Advancing genomic approaches to the molecular diagnosis of mitochondrial disease

Stenton, Sarah L.; Prokisch, Holger

doi:10.1042/ebc20170110

Cited by 57 publications

(43 citation statements)

References 65 publications

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“…As nDNA got into the scene in 1995 with the first report of Leigh syndrome determined by a recessive homozygous mutation affecting the SDHA subunit of complex II [11], the list of disease‐causing nuclear genes encoding mitochondrial proteins has been growing exponentially, especially after the introduction of next‐generation sequencing and other high‐throughput approaches [129,130], with a current pace of monthly reports of new genes. Initially, mtDNA was thought to be the most frequently implicated in adult diseases, but currently nDNA approximately equals mtDNA for mitochondrial diseases in adults [131].…”

Section: Mitochondrial Disease Due To Ndna Gene Mutations Altering Otmentioning

confidence: 99%

“…Initially, mtDNA was thought to be the most frequently implicated in adult diseases, but currently nDNA approximately equals mtDNA for mitochondrial diseases in adults [131]. Furthermore, from the restrictive view of genetic defects affecting only the OXPHOS metabolism, as the landscape of mitochondrial functions key to cellular metabolism and homeostasis became much wider, the nDNA genetic causes for mitochondrial diseases have been recently grouped in a few major categories [129], based on the different pathogenic mechanisms (Fig. 1): Genes implicated in mtDNA expression (transcription and translation) Genes implicated in expressing and assembling OXPHOS Genes implicated in cofactors Genes implicated in substrates Genes implicated in inhibitors Genes implicated in homeostatic processes, including mitochondrial dynamics and transporters. …”

Section: Mitochondrial Disease Due To Ndna Gene Mutations Altering Otmentioning

confidence: 99%

“…Another large area to direct the diagnosis is also biochemistry, with a series of assays that may evaluate individuals’ respiratory complex function, as well as handling of substrates, cofactors and inhibitors, ultimately including also homeostatic processes, such as mitochondrial dynamics and transporters. The increasing use of combined omics to profile specific diseases and phenotypes will change drastically both the diagnostic algorithm and the natural history studies of this very large catalog of nDNA‐related mitochondrial disease [129,130]. Yet relying on the most recent epidemiological figures provided in north‐east of England, current estimation indicates that 5.9 in 100 000 are potentially at‐risk individuals of nDNA‐related mitochondrial disease [109].…”

Section: Mitochondrial Disease Due To Ndna Gene Mutations Altering Otmentioning

confidence: 99%

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Mitochondrial diseases in adults

et al. 2020

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Mitochondrial medicine is a field that expanded exponentially in the last 30 years. Individually rare, mitochondrial diseases as a whole are probably the most frequent genetic disorder in adults. The complexity of their genotype–phenotype correlation, in terms of penetrance and clinical expressivity, natural history and diagnostic algorithm derives from the dual genetic determination. In fact, in addition to the about 1.500 genes encoding mitochondrial proteins that reside in the nuclear genome (nDNA), we have the 13 proteins encoded by the mitochondrial genome (mtDNA), for which 22 specific tRNAs and 2 rRNAs are also needed. Thus, besides Mendelian genetics, we need to consider all peculiarities of how mtDNA is inherited, maintained and expressed to fully understand the pathogenic mechanisms of these disorders. Yet, from the initial restriction to the narrow field of oxidative phosphorylation dysfunction, the landscape of mitochondrial functions impinging on cellular homeostasis, driving life and death, is impressively enlarged. Finally, from the clinical standpoint, starting from the neuromuscular field, where brain and skeletal muscle were the primary targets of mitochondrial dysfunction as energy‐dependent tissues, after three decades virtually any subspecialty of medicine is now involved. We will summarize the key clinical pictures and pathogenic mechanisms of mitochondrial diseases in adults.

