Whole mitochondrial genome analysis in South Indian patients with Leber's hereditary optic neuropathy

Saikia, Bibhuti Ballav; Dubey, Suneeta; Shanmugam, Mahesh Kumar; Sundaresan, Periasamy

doi:10.1016/j.mito.2016.10.006

Cited by 8 publications

(4 citation statements)

References 37 publications

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“…After all, only a very few studies so far focused on haplogroup investigation of LHON cohorts who were harboring the m.14495A>G mutation, with limited data available. Recently, in addition to M haplogroup being reported again as a high-risk factor for LHON, another interesting finding has been noted that in South Indian population, the number of mtDNA mutations is higher in LHON patients than in healthy controls 33. In the present study, a total of 46 mutations were found in each matrilineal relative (Supplementary Table S1), far exceeding the reported average number of variations in healthy controls (26.23 ± 4.17),33 further indicating that individual with our mtDNA haplogroup background would become more susceptible to LHON.…”

Section: Discussionmentioning

confidence: 94%

Leber's Hereditary Optic Neuropathy–Specific Heteroplasmic Mutation m.14495A>G Found in a Chinese Family

Duan

Qin

et al. 2019

Trans. Vis. Sci. Tech.

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Purpose Leber's hereditary optic neuropathy (LHON) is a mitochondrial DNA (mtDNA)-associated, maternally inherited eye disease. Mutation heteroplasmy level is one of the leading causes to trigger LHON manifestation. In this study, we aimed to identify the causative mutation in a large Han Chinese family with LHON and explore the underlying pathogenic mechanism in this LHON family. Methods The whole-mtDNA sequence was amplified by long-range PCR. Mutations were subsequently identified by next-generation sequencing (NGS) and validated by Sanger sequencing. The heteroplasmy rates of those family members were determined by digital PCR (dPCR). Mitochondrial haplogroups were assigned based on mtDNA tree build 17. Results The m.14495A>G mutation was identified as causative due to its higher heteroplasmy level (>50%) in patients than in their unaffected relatives. All mutation carriers belong to M7b1a1 and are assigned to Asian mtDNA lineage. Interestingly, our result revealed that high mtDNA copy number in carrier might prevent LHON manifestation. Conclusions This is the first report of m.14495A>G mutation in Asian individuals with LHON. Our study shows that dPCR technology can provide more reliable results in mutation heteroplasmy assay and determination of the cellular mtDNA content, making it a potentially promising tool for clinical precise diagnosis of LHON. Furthermore, our results also add evidence to the opinion that higher mtDNA content may protect mutation carriers from LHON. Translational Relevance dPCR can be used for the assessment of LHON disease, and a new genetic-based diagnostic strategy has been proposed for LHON patients with the m.14495A>G mutation.

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Section: Discussionmentioning

confidence: 94%

Leber's Hereditary Optic Neuropathy–Specific Heteroplasmic Mutation m.14495A>G Found in a Chinese Family

Duan

Qin

et al. 2019

Trans. Vis. Sci. Tech.

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“…We performed a systemic study of three primary LHON variants and analysed the same to understand their genetic heterogeneity and how their frequencies vary from one geographical location to another as a function of population, ethnicity, and study sample size. The study included a total of 42, 35, and 30 data points for m.11778G>A [ 3 , 9 , 10 , 11 , 14 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ], m.14484T>C [ 3 , 8 , 11 , 14 , 26 , 27 , 29 , 31 , 33 , 34 , 35 ...…”

Section: Resultsmentioning

confidence: 99%

“…However, no significant difference in the frequency of M7b1′2 and M8a between case and control subjects was observed, despite their evident effect on the clinical expression of the disease [ 13 ]. Later, Saikia et al (2017), reported for the first time an association of the M haplogroup ( p = 0.028) with LHON [ 14 ]. In contrast, our previous studies did not show any specific correlation between haplogroup background and LHON expression [ 8 , 9 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Genetic Heterogeneity in Leber’s Hereditary Optic Neuropathy: Original Study with Meta-Analysis

Jha

Dawar

Hasan

et al. 2021

Genes

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Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disorder that causes loss of central vision. Three primary variants (m.3460G>A, m.11778G>A, and m.14484T>C) and about 16 secondary variants are responsible for LHON in the majority of the cases. We investigated the complete mitochondrial DNA (mtDNA) sequences of 189 LHON patients and found a total of 54 disease-linked pathogenic variants. The primary variants m.11778G>A and m.14484T>C were accountable for only 14.81% and 2.64% cases, respectively. Patients with these two variants also possessed additional disease-associated variants. Among 156 patients who lacked the three primary variants, 16.02% harboured other LHON-associated variants either alone or in combination with other disease-associated variants. Furthermore, we observed that none of the haplogroups were explicitly associated with LHON. We performed a meta-analysis of m.4216T>C and m.13708G>A and found a significant association of these two variants with the LHON phenotype. Based on this study, we recommend the use of complete mtDNA sequencing to diagnose LHON, as we found disease-associated variants throughout the mitochondrial genome.

