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

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

    Research output: Contribution to journalArticle

    18 Citations (Scopus)

    Abstract

    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.
    LanguageEnglish
    Pages279-284
    Number of pages5
    JournalGenetics in Medicine
    Volume17
    Issue number4
    DOIs
    Publication statusAccepted/In press - 7 Aug 2014

    Fingerprint

    High-Throughput Nucleotide Sequencing
    Mitochondrial Genome
    Mitochondrial DNA
    Mutation
    Glaucoma
    Genome
    Ions
    Genetic Databases
    Mitochondrial Genes
    Human Genome
    Ireland
    Primary Open Angle Glaucoma
    India
    Pressure
    Polymerase Chain Reaction

    Keywords

    • Genetics
    • Glaucoma
    • Mitochondrial genome
    • Next-generation sequencing

    Cite this

    Sundaresan, Periasamy ; Simpson, David A. ; Sambare, Chitra ; Duffy, Seamus ; Lechner, Judith ; Dastane, Aditi ; Dervan, Edward W. ; Vallabh, Neeru ; Chelerkar, Vidya ; Deshpande, Madan ; O'Brien, Colm ; McKnight, Amy Jayne ; Willoughby, Colin. / Whole-mitochondrial genome sequencing in primary open-angle glaucoma using massively parallel sequencing identifies novel and known pathogenic variants. In: Genetics in Medicine. 2014 ; Vol. 17, No. 4. pp. 279-284.
    @article{276940098f3c4a76be36bfc8963810c1,
    title = "Whole-mitochondrial genome sequencing in primary open-angle glaucoma using massively parallel sequencing identifies novel and known pathogenic variants",
    abstract = "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.",
    keywords = "Genetics, Glaucoma, Mitochondrial genome, Next-generation sequencing",
    author = "Periasamy Sundaresan and Simpson, {David A.} and Chitra Sambare and Seamus Duffy and Judith Lechner and Aditi Dastane and Dervan, {Edward W.} and Neeru Vallabh and Vidya Chelerkar and Madan Deshpande and Colm O'Brien and McKnight, {Amy Jayne} and Colin Willoughby",
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    Sundaresan, P, Simpson, DA, Sambare, C, Duffy, S, Lechner, J, Dastane, A, Dervan, EW, Vallabh, N, Chelerkar, V, Deshpande, M, O'Brien, C, McKnight, AJ & Willoughby, C 2014, 'Whole-mitochondrial genome sequencing in primary open-angle glaucoma using massively parallel sequencing identifies novel and known pathogenic variants', Genetics in Medicine, vol. 17, no. 4, pp. 279-284. https://doi.org/10.1038/gim.2014.121

    Whole-mitochondrial genome sequencing in primary open-angle glaucoma using massively parallel sequencing identifies novel and known pathogenic variants. / Sundaresan, Periasamy; Simpson, David A.; Sambare, Chitra; Duffy, Seamus; Lechner, Judith; Dastane, Aditi; Dervan, Edward W.; Vallabh, Neeru; Chelerkar, Vidya; Deshpande, Madan; O'Brien, Colm; McKnight, Amy Jayne; Willoughby, Colin.

    In: Genetics in Medicine, Vol. 17, No. 4, 07.08.2014, p. 279-284.

    Research output: Contribution to journalArticle

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    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

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