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Frequency of primary mutations of Leber's hereditary optic neuropathy patients in North Indian population.

ABSTRACT: PURPOSE:Leber's hereditary optic neuropathy (LHON) is an inherited optic neuropathy characterized by subacute painless vision loss. The majority of LHON is caused due to one of the three primary mutations in the mitochondrial DNA (m.G3460A, m.G11778A, and m.T14484C). The frequency of these mutations differs in different populations. The purpose of this study is to observe the frequency of three common primary mutations in the North Indian population. METHODS:Forty LHON patients within the age group of 10-50 years underwent molecular testing for primary mutations. For two patients, testing for mother and other siblings was also carried out, using bidirectional sequencing. RESULTS:A total of 11 out of 40 (27.5%) patients were found to be carrying m.G11778A mutation. Siblings of two probands were also positive for the same mutation. In one family, two primary mutations (m.G11778A and m.T14484C) were found in the proband and in the mother as well. CONCLUSION:In this study, 27.5% mutation was detected in North Indian LHON families. These results suggest that m.G11778A mutation is more frequent in this population. The results of the present study are compatible with studies of an Asian population and Northern European population.

SUBMITTER: Mishra A

PROVIDER: S-EPMC5700584 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Frequency of primary mutations of Leber's hereditary optic neuropathy patients in North Indian population.

Mishra Anushree A Devi Saranya S Saxena Rohit R Gupta Neerja N Kabra Madhulika M Chowdhury Madhumita Roy MR

Indian journal of ophthalmology 20171101 11

<h4>Purpose</h4>Leber's hereditary optic neuropathy (LHON) is an inherited optic neuropathy characterized by subacute painless vision loss. The majority of LHON is caused due to one of the three primary mutations in the mitochondrial DNA (m.G3460A, m.G11778A, and m.T14484C). The frequency of these mutations differs in different populations. The purpose of this study is to observe the frequency of three common primary mutations in the North Indian population.<h4>Methods</h4>Forty LHON patients wi ...[more]

PMID: 29133642

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Project description:PurposeTo screen mitochondrial DNA (mtDNA) variations in Leber hereditary optic neuropathy (LHON).MethodsTen LHON patients were selected from neuro-ophthalmology clinics of All India Institute of Medical Sciences (AIIMS), New Delhi, India. Clinical evaluation included slit-lamp biomicroscopy, fundus examination, and neuroimaging. DNA was isolated from whole blood samples. The entire coding region of the mitochondrial genome was amplified by PCR in ten patients and 20 controls. The full mtDNA genome except D-loop was sequenced. All sequences were analyzed against mitochondrial reference sequence NC_012920.ResultsMtDNA sequencing revealed a total of 30 nucleotide variations in the ten LHON patients and 29 in the 20 controls. Of 30 changes, 30.00% (9/30) were nonsynonymous, and the remaining 70.00% (21/30) were synonymous. In controls, a total of five changes were nonsynonymous. Out of the total 14 nonsynonymous changes observed in cases and controls, four (p.A52T in nicotinamide adenine dinucleotide [NADH] dehydrogenase [ND1] protein; p.L128Q in ND2; p.W48R in ATPase6; p.R340H in ND4 protein) were pathogenic. Four patients were positive for either of pathogenic changes. In total, 16.66% (5/30) variations were novel out of which 40.00% (2/5) were nonsynonymous. All novel variations were submitted to the GenBank database, and accession numbers were obtained. Primary LHON mutations in complex I genes have been considered a hallmark feature of LHON patients, and primary LHON mutations were present in two cases in this study. Mutations in complex I genes (ND genes) account for 50%-90% of LHON pedigrees in different ethnic pedigrees. In this study the highest numbers of changes were also present in complex I genes (46.66%; 14/30) followed by complex IV (30.00%; 9/30), complex III (16.66%; 5/30), and then complex V (6.66%; 2/30). Complex I had 5/30 (16.66%) nonsynonymous changes, complex III had 1/30 (3.33%), complex IV had 1/30 (3.33%), and complex V had 2/30 (6.66%) nonsynonymous changes. Nonsynonymous mutations in cytochrome c oxidase (COX) genes have been reported previously in LHON patients. Nonsynonymous mtDNA variations may adversely affect the respiratory chain and impair the oxidative phosphorylation (OXPHOS) pathway, resulting in low ATP production and elevated reactive oxygen species (ROS) levels, which cause oxidative stress. It has previously been reported that oxidative stress (OS) leads to oxidative damage of cellular macromolecules, such as mitochondrial and nuclear DNA, proteins, and lipids along with energy depletion and a local imbalance of calcium homeostasis, resulting in neuronal degeneration. OS is the underlying etiology in several ocular diseases and also plays an essential role in LHON.ConclusionsA total of five novel mtDNA variations were identified in this study. Nonsynonymous mtDNA variations may adversely affect the respiratory chain and impair the OXPHOS pathway, resulting in low ATP production and elevated ROS levels. OS further damages both nuclear and mtDNA. This preliminary study describes mtDNA sequence variations in a relatively small number of LHON patients of north Indian ethnic origin. However, these results should be confirmed in other populations. Early diagnosis of mtDNA variations and prompt anti-oxidant administration in these cases may delay OS-induced injury to retinal ganglion cells (RGCs) and hence improve visual prognosis.

Dataset Information

Frequency of primary mutations of Leber's hereditary optic neuropathy patients in North Indian population.

Publications

Frequency of primary mutations of Leber's hereditary optic neuropathy patients in North Indian population.

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