peripheral blood of normal tension glaucoma patients and normal control subjects. Sequencing of the entire mitochondrial DNA (mtDNA) using NGS revealed new genetic risk variants for normal tension glaucoma patients (discovery sample, n = 20). For the candidate genetic variants, we performed a disease-gene association study in the independent case-control populations (validation sample; NTG, n = 196 and normal control, n = 202) using Sanger sequencing.

RESULTS:

This study identified 148 different novel mtDNA-sequence changes. Of these, 21 sequence variants identified at a frequency greater than 15% were located in the ND2-ND6, RNR1, RNR2, COX1, COX3, ATP6, ATP8, and CYTB genes. Of the 21 candidate genetic variants, the frequencies of m.4883C>T (ND2 gene), m.9540T>C (COX3 gene), and m.14766C>T (CYTB gene) were significantly different between NTG patients and controls (28.4% vs. 15.3%, P = 0.002; 56.5% vs. 44.4%, P = 0.020; and 3.1% vs. 0.0%, P = 0.030, respectively). The association with m.4883C>T in the ND2 gene resisted the Bonferroni correction for multiple tests. The NTG patients of T genotype in the m.4883C>T variant have more advanced visual field loss than those who carry the C genotype (P = 0.009).

CONCLUSIONS:

This study reveals a spectrum of mtDNA variants in patients with normal tension glaucoma. Our results identified a synonymous change, m.4883C>T variant, which was more prevalent in the NTG cohorts than in the controls. This finding suggests that the identified variant may be a genetic risk factor for the development of normal tension glaucoma.

Invest Ophthalmol Vis Sci. 2014 Feb 24;55(2):986-92. doi: 10.1167/iovs.13-12968.
Mitochondrial DNA variant discovery in normal-tension glaucoma patients by next-generation sequencing.
Jeoung JW1, Seong MW, Park SS, Kim DM, Kim SH, Park KH.

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Mitochondrial DNA Variant Discovery in Normal-Tension Glaucoma Patients by Next-Generation Sequencing