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Mitochondrial DNA nucleotide changes in primary congenital glaucoma patients.

ABSTRACT: PURPOSE: Primary congenital glaucoma (PCG) is the second most common cause of blindness, accounting for 0.01%-0.04% of total blindness worldwide. Most congenital glaucoma cases are mapped to the GLC3A locus, and many aspects of PCG are still unknown. Recent studies have reported an increased frequency of mitochondrial DNA (mtDNA) sequence changes in primary open-angle glaucoma, primary angle-closure glaucoma, and pseudoexfoliation glaucoma compared to controls. Thus, this study was planned with the aim of detecting mitochondrial DNA variations in PCG cases. METHODS: Twenty primary congenital glaucoma cases were selected from Dr. R. P. Centre for Ophthalmic Sciences of All India Institute of Medical Sciences (AIIMS), New Delhi, India. DNA was isolated from whole blood samples. The entire coding region of the mitochondrial genome was amplified by PCR in 20 patients and 20 controls. The full mtDNA genome was sequenced and analyzed against mitochondrial reference sequence NC_012920. RESULTS: MtDNA sequencing revealed a total of 195 nucleotide variations in PCG patients and 58 in controls. Of the 195 changes, 43 (22.05%) were nonsynonymous, 82 (42.05%) were synonymous, and 30 were in RNA genes. A total of 39/195 (20.00%) variations were observed in the D-loop (hypervariable region), 19/195 (9.74%) in different ribosomal RNA (rRNAs), 11/195 (5.64%) in transfer RNA (tRNAs), 66/195 (33.84%) in complex I, 17/195 (8.71%) in complex III, 27/195 (13.84%) in complex IV, and 15/195 (7.69%) in complex V. Of 58 variations in the controls, 14 were nonsynonymous changes. The Sorting Intolerant from Tolerant and Polymorphism Phenotyping analyses of all nonsynonymous changes from patients revealed two pathogenic changes in NADH-ubiquinone oxidoreductase chain 2 (ND2) and cytochrome oxidase subunit III (COXIII) subunits. In one of the patients, the insertion of cytosine introduced a frame shift change (p.Ile104AsnfsX26) in the cytochrome b (CYB) subunit of the electron transport chain. In another patient, a variation (G8572A) in ATP synthase 8 (ATpase8) led to the introduction of a stop codon or termination at amino acid position 69. Haplogroup/phylogenetic analysis of mtDNA showed that primary congenital glaucoma patients belong to three macrohaplogroups: M (4), N (15), and L (1). Fifty percent of the patients belonged to the H2a2a lineage of the N-derived haplogroup. CONCLUSIONS: Although several mutations were found at a higher frequency among our population, there is a need to complement this study with functional studies and to analyze a large number of samples in different populations of different haplogroups, as penetrance varies among haplogroups.

SUBMITTER: Kumar M

PROVIDER: S-EPMC3566903 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Mitochondrial DNA nucleotide changes in primary congenital glaucoma patients.

Kumar Manoj M Tanwar Mukesh M Faiq Muneeb Ahmad MA Pani Jhumur J Shamsi Monis Bilal MB Dada Tanuj T Dada Rima R

Molecular vision 20130201

<h4>Purpose</h4>Primary congenital glaucoma (PCG) is the second most common cause of blindness, accounting for 0.01%-0.04% of total blindness worldwide. Most congenital glaucoma cases are mapped to the GLC3A locus, and many aspects of PCG are still unknown. Recent studies have reported an increased frequency of mitochondrial DNA (mtDNA) sequence changes in primary open-angle glaucoma, primary angle-closure glaucoma, and pseudoexfoliation glaucoma compared to controls. Thus, this study was planne ...[more]

