Mitochondrial DNA Haplogroups and Age-Related Maculopathy

Jones, Michael W. M.; Manwaring, Neil; Wang, Jie Jin; Rochtchina, Elena; Mitchell, Paul; Sue, Carolyn M.

doi:10.1001/archopht.125.9.1235

Cited by 89 publications

(66 citation statements)

References 45 publications

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“…Emerging evidence has suggested a key role for mitochondrial dysfunction in the AMD pathogenesis with the mitochondrial genome shown to impact AMD susceptibility. 49,50 As mitochondria comprise up to 74% to 85% of cone ellipsoids, 51 whether the IS ellipsoids coincide with the SD-OCT EZ remains of key interest and debate. 52,53 Reflectivity of photoreceptors on SD-OCT has been postulated to originate from light scattering or waveguiding.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Analysis of the Ellipsoid Zone Intensity in Phenotypic Variations of Intermediate Age-Related Macular Degeneration

Gin

Chew

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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Citation: Gin TJ, Wu Z, Chew SKH, Guymer RH, Luu CD. Quantitative analysis of the ellipsoid zone intensity in phenotypic variations of intermediate age-related macular degeneration. Invest Ophthalmol Vis Sci. 2017;58:207958: -208658: . DOI:10.1167 PURPOSE. Reduction of the ellipsoid zone (EZ) intensity has been reported in eyes with agerelated macular degeneration (AMD). This study determined whether overall EZ intensity, in retinal locations undisturbed by pathologic features, is associated with the presence of clinical features, which are known important phenotypic risk factors for disease progression, large drusen, reticular pseudodrusen (RPD), and pigmentary abnormalities. METHODS.A horizontal B-scan through the foveola on spectral-domain optical coherence tomography (SD-OCT) was performed in both eyes of 75 participants with bilateral intermediate AMD and 10 age-similar control participants. Eyes with AMD were classified as per the presence of large drusen, RPD, and hyperpigmentary changes. The relative EZ intensity profile, up to an eccentricity of 3400 lm, was averaged over seven 1000-lm retinal segments. The association between relative EZ intensity profile over seven retinal segments and AMD pathologic features was analyzed.RESULTS. The average relative EZ intensities were significantly reduced in eyes with intermediate AMD compared to normal eyes (P 0.025) and with increasing age (P 0.020). On multivariate analyses, only the presence of hyperpigmentary changes and increasing age were significantly associated with reduced overall relative intensities (P 0.024), but not the presence of large drusen or RPD (P ‡ 0.115).CONCLUSIONS. The presence of hyperpigmentary change in the macula in association with large drusen, not large drusen alone, nor large drusen with RPD, was significantly associated with a generalised reduction in EZ intensity. Quantitative assessment of the relative EZ intensity may serve as an effective biomarker of disease severity and progression.

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Section: Discussionmentioning

confidence: 99%

Quantitative Analysis of the Ellipsoid Zone Intensity in Phenotypic Variations of Intermediate Age-Related Macular Degeneration

Gin

Chew

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…Haplogroup H correlates with reduced risk of age-related macular degeneration, while haplogroups J and U are associated with increased risk of macular degeneration as well as increased drusen levels and retinal pigment abnormalities (Jones et al 2007;Udar et al 2009). Haplogroup H and H-nt 4336 are associated with increased risk, and haplogroups J and Uk with decreased risk, for developing PD (Shoffner et al 1993;van der Walt et al 2003;Ghezzi et al 2005;Khusnutdinova et al 2008).…”

Section: Adaptive Mtdna Variantsmentioning

confidence: 99%

The pathophysiology of mitochondrial disease as modeled in the mouse

Wallace¹,

Fan²

2009

Genes Dev.