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Section: Mitochondrial Disease Due To Ndna Gene Mutations Altering Otmentioning

confidence: 99%

Section: Mitochondrial Disease Due To Ndna Gene Mutations Altering Otmentioning

confidence: 99%

Section: Mitochondrial Disease Due To Ndna Gene Mutations Altering Otmentioning

confidence: 99%

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Mitochondrial diseases in adults

et al. 2020

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“…All remaining protein components of the mitochondrial gene maintenance and expression machineries such as proteins responsible for mtDNA transcription, precursor RNA processing enzymes, the mitoribosomal proteins, mitochondrial aminoacyl tRNA synthetases, and others are encoded by the nuclear genes (Hallberg & Larsson, ; Rorbach & Minczuk, ). More than 50 nuclear‐encoded mitochondrial proteins involved in mitochondrial gene expression are linked to heritable disorders (Frazier, Thorburn, & Compton, ; Powell, Nicholls, & Minczuk, ; Rahman & Rahman, ; Stenton & Prokisch, ; Van Haute et al, ).…”

Section: Introductionmentioning

confidence: 99%

Mutations inELAC2associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3′‐end processing

et al. 2019

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Mutations in either 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 metabolism, including ELAC2. The ELAC2 gene codes for the mitochondrial RNase Z, responsible for endonucleolytic cleavage of the 3′ ends of mitochondrial pre‐tRNAs. Here, we report the identification of 16 novel ELAC2 variants in individuals presenting with mitochondrial respiratory chain deficiency, hypertrophic cardiomyopathy (HCM), and lactic acidosis. We provide evidence for the pathogenicity of the novel missense variants by studying the RNase Z activity in an in vitro system. We also modeled the residues affected by a missense mutation in solved RNase Z structures, providing insight into enzyme structure and function. Finally, we show that primary fibroblasts from the affected individuals have elevated levels of unprocessed mitochondrial RNA precursors. Our study thus broadly confirms the correlation of ELAC2 variants with severe infantile‐onset forms of HCM and mitochondrial respiratory chain dysfunction. One rare missense variant associated with the occurrence of prostate cancer (p.Arg781His) impairs the mitochondrial RNase Z activity of ELAC2, suggesting a functional link between tumorigenesis and mitochondrial RNA metabolism

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“…All remaining protein components of the mitochondrial gene maintenance and expression machinery such as proteins responsible for mtDNA transcription, precursor RNA processing enzymes, the mitoribosomal proteins, mitochondrial aminoacyl tRNA synthetases and others are encoded by the nuclear genes [1,2]. More than 50 nuclear-encoded mitochondrial proteins involved in mitochondrial gene expression are linked to heritable disorders [3][4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3’-end processing

Saoura

Powell

Kopajtich

et al. 2018

Preprint

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Dysfunction of mitochondrial gene expression, caused by mutations in either the mitochondrial or nuclear genomes, is 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 metabolism. For instance, pathogenic mutations have been identified in the genes encoding enzymes involved in the precursor transcript processing, including ELAC2. The ELAC2 gene codes for the mitochondrial RNase Z, which is responsible for endonucleolytic cleavage of the 3' ends of mitochondrial pre-tRNAs. Here, we report the identification of sixteen novel ELAC2 variants in individuals presenting with mitochondrial respiratory chain deficiency, hypertrophic cardiomyopathy and lactic acidosis. We provided further evidence for the pathogenicity of the three previously reported variants by studying the RNase Z activity in an in vitro system and applied this recombinant system to investigate all novel missense variants, confirming the pathogenic role of these new ELAC2 mutations. We also modelled the residues affected by missense mutation in solved RNase Z structures, providing insight into enzyme structure and function. Finally, we show that primary fibroblasts from the individuals with novel ELAC2 variants have elevated levels of unprocessed mitochondrial RNA precursors. Our study thus broadly confirms the correlation of ELAC2 variants with severe infantile-onset forms of hypertrophic cardiomyopathy and mitochondrial respiratory chain dysfunction. One rare missense variant associated with the occurrence of prostate cancer (p.Arg781His) impairs the mitochondrial RNase Z activity of ELAC2, possibly indicating a functional link between tumorigenesis and mitochondrial RNA metabolism.

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Advancing genomic approaches to the molecular diagnosis of mitochondrial disease

Cited by 57 publications

References 65 publications

Mitochondrial diseases in adults

Mitochondrial diseases in adults

Mutations inELAC2associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3′‐end processing

Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3’-end processing

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