PMID: 23401651

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Project description:PurposeTo screen mitochondrial DNA (mtDNA) for nucleotide variations in primary congenital glaucoma (PCG).MethodsThe entire coding region of the mitochondrial genome was amplified by polymerase chain reaction from 35 PCG patients and 40 controls. The full mtDNA genome except the D-loop was sequenced. All sequences were analyzed against mitochondrial reference sequence NC_012920.ResultsMtDNA sequencing revealed a total of 132 and 58 nucleotide variations in PCG and controls, respectively. Of 132 nucleotide variations, 42 (31.81%) were non-synonymous and 82 (62.12%) were synonymous changes, and 8 were in RNA genes. The highest number of nucleotide variations were recorded in complex I followed by complex IV, then complex V. Eight patients (22.85%) had potentially pathogenic mtDNA nucleotide changes and twenty (57.14%) had mtDNA sequence changes associated with elevated reactive oxygen species (ROS) production. Mitochondria not only constitute the energy-generating system in the cell, but are also critically involved in calcium signaling and apoptosis. Mitochondrial function can be affected by mutations in mitochondrial and nuclear DNA, chemical insults to components of the electron transport chain, and a lack of substrates such as oxygen. Mitochondrial dysfunction results in an excessive generation of free radicals and reduced mitochondrial respiration. Developing trabecular meshwork (TM) is deficient in antioxidant enzymes, and thus is more susceptible to oxidative stress (OS) induced damage. Previous studies have documented certain mtDNA sequence variations associated with elevated ROS levels and OS. Three such changes (G10398A, A12308G, and G13708A) were present in our patients. Elevated ROS may cause OS. This OS may further damage mtDNA and may cause decreased mitochondrial respiration. This may lead to impaired growth, development and differentiation of TM and consequently trabecular-dysgenesis, which is a characteristic feature of PCG. OS affects both TM and retinal ganglion cells (RGCs) and may be involved in the neuronal death affecting the optic nerve in glaucoma. There are several studies which point to mitochondrial dysfunction in different types of glaucoma and critically participate in RGC death. Recent studies also implicate mitochondrial dysfunction-associated OS as a risk factor for glaucoma patients. It has been reported that elevated hydrostatic pressure causes breakdown of the mitochondrial network by mitochondrial fission and induce cristae depletion and cellular ATP reduction in differentiated RGC-5 cells in vitro as well as in vivo.ConclusionsA total of 44 novel mtDNA variations were identified in this study. Non-synonymous mtDNA variations may adversely affect respiratory chain, impair OXPHOS pathway result in low ATP production, high ROS production and impair growth, development and differentiation of TM lead to trabecular-dysgenesis and consequently RGC's death. Such cases with mtDNA variations and consequent OS may benefit by early diagnosis and prompt management by antioxidant therapy. This may delay OS induced injury to TM and RGCs and hence improve visual prognosis.

Project description:Primary congenital glaucoma (PCG) is the most common type of infantile glaucoma, yet it remains a relatively rare disease, because the disease is often transmitted in an autosomal recessive pattern. However, PCG occurs up to 10 times more frequently in certain ethnic and geographical groups where consanguineous relationships are common. The aim of this study was to investigate the distribution of mutations in the cytochrome P450 1B1 gene ( CYP1B1 ) in patients with PCG among different populations around the world from 2011 until May 2016. We referred to the electronic databases, such as Medline, Clinicalkey, Scopus, and ScienceDirect, to search for articles that were published in this area. Nineteen records were included in this qualitative synthesis. CYP1B1 mutations were assessed in 1,220 patients with PCG and identified in 41.6% of them. According to these studies, 99 mutations including 60 novel mutations were found. Nonsignificant difference in the sex ratio has been reported. This current review shows that consanguinity plays an important role in the PCG pathogenesis and transmission; however, sporadic mutations have been found in some cases. A difference in penetrance was highlighted by some mutations. The CYP1B1 mutations were mostly found in the Middle East and the Maghreb with a rate of 64.8 and 54.4%, respectively, followed by Europe (34.7%), Asia (21.3%), and finally the United States (14.9%). Founder mutations in different geographical areas have been discovered. For instance, the p.Gly61Glu, p.Arg390His, p.Gly61Glu, c.4,339delG, p.E387Lys, and p.Val320Leu were considered founder mutations for Iran/Saudi Arabia, Pakistan, Lebanon, Morocco, Europe, and Vietnam/South Korea, respectively. Many common mutations in different countries were found, such as in Morocco, where its mutations were similar to seven other countries. These findings suggest that the ethnic differences and the geographical distribution of PCG give us a large CYP1B1 mutation pattern. Genetic tests looking for founder and common mutations should be the first step in genetic screening for patients with PCG.

