Whole-mitochondrial genome sequencing in primary open-angle glaucoma using massively parallel sequencing identifies novel and known pathogenic variants

Sundaresan, Periasamy; Simpson, David; Sambare, Chitra; Duffy, Seamus; Lechner, Judith; Dastane, Aditi; Dervan, Edward; Vallabh, Neeru A.; Chelerkar, Vidya; Deshpande, Madan; O’Brien, Colm; McKnight, Amy Jayne; Willoughby, Colin E.

doi:10.1038/gim.2014.121

Cited by 40 publications

(41 citation statements)

References 35 publications

(56 reference statements)

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“…Approximately one-third of mutations were in one of the complex-I mitochondrial genes (ND5 gene). 59 Complex-I defects have been demonstrated in the lymphoblasts of POAG patients, leading to decreased rates of respiration and ATP production. 60 Taken together with various dysregulated oxidation-related factors found in previous studies, we also assume that the elevation of hsa-miR-210-3p itself may be a signal of systemic mitochondrial dysfunction and thus be a cause of POAG.…”

Section: Discussionmentioning

confidence: 99%

Discovery and Validation of Circulating Hsa-miR-210-3p as a Potential Biomarker for Primary Open-Angle Glaucoma

Liu

Wang

Chen

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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Citation: Liu Y, Wang Y, Chen Y, et al. Discovery and validation of circulating hsa-miR-210-3p as a potential biomarker for primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2019;60:2925-2934. https://doi.org/ 10.1167/iovs.19-26663PURPOSE. Blood-based examination tools for glaucoma diagnosis in clinical practice, which can be useful for screening patients when traditional ophthalmic examinations cannot be utilized, are not available thus far. This study aimed to identify circulating microRNAs (miRNAs) associated with primary open-angle glaucoma (POAG) and explore their utility as diagnostic markers. METHODS.A total of 136 POAG patients and controls were enrolled. Next-generation RNA sequencing was used to explore the expression profile of circulating miRNAs in the sequencing set, and potential miRNAs from independent samples in both the screening and validation sets were validated by quantitative real-time polymerase chain reaction (qRT-PCR). Receiver operating characteristic (ROC) analysis was used to evaluate the ability of certain miRNAs to distinguish POAG patients from control subjects. RESULTS.Using sequencing and qRT-PCR, hsa-miR-210-3p was found to be elevated in POAG patients in all sets. ROC analysis of the screening and validation sets revealed that hsa-miR-210-3p differentiated between POAG patients and matched controls with an area under the curve (AUC) of 0.846 (sensitivity: 84.6%; specificity: 80.8%) and 0.813 (sensitivity: 84.8%; specificity: 69.7%), respectively. In case of all nonsequencing participants, analysis revealed that hsa-miR-210-3p differentiated between severe POAG patients and controls with an AUC of 0.880 (sensitivity: 85.4%; specificity: 85.7%). In addition, the expression of hsa-miR-210-3p was associated with visual field defects of jmean deviationj (b ¼ 0.237; P ¼ 0.022) and average retinal nerve fiber layer thickness (b ¼ À5.792; P ¼ 0.014). CONCLUSIONS.Circulating hsa-miR-210-3p may serve as a potential diagnostic marker for POAG (especially for severe POAG patients).

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Section: Discussionmentioning

confidence: 99%

Discovery and Validation of Circulating Hsa-miR-210-3p as a Potential Biomarker for Primary Open-Angle Glaucoma

Liu

Wang

Chen

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…20,22 However, previous studies in human glaucoma have been cross-sectional and, therefore, unable to identify the severity (rate of progressive deterioration) of the neuropathy in relation to risk factors.…”

Section: Accepted Manuscriptmentioning

confidence: 98%

Resistance to the most common optic neuropathy is associated with systemic mitochondrial efficiency

Lascaratos

Chau²,

Zhu

et al. 2015

Neurobiology of Disease

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“…DNA analysis has demonstrated increased mitochondrial DNA content 38 as well as a spectrum of mtDNA mutations and mutations in nuclear-encoded mitochondrial protein-coding genes in both open-angle and normal tension glaucoma patients 39–45 . Such mitochondrial abnormalities were present in peripheral blood leukocytes suggesting a systemic susceptibility to metabolic abnormalities (as opposed to mitochondrial changes in the eye as a consequence of high IOP) 46 . Increased mitochondrial DNA content provides evidence of imbalance between mitochondrial and nuclear genomes that predispose to mitochondrial dysfunction.…”

Section: Mitochondria and Human Glaucomamentioning

confidence: 99%

Glaucoma as a Metabolic Optic Neuropathy: Making the Case for Nicotinamide Treatment in Glaucoma

Williams

Harder

John

2017

Journal of Glaucoma

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Mitochondrial dysfunction may be an important, if not essential, component of human glaucoma. Using transcriptomics followed by molecular and neurobiological techniques, we have recently demonstrated that mitochondrial dysfunction within retinal ganglion cells is an early feature in the DBA/2J mouse model of inherited glaucoma. Guided by these findings, we discovered that the retinal level of nicotinamide adenine dinucleotide (NAD, a key molecule for mitochondrial health) declines in an age-dependent manner. We hypothesized that this decline in NAD renders retinal ganglion cells susceptible to damage during periods of elevated intraocular pressure. To replete NAD levels in this glaucoma, we administered nicotinamide (the amide of vitamin B3). At the lowest dose tested, nicotinamide robustly protected from glaucoma (~70% of eyes had no detectable glaucomatous neurodegeneration). At this dose, nicotinamide had no influence on intraocular pressure and so its affect was neuroprotective. At the highest dose tested, 93% of eyes had no detectable glaucoma. This represents a ~10-fold decrease in the risk of developing glaucoma. At this dose, intraocular pressure still became elevated but there was a reduction in the degree of elevation showing an additional benefit. Thus, nicotinamide is unexpectedly potent at preventing this glaucoma and is an attractive option for glaucoma therapeutics. Our findings demonstrate the promise for both preventing and treating glaucoma via interventions that bolster metabolism during increasing age and during periods of elevated intraocular pressure. Nicotinamide prevents age-related declines in NAD (a decline that occurs in different genetic contexts and species). NAD precursors are reported to protect from a variety of neurodegenerative conditions. Thus, nicotinamide may provide a much needed neuroprotective treatment against human glaucoma. This manuscript summarizes human data implicating mitochondria in glaucoma, and argues for studies to further assess the safety and efficacy of nicotinamide in human glaucoma care.

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Whole-mitochondrial genome sequencing in primary open-angle glaucoma using massively parallel sequencing identifies novel and known pathogenic variants

Cited by 40 publications

References 35 publications

Discovery and Validation of Circulating Hsa-miR-210-3p as a Potential Biomarker for Primary Open-Angle Glaucoma

Discovery and Validation of Circulating Hsa-miR-210-3p as a Potential Biomarker for Primary Open-Angle Glaucoma

Resistance to the most common optic neuropathy is associated with systemic mitochondrial efficiency

Glaucoma as a Metabolic Optic Neuropathy: Making the Case for Nicotinamide Treatment in Glaucoma

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