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“…There may be genetic compensation at play, with the mtDNA copy number in key tissues upregulated by a range of mechanisms as yet not completely understood, although this remains controversial. 27 , 28 In addition to the penetrance of the mutations the synergistic effects of other rarer additional gene mutations 27 , 29 , 30 as well as environmental factors may all be contributors to the severity of LHON.…”

Section: Lhonmentioning

confidence: 99%

New avenues for therapy in mitochondrial optic neuropathies

Trigano

Freeman

et al. 2021

Therapeutic Advances in Rare Disease

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Mitochondrial optic neuropathies are a group of optic nerve atrophies exemplified by the two commonest conditions in this group, autosomal dominant optic atrophy (ADOA) and Leber’s hereditary optic neuropathy (LHON). Their clinical features comprise reduced visual acuity, colour vision deficits, centro-caecal scotomas and optic disc pallor with thinning of the retinal nerve fibre layer. The primary aetiology is genetic, with underlying nuclear or mitochondrial gene mutations. The primary pathology is owing to retinal ganglion cell dysfunction and degeneration. There is currently only one approved treatment and no curative therapy is available. In this review we summarise the genetic and clinical features of ADOA and LHON and then examine what new avenues there may be for therapeutic intervention. The therapeutic strategies to manage LHON and ADOA can be split into four categories: prevention, compensation, replacement and repair. Prevention is technically an option by modifying risk factors such as smoking cessation, or by utilising pre-implantation genetic diagnosis, although this is unlikely to be applied in mitochondrial optic neuropathies due to the non-life threatening and variable nature of these conditions. Compensation involves pharmacological interventions that ameliorate the mitochondrial dysfunction at a cellular and tissue level. Replacement and repair are exciting new emerging areas. Clinical trials, both published and underway, in this area are likely to reveal future potential benefits, since new therapies are desperately needed. Plain language summary Optic nerve damage leading to loss of vision can be caused by a variety of insults. One group of conditions leading to optic nerve damage is caused by defects in genes that are essential for cells to make energy in small organelles called mitochondria. These conditions are known as mitochondrial optic neuropathies and two predominant examples are called autosomal dominant optic atrophy and Leber’s hereditary optic neuropathy. Both conditions are caused by problems with the energy powerhouse of cells: mitochondria. The cells that are most vulnerable to this mitochondrial malfunction are called retinal ganglion cells, otherwise collectively known as the optic nerve, and they take the electrical impulse from the retina in the eye to the brain. The malfunction leads to death of some of the optic nerve cells, the degree of vision loss being linked to the number of those cells which are impacted in this way. Patients will lose visual acuity and colour vision and develop a central blind spot in their field of vision. There is currently no cure and very few treatment options. New treatments are desperately needed for patients affected by these devastating diseases. New treatments can potentially arise in four ways: prevention, compensation, replacement and repair of the defects. Here we explore how present and possible future treatments might provide hope for those suffering from these conditions.

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Whole mitochondrial genome analysis in South Indian patients with Leber's hereditary optic neuropathy

Cited by 8 publications

References 37 publications

Leber's Hereditary Optic Neuropathy–Specific Heteroplasmic Mutation m.14495A>G Found in a Chinese Family

Leber's Hereditary Optic Neuropathy–Specific Heteroplasmic Mutation m.14495A>G Found in a Chinese Family

Mitochondrial Genetic Heterogeneity in Leber’s Hereditary Optic Neuropathy: Original Study with Meta-Analysis

New avenues for therapy in mitochondrial optic neuropathies

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Whole mitochondrial genome analysis in South Indian patients with Leber's hereditary optic neuropathy

Cited by 8 publications

References 37 publications

Leber's Hereditary Optic Neuropathy–Specific Heteroplasmic Mutation m.14495A&gt;G Found in a Chinese Family

Leber's Hereditary Optic Neuropathy–Specific Heteroplasmic Mutation m.14495A&gt;G Found in a Chinese Family

Mitochondrial Genetic Heterogeneity in Leber’s Hereditary Optic Neuropathy: Original Study with Meta-Analysis

New avenues for therapy in mitochondrial optic neuropathies

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Leber's Hereditary Optic Neuropathy–Specific Heteroplasmic Mutation m.14495A>G Found in a Chinese Family

Leber's Hereditary Optic Neuropathy–Specific Heteroplasmic Mutation m.14495A>G Found in a Chinese Family