TY - JOUR
T1 - Whole-mitochondrial genome sequencing in primary open-angle glaucoma using massively parallel sequencing identifies novel and known pathogenic variants
AU - Sundaresan, Periasamy
AU - Simpson, David A.
AU - Sambare, Chitra
AU - Duffy, Seamus
AU - Lechner, Judith
AU - Dastane, Aditi
AU - Dervan, Edward W.
AU - Vallabh, Neeru
AU - Chelerkar, Vidya
AU - Deshpande, Madan
AU - O'Brien, Colm
AU - McKnight, Amy Jayne
AU - Willoughby, Colin
PY - 2014/8/7
Y1 - 2014/8/7
N2 - PURPOSE:The aim of this study was to determine whether mutations in mitochondrial DNA play a role in high-pressure primary open-angle glaucoma (OMIM 137760) by analyzing new data from massively parallel sequencing of mitochondrial DNA.METHODS:Glaucoma patients with high-tension primary open-angle glaucoma and ethnically matched and age-matched control subjects without glaucoma were recruited. The entire human mitochondrial genome was amplified in two overlapping fragments by long-range polymerase chain reaction and used as a template for massively parallel sequencing on an Ion Torrent Personal Genome Machine. All variants were confirmed by conventional Sanger sequencing.RESULTS:Whole-mitochondrial genome sequencing was performed in 32 patients with primary open-angle glaucoma from India (n = 16) and Ireland (n = 16). In 16 of the 32 patients with primary open-angle glaucoma (50% of cases), there were 22 mitochondrial DNA mutations consisting of 7 novel mutations and 8 previously reported disease-associated sequence variants. Eight of 22 (36.4%) of the mitochondrial DNA mutations were in complex I mitochondrial genes.CONCLUSION:Massively parallel sequencing using the Ion Torrent Personal Genome Machine with confirmation by Sanger sequencing detected a pathogenic mitochondrial DNA mutation in 50% of the primary open-angle glaucoma cohort. Our findings support the emerging concept that mitochondrial dysfunction results in the development of glaucoma and, more specifically, that complex I defects play a significant role in primary open-angle glaucoma pathogenesis.
AB - PURPOSE:The aim of this study was to determine whether mutations in mitochondrial DNA play a role in high-pressure primary open-angle glaucoma (OMIM 137760) by analyzing new data from massively parallel sequencing of mitochondrial DNA.METHODS:Glaucoma patients with high-tension primary open-angle glaucoma and ethnically matched and age-matched control subjects without glaucoma were recruited. The entire human mitochondrial genome was amplified in two overlapping fragments by long-range polymerase chain reaction and used as a template for massively parallel sequencing on an Ion Torrent Personal Genome Machine. All variants were confirmed by conventional Sanger sequencing.RESULTS:Whole-mitochondrial genome sequencing was performed in 32 patients with primary open-angle glaucoma from India (n = 16) and Ireland (n = 16). In 16 of the 32 patients with primary open-angle glaucoma (50% of cases), there were 22 mitochondrial DNA mutations consisting of 7 novel mutations and 8 previously reported disease-associated sequence variants. Eight of 22 (36.4%) of the mitochondrial DNA mutations were in complex I mitochondrial genes.CONCLUSION:Massively parallel sequencing using the Ion Torrent Personal Genome Machine with confirmation by Sanger sequencing detected a pathogenic mitochondrial DNA mutation in 50% of the primary open-angle glaucoma cohort. Our findings support the emerging concept that mitochondrial dysfunction results in the development of glaucoma and, more specifically, that complex I defects play a significant role in primary open-angle glaucoma pathogenesis.
KW - Genetics
KW - Glaucoma
KW - Mitochondrial genome
KW - Next-generation sequencing
UR - https://pure.ulster.ac.uk/en/searchAll/index/?search=11660242&pageSize=25&showAdvanced=false&allConcepts=true&inferConcepts=true&searchBy=PartOfNameOrTitle
U2 - 10.1038/gim.2014.121
DO - 10.1038/gim.2014.121
M3 - Article
SN - 1530-0366
VL - 17
SP - 279
EP - 284
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 4
ER -