Mitochondrial diseases

Soca, Pedro Enrique Miguel

doi:10.1038/nrdp.2016.81

Cited by 5 publications

(2 citation statements)

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“…Mitochondria are the sites of oxidative phosphorylation (OXPHOS) within eukaryotic cells, and mitochondrial diseases are a large group of genetic disorders that manifest with heterogeneous clinical features, characterized by defects in OXPHOS caused by mutations in genes that encode proteins involved in mitochondrial function (1, 2). The most common subgroups include mitochondrial encephalomyopathy with lactate acidosis and stroke-like episodes (MELAS), Leigh syndrome (LS), etc.…”

Section: Introductionmentioning

confidence: 99%

A Chinese Family With Adult-Onset Leigh-Like Syndrome Caused by the Heteroplasmic m.10191T>C Mutation in the Mitochondrial MTND3 Gene

Wang

Liu

et al. 2019

Front. Neurol.

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Leigh syndrome (LS) is a mitochondrial disease of infancy and early childhood, that is rarely seen in adults. The high degree of genetic and clinical heterogeneity makes LS a very complex syndrome. The clinical manifestations include neurological symptoms and various non-neurological symptoms, with different mutations differing in presentations and therapies. The m.10191T>C mutation in the mitochondrial DNA gene encoding in the respiratory chain complex I (CI) subunit of MTND3 results in the substitution of a highly conserved amino acid (p.Ser45Pro) within the ND3 protein, leading to CI dysfunction and causing a broad clinical spectrum of disorders that includes LS. Patients with the m.10191T>C mutation are rare in general, even more so in adults. In the present study, we report a family of patients with very rare adult-onset Leigh-like syndrome with the m.10191T>C mutation. The 24-year-old proband presented with seizures 6 years ago and developed refractory status epilepticus on admission. She had acute encephalopathy accompanied by lactic acidosis, symmetrical putamen and scattered cortical lesions. The video electroencephalogram suggested focal-onset seizures. She harbored the heteroplasmic m.10191T>C mutation in her blood and fibroblasts. Her aunt was diagnosed with mitochondrial disease at the age of 42, and had the heteroplasmic m.10191T>C mutation in her fibroblasts. Her aunt's son (cousin) died of respiratory failure at the age of 8, and we suspected he was also a case of LS. Furthermore, we reviewed the previously reported patients with the m.10191T>C mutation and summarized their characteristics. Recognizing the characteristics of these patients will help us improve the clinical understanding of LS or Leigh-like syndrome.

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Section: Introductionmentioning

confidence: 99%

A Chinese Family With Adult-Onset Leigh-Like Syndrome Caused by the Heteroplasmic m.10191T>C Mutation in the Mitochondrial MTND3 Gene

Wang

Liu

et al. 2019

Front. Neurol.

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“…Mitochondrial diseases are characterized by respiratory chain dysfunction and often manifest as multisystemic involvement, leading to a spectrum of symptoms 1 . These conditions often result from mutations in either the mitochondrial DNA (mtDNA) or nuclear genomes 2 . The mtDNA is a compact, double-stranded circular DNA with a high copy number.…”

Section: Introductionmentioning

confidence: 99%

Adenine base editing corrects point mutation in mitochondrial single-stranded binding protein (SSBP1) to improve mitochondrial function

Cha,

Lee,

Yun

et al. 2023

Preprint

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Mutations in nuclear genes that regulate the mitochondrial DNA (mtDNA) replication machinery have been linked to mtDNA depletion syndromes. Through whole-genome sequencing, we identified a heterozygous missense mutation (c.272G>A:p.Arg91Gln) in single-stranded binding protein 1 (SSBP1), a crucial protein involved in mtDNA replication. The proband manifested symptoms including sensorineural deafness, congenital cataract, optic atrophy, macular dystrophy, and myopathy, all of which are compatible with mtDNA depletion disease. We found that thisSSBP1mutation impeded multimer formation and DNA-binding affinity, which led to reduced efficiency of mtDNA replication and altered mitochondria dynamics. To correct this mutation, we tested two adenine base editor (ABE) variants using patient-derived fibroblasts. One variant, NG-Cas9-based ABE8e (NG-ABE8e), exhibited higher editing efficacy (up to 30% editing), and edited cells showed signs of improved mitochondrial replication and function, including increased mtDNA and ATP production. However, these cells also had higher frequencies of off-target editing of nearby nucleotides, but the risks from bystander editing were limited due to mostly silent mutations and off-target sites in non-translated regions. The other variant, NG-Cas9-based ABE8eWQ (NG-ABE8eWQ), had a safer therapeutic profile with very few off-target effects, but this came at the cost of lower editing efficacy (up to 10% editing). Despite this, NG-ABE8eWQ-edited cells still restored replication and improved mtDNA copy number, which in turn recovery of compromised mitochondrial function. As these therapeutic strategies make their way into the clinic, our research suggests that base editing-based gene therapies may be a promising treatment for mitochondrial diseases, including those associated withSSBP1mutations.

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A Bioinformatics Pipeline for Estimating Mitochondria DNA Copy Number and Heteroplasmy Levels from Whole Genome Sequencing Data

Battle

Puiu

Boerwinkle

et al. 2021

Preprint

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Mitochondrial diseases are a heterogeneous group of disorders that can be caused by mutations in the nuclear or mitochondrial genome. Mitochondrial DNA variants may exist in a state of heteroplasmy, where a percentage of DNA molecules harbor a variant, or homoplasmy, where all DNA molecules have a variant. The relative quantity of mtDNA in a cell, or copy number (mtDNA-CN), is associated with mitochondrial function, human disease, and mortality. To facilitate accurate identification of heteroplasmy and quantify mtDNA-CN, we built a bioinformatics pipeline that takes whole genome sequencing data and outputs mitochondrial variants, and mtDNA-CN. We incorporate variant annotations to facilitate determination of variant significance. Our pipeline yields uniform coverage by remapping to a circularized chrM and recovering reads falsely mapped to nuclear-encoded mitochondrial sequences. Notably, we construct a consensus chrM sequence for each sample and recall heteroplasmy against the sample's unique mitochondrial genome. We observe an approximately 3-fold increased association with age for heteroplasmic variants in non-homopolymer regions and, are better able to capture genetic variation in the D-loop of chrM compared to existing software. Our bioinformatics pipeline more accurately captures features of mitochondrial genetics than existing pipelines that are important in understanding how mitochondrial dysfunction contributes to disease.

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Mitochondrial diseases

Cited by 5 publications

References 0 publications

A Chinese Family With Adult-Onset Leigh-Like Syndrome Caused by the Heteroplasmic m.10191T>C Mutation in the Mitochondrial MTND3 Gene

A Chinese Family With Adult-Onset Leigh-Like Syndrome Caused by the Heteroplasmic m.10191T>C Mutation in the Mitochondrial MTND3 Gene

Adenine base editing corrects point mutation in mitochondrial single-stranded binding protein (SSBP1) to improve mitochondrial function

A Bioinformatics Pipeline for Estimating Mitochondria DNA Copy Number and Heteroplasmy Levels from Whole Genome Sequencing Data

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