Project description:BackgroundPrimary congenital glaucoma (PCG) manifests within the first few years of a child's life and is not associated with any other systemic or ocular abnormalities. PCG results in considerable morbidity even in developed countries. Several surgical techniques for treating this condition, and lowering the intraocular pressure (IOP) associated with it, have been described.ObjectivesTo compare the effectiveness and safety of different surgical techniques for PCG.Search methodsWe searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2014, Issue 6), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2014), EMBASE (January 1980 to June 2014), (January 1982 to June 2014), PubMed (January 1946 to June 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 23 June 2014.Selection criteriaWe included all randomized and quasi-randomized trials in which different types of surgical interventions were compared in children under five years of age with PCG.Data collection and analysisWe used standard methodological procedures specified by The Cochrane Collaboration.Main resultsWe included a total of six trials (four randomized and two quasi-randomized) with 102 eyes in 61 children. Two trials were conducted in the USA and one trial each in Egypt, Israel, Lebanon and Saudi Arabia. All trials included children aged younger than one year when diagnosed with PCG, and followed them for periods ranging from six months to five years.No two trials compared the same pair of surgical interventions, so we did not perform any meta-analysis. One trial compared trabeculotomy versus goniotomy; a second trial compared combined trabeculectomy-trabeculotomy with mitomycin C versus trabeculectomy-trabeculotomy with mitomycin C and deep sclerectomy; a third trial compared combined trabeculotomy-trabeculectomy versus trabeculotomy; a fourth trial compared one goniotomy versus two goniotomies; a fifth trial compared trabeculotomy versus viscocanalostomy; and the sixth trial compared surgical goniotomy versus neodymium-YAG laser goniotomy. For IOP change and surgical success (defined by IOP achieved), none of the trials reported a difference between pairs of surgical techniques. However, due to the limited sample sizes for all trials (average of 10 children per trial), the evidence as to whether a particular surgical technique is effective and which surgical technique is better still remains uncertain. Adverse events, such as choroidal detachment, shallow anterior chamber and hyphema, were reported from four trials. None of the trials reported quality of life or economic data.These trials were neither designed nor reported well overall. Two trials were quasi-randomized trials and judged to have high risk of selection bias; four trials were at unclear or high risk for performance bias and detection bias; and we judged one trial to have high risk of attrition bias due to high proportions of losses to follow-up. Due to poor study design and reporting, the reliability and applicability of evidence remain unclear.Authors' conclusionsNo conclusions could be drawn from the trials included in this review due to paucity of data. More research is needed to determine which of the many surgeries performed for PCG are effective.

Project description:BACKGROUND: CYP1B1 is the most commonly mutated gene in primary congenital glaucoma (PCG). This study was undertaken to identify mutations in CYP1B1 in the Western region of Saudi Arabia. METHODS: Blood of patients who had typical findings of PCG, were screened by direct sequencing of all coding exons and splice junctions of the CYP1B1 gene. RESULTS: 34 patients were studied; 18 patients belonged to 8 families, and 16 patients were non-familial, isolated PCG. Consanguinity was found in 27/34 (79.4%) of cases. All patients were diagnosed to have bilateral PCG at birth except one child, who had glaucoma in the right eye. More males (61.8%) were affected than females (38.2%). 79.4% (27/34) of patients were solved with pathogenic mutations and 20.6% (7/34) remained unsolved. Of the solved ones, 22.2% (6/27) of patients carry a pathogenic allele on one allele while the other allele remained yet to be determined. Direct sequencing of exon 2 revealed two pathogenic variants (p.Gly61Glu, p.Glu229Lys). P.Gly61Glu substitution was found both homozygously in 63% (17/27) of cases, and heterozygously in one patient. P.Glu229Lys variant was found heterozygous in 3.7% (1/27) of cases. One pathogenic variant (p.Arg469Trp) was found in exon 3, and is present homozygously in 14.8% (4/27) of cases while four patients have this variant heterozygously. All mutations were reported previously in the Saudi population, except p.Glu229Lys. Severe cases were associated with p.Gly61Glu, and p.Arg469Trp in 50% and 30% of ten patients respectively. CONCLUSIONS: This study confirms that CYP1B1 mutations are the most frequent cause of PCG in the Saudi population, with p.Gly61Glu being the major disease-associated mutation. P.Glu229Lys is a newly discovered mutation in our PCG patients. Patient lacking mutation in CYP1B1 gene seems likely, to have another genetic loci involved in the pathogenesis of the disease, and need further study. Genetic studies of recessive diseases such as PCG is important in consanguineous populations, since it will increase awareness and allows genetic counseling to be offered to patients and their relatives. This will not only reduce the disease to be inherited to future generations, but will also reduce the disease burden in the community.

Dataset Information

Mitochondrial DNA nucleotide changes in primary congenital glaucoma patients.

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Mitochondrial DNA nucleotide changes in primary congenital glaucoma patients.

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