Special Issue "Expanding the Genetic Landscape of Mitochondrial Diseases"

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (20 September 2021).

Special Issue Editors

Dr. Monika Olahova
E-Mail Website
Guest Editor
Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
Interests: mitochondrial disease; mitochondria in health and disease; OXPHOS; mitochondrial gene expression; disease models and mechanisms; genome editing
Prof. Dr. Robert W. Taylor
E-Mail Website
Co-Guest Editor
Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
Interests: mitochondrial disease; mitochondrial genetics; diagnostics; genomics; disease mechanisms

Special Issue Information

Dear Colleagues,

Inherited metabolic disorders, in particular those affecting mitochondrial bioenergetics, hallmark a clinically and genetically heterogenous group of diseases associated with more than 300 monogenic disorders. Two distinct genomes (mitochondrial DNA and nuclear DNA) can underlie mitochondrial disease pathogenesis, making the diagnosis a challenging area of genetics. However, recent advances in next-generation sequencing (NGS) techniques and improvements in analytical approaches, alongside ‘omics’ studies, have revolutionized the genetic diagnosis of mitochondrial diseases, leading to a rapid discovery of novel disease genes. Detailed functional characterization of disease-causing variants is required to confirm the genetic diagnosis and elucidate pathological mechanisms driving mitochondrial disorders. By integrating studies using patient samples, cell or animal models, as well as ‘omics’ approaches including transcriptomics and proteomics analyses, unbiased genotype-driven diagnosis of mitochondrial diseases can be achieved, which will also provide new insights into different aspects of mitochondrial biology.

The purpose of this Special Issue of Genes is to highlight current trends in the clinical and genetic diagnosis of mitochondrial disorders, ultimately leading to novel gene discovery and the establishment of pathogenic parameters that influence the disease state. This Special Issue welcomes studies in the field of mitochondrial disease diagnosis, using massively parallel sequencing (MPS) technologies, ‘omics’ approaches, and/or model systems to enable the establishment of disease etiology. In addition, articles on emerging treatment strategies, e.g., generation of models for testing, translation of MPS into new diagnostic strategies, and related ethical issues are welcome.

Dr. Monika Olahova
Prof. Dr. Robert W. Taylor
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • mitochondrial diseases
  • genotype–phenotype correlations
  • mitochondrial dysfunction
  • diagnosis of mitochondrial diseases
  • next-generation sequencing technologies (e.g., WES, WGS)
  • novel mitochondrial gene discovery
  • mitochondrial DNA variants
  • nuclear DNA variants in genes encoding mitochondrial proteins
  • ‘omics’ studies (transcriptomics, proteomics, metabolomics, etc.)
  • emerging therapeutic strategies.

Published Papers (6 papers)

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Research

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Article
The Genetic Landscape of Mitochondrial Diseases in Spain: A Nationwide Call
Genes 2021, