Paediatrics (RCH) - Research Publications

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Author: Hewitt, Alexander × Author: Trounce, Ian × Author: van Bergen, Nicole ×

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    Mitochondrial DNA Variation and Disease Susceptibility in Primary Open-Angle Glaucoma
    Singh, LN ; Crowston, JG ; Sanchez, MIGL ; Van Bergen, NJ ; Kearns, LS ; Hewitt, AW ; Yazar, S ; Mackey, DA ; Wallace, DC ; Trounce, IA (ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2018-09)
    PURPOSE: To determine whether mitochondrial DNA haplogroups or rare variants associate with primary open-angle glaucoma in subjects of European descent. METHODS: A case-control comparison of age- and sex-matched cohorts of 90 primary open-angle glaucoma patients and 95 population controls. Full mitochondrial DNA sequences from peripheral blood were generated by next-generation sequencing and compared to the revised Cambridge Reference Sequence to define mitochondrial haplogroups and variants. RESULTS: Most subjects were of the major European haplogroups H, J, K, U, and T. Logistic regression analysis showed haplogroup U to be significantly underrepresented in male primary open-angle glaucoma subjects (odds ratio 0.25; 95% confidence interval [CI] 0.09-0.67; P = 0.007; Bonferroni multiple testing P = 0.022). Variants in the mitochondrial DNA gene MT-ND2 were overrepresented in the control group (P = 0.005; Bonferroni multiple testing correction P = 0.015). CONCLUSIONS: Mitochondrial DNA ancestral lineages modulate the risk for primary open-angle glaucoma in populations of European descent. Haplogroup U and rare variants in the mitochondrial DNA-encoded MT-ND2 gene may be protective against primary open-angle glaucoma. Larger studies are warranted to explore haplogroup associations with disease risk in different ethnic groups and define biomarkers of primary open-angle glaucoma endophenotypes to target therapeutic strategies.
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    Mitochondrial replacement in an iPSC model of Leber's hereditary optic neuropathy
    Wong, RCB ; Lim, SY ; Hung, SSC ; Jackson, S ; Khan, S ; Van Bergen, NJ ; De Smit, E ; Liang, HH ; Kearns, LS ; Clarke, L ; Mackey, DA ; Hewitt, AW ; Trounce, IA ; Pebay, A (IMPACT JOURNALS LLC, 2017-04)
    Cybrid technology was used to replace Leber hereditary optic neuropathy (LHON) causing mitochondrial DNA (mtDNA) mutations from patient-specific fibroblasts with wildtype mtDNA, and mutation-free induced pluripotent stem cells (iPSCs) were generated subsequently. Retinal ganglion cell (RGC) differentiation demonstrates increased cell death in LHON-RGCs and can be rescued in cybrid corrected RGCs.