186

150

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It is now clear that mitochondrial defects are associated with a plethora of clinical phenotypes in man and mouse. This is the result of the mitochondria's central role in energy production, reactive oxygen species (ROS) biology, and apoptosis, and because the mitochondrial genome consists of roughly 1500 genes distributed across the maternal mitochondrial DNA (mtDNA) and the Mendelian nuclear DNA (nDNA). While numerous pathogenic mutations in both mtDNA and nDNA mitochondrial genes have been identified in the past 21 years, the causal role of mitochondrial dysfunction in the common metabolic and degenerative diseases, cancer, and aging is still debated. However, the development of mice harboring mitochondrial gene mutations is permitting demonstration of the direct cause-and-effect relationship between mitochondrial dysfunction and disease. Mutations in nDNA-encoded mitochondrial genes involved in energy metabolism, antioxidant defenses, apoptosis via the mitochondrial permeability transition pore (mtPTP), mitochondrial fusion, and mtDNA biogenesis have already demonstrated the phenotypic importance of mitochondrial defects. These studies are being expanded by the recent development of procedures for introducing mtDNA mutations into the mouse. These studies are providing direct proof that mtDNA mutations are sufficient by themselves to generate major clinical phenotypes. As more different mtDNA types and mtDNA gene mutations are introduced into various mouse nDNA backgrounds, the potential functional role of mtDNA variation in permitting humans and mammals to adapt to different environments and in determining their predisposition to a wide array of diseases should be definitively demonstrated.

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“…In addition, studies on the mtDNA ancestral variants show that Northern European mtDNA haplogroups (J, T, and U) are associated with increased incidence of AMD [7,8,[11][12][13][14][15][16][17]. Mutations associated with mitochondria are often associated with disorders of multiple systems.…”

Section: Discussionmentioning

confidence: 99%

“…There is increasing evidence that alterations in the mitochondrial DNA (mtDNA) and in mitochondrial function may play a role in agerelated macular degeneration (AMD), a retinal disorder that is a leading cause of vision loss in people over 60 years of age [1][2][3][4][5][6][7][8]. Atrophic AMD is a severe form of the disease that exhibits loss of the retinal pigment epithelial (RPE) cells and overlying photoreceptors.…”

Section: Introductionmentioning

confidence: 99%

CKMT2 mutation in a patient with fatigue, age-related macular degeneration, deafness and atrial fibrillation

Udar¹,

Atilano²,

Boyer³

et al. 2017

Biomed Genet Genomics

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Purpose: The purpose of this study was to screen for mutations within mitochondrial creatine kinase (CKMT) genes, which encode for isoenzymes critical for high energy metabolism, such as that found in retina.Methods: DNA was extracted from lymphocytes of clinically characterized age-related macular degeneration (AMD) patients (n=71). Flanking primers were used to polymerase chain reaction (PCR) amplify and sequence the exons, the open reading frame, and promoter regions of the CKMT1A, CKMT1B and CKMT2 genes. An additional 72 individuals with AMD were screened for the novel CKMT2 mutation in exon 4 (NM_001825.2 c.274C>T) by PCR and enzyme digestion. The RNA was extracted from cultured human retinal pigment epithelial cells (ARPE-19) and reverse transcript-PCR (RT-PCR) was performed with primers for the CKMT2 gene. Results:With our screening procedure, we identified 5 DNA variants in the CKMT2 gene, 2 of which were novel (NM_001825.2 c.274C>T; 92Q>X, Exon 4 and NM_001825.2.-498G>GA; 5'UTR, Exon 1). The putative termination mutation in the CKMT2 gene (NM_001825.2 c.274C>T; 92Q>X) was in a proband individual but lacking in his unaffected son and 142 unrelated AMD patients. Cultured human RPE cells can express the sarcomeric mitochondrial CKMT2 gene product. Conclusions:This is the first report of a termination mutation within the human CKMT2 gene, which is critical for transfer of high-energy phosphate from mitochondria to creatine, a cytosolic carrier. Clinically, the subject had AMD, exercise fatigue, atrial fibrillation and deafness, all of which are known to be related to mitochondrial dysfunctions. Based upon our finding, we propose this CKMT2 mutation may be a candidate gene for the phenotypes that include this quartet of symptoms.

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Mitochondrial DNA Haplogroups and Age-Related Maculopathy

Cited by 89 publications

References 45 publications

Quantitative Analysis of the Ellipsoid Zone Intensity in Phenotypic Variations of Intermediate Age-Related Macular Degeneration

Quantitative Analysis of the Ellipsoid Zone Intensity in Phenotypic Variations of Intermediate Age-Related Macular Degeneration

The pathophysiology of mitochondrial disease as modeled in the mouse

CKMT2 mutation in a patient with fatigue, age-related macular degeneration, deafness and atrial fibrillation

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