9 research outputs found
TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease
Mutations in the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA biology. The TEFM gene encodes the mitochondrial transcription elongation factor responsible for enhancing the processivity of mitochondrial RNA polymerase, POLRMT. We report for the first time that TEFM variants are associated with mitochondrial respiratory chain deficiency and a wide range of clinical presentations including mitochondrial myopathy with a treatable neuromuscular transmission defect. Mechanistically, we show muscle and primary fibroblasts from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts. Finally, tefm knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function, strengthening the genotype-phenotype correlation. Our study highlights that TEFM regulates mitochondrial transcription elongation and its defect results in variable, tissue-specific neurological and neuromuscular symptoms
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Increased diagnostic yield by reanalysis of whole exome sequencing data in mitochondrial disease
BACKGROUND: The genetic diagnosis of mitochondrial disorders is complicated by its genetic and phenotypic complexity. Next generation sequencing techniques have much improved the diagnostic yield for these conditions. A cohort of individuals with multiple respiratory chain deficiencies, reported in the literature 10 years ago, had a diagnostic rate of 60% by whole exome sequencing (WES) but 40% remained undiagnosed.
OBJECTIVE: We aimed to identify a genetic diagnosis by reanalysis of the WES data for the undiagnosed arm of this 10-year-old cohort of patients with suspected mitochondrial disorders.
METHODS: The WES data was transferred and processed by the RD-Connect Genome-Phenome Analysis Platform (GPAP) using their standardized pipeline. Variant prioritisation was carried out on the RD-Connect GPAP.
RESULTS: Singleton WES data from 14 individuals was reanalysed. We identified a possible or likely genetic diagnosis in 8 patients (8/14, 57%). The variants identified were in a combination of mitochondrial DNA (n=1, MT-TN), nuclear encoded mitochondrial genes (n=2, PDHA1, and SUCLA2) and nuclear genes associated with nonmitochondrial disorders (n=5, PNPLA2, CDC40, NBAS and SLC7A7). Variants in both the NBAS and CDC40 genes were established as disease causing after the original cohort was published. We increased the diagnostic yield for the original cohort by 15% without generating any further genomic data.
CONCLUSIONS: In the era of multiomics we highlight that reanalysis of existing WES data is a valid tool for generating additional diagnosis in patients with suspected mitochondrial disease, particularly when more time has passed to allow for new bioinformatic pipelines to emerge, for the development of new tools in variant interpretation aiding in reclassification of variants and the expansion of scientific knowledge on additional genes.Addenbrookes Charitable Trust, Evelyn Trust, Stoneygate Trust, Lily Foundation, Action for A
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Case report: Mutations in DNAJC30 causing autosomal recessive Leber Hereditary Optic Neuropathy are common amongst Eastern European individuals.
Background: Leber Hereditary Optic Neuropathy (LHON) is the most common inherited mitochondrial disease characterised by bilateral, painless, subacute visual loss with a peak age of onset in the second to third decade. Historically, LHON was thought to be
exclusively maternally inherited due to mutations in mitochondrial DNA (mtDNA) however, recent studies have identified an autosomal recessive form of LHON (arLHON) caused by point mutations in the nuclear gene, DNAJC30.Case Presentations: Here we report the cases of three Eastern European individuals
presenting with bilateral painless visual loss, one of whom was also exhibiting motor symptoms. After a several year-long diagnostic journey, all three patients were found to carry the homozygous c.152A>G (p.Tyr51Cys) mutation in DNAJC30. This has been identified as the most common arLHON pathogenic variant and has been shown to exhibit a significant founder effect amongst Eastern European individuals.This finding adds to the growing cohort of patients with arLHON and demonstrates the importance of DNAJC30 screening in patients with molecularly undiagnosed LHON, particularly in Eastern European individuals. It is of heightened translational significance as patients diagnosed with arLHON exhibit a better prognosis and response to therapeutic treatment with the co-enzyme Q10 analogue idebenone.R.H. is a Wellcome Trust Investigator (109915/Z/15/Z), who receives support from the Medical Research Council (UK) (MR/V009346/1), the Addenbrookes Charitable Trust (G100142), the Evelyn Trust, the Stoneygate Trust, the Lily Foundation, Action for AT and an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/ S005021/1. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. RH is part of the PROSPAX consortium under the frame of EJP RD, the European Joint Programme on Rare Diseases, under the EJP RD COFUND-EJP N°825575
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Case report: Mutations in DNAJC30 causing autosomal recessive Leber hereditary optic neuropathy are common amongst Eastern European individuals
Peer reviewed: TrueAcknowledgements: This research was made possible through access to data in the National Genomic Research Library, which is managed by Genomics England Limited (a wholly-owned company of the Department of Health and Social Care). The National Genomic Research Library holds data provided by patients and collected by the NHS as part of their care and data collected as part of their participation in research.Background: Leber Hereditary Optic Neuropathy (LHON) is the most common inherited mitochondrial disease characterized by bilateral, painless, subacute visual loss with a peak age of onset in the second to third decade. Historically, LHON was thought to be exclusively maternally inherited due to mutations in mitochondrial DNA (mtDNA); however, recent studies have identified an autosomal recessive form of LHON (arLHON) caused by point mutations in the nuclear gene, DNAJC30. Case Presentations: In this study, we report the cases of three Eastern European individuals presenting with bilateral painless visual loss, one of whom was also exhibiting motor symptoms. After a several-year-long diagnostic journey, all three patients were found to carry the homozygous c.152A>G (p.Tyr51Cys) mutation in DNAJC30. This has been identified as the most common arLHON pathogenic variant and has been shown to exhibit a significant founder effect amongst Eastern European individuals. Conclusion: This finding adds to the growing cohort of patients with arLHON and demonstrates the importance of DNAJC30 screening in patients with molecularly undiagnosed LHON, particularly in Eastern European individuals. It is of heightened translational significance as patients diagnosed with arLHON exhibit a better prognosis and response to therapeutic treatment with the co-enzyme Q10 analog idebenone
TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease
: Mutations in the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA biology. The TEFM gene encodes the mitochondrial transcription elongation factor responsible for enhancing the processivity of mitochondrial RNA polymerase, POLRMT. We report for the first time that TEFM variants are associated with mitochondrial respiratory chain deficiency and a wide range of clinical presentations including mitochondrial myopathy with a treatable neuromuscular transmission defect. Mechanistically, we show muscle and primary fibroblasts from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts. Finally, tefm knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function, strengthening the genotype-phenotype correlation. Our study highlights that TEFM regulates mitochondrial transcription elongation and its defect results in variable, tissue-specific neurological and neuromuscular symptoms
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TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease
Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): 309548Funder: Lily Mae Foundation; doi: https://doi.org/10.13039/100012336AbstractMutations in the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA biology. The TEFM gene encodes the mitochondrial transcription elongation factor responsible for enhancing the processivity of mitochondrial RNA polymerase, POLRMT. We report for the first time that TEFM variants are associated with mitochondrial respiratory chain deficiency and a wide range of clinical presentations including mitochondrial myopathy with a treatable neuromuscular transmission defect. Mechanistically, we show muscle and primary fibroblasts from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts. Finally, tefm knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function, strengthening the genotype-phenotype correlation. Our study highlights that TEFM regulates mitochondrial transcription elongation and its defect results in variable, tissue-specific neurological and neuromuscular symptoms.</jats:p
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TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease.
Mutations in the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA biology. The TEFM gene encodes the mitochondrial transcription elongation factor responsible for enhancing the processivity of mitochondrial RNA polymerase, POLRMT. We report for the first time that TEFM variants are associated with mitochondrial respiratory chain deficiency and a wide range of clinical presentations including mitochondrial myopathy with a treatable neuromuscular transmission defect. Mechanistically, we show muscle and primary fibroblasts from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts. Finally, tefm knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function, strengthening the genotype-phenotype correlation. Our study highlights that TEFM regulates mitochondrial transcription elongation and its defect results in variable, tissue-specific neurological and neuromuscular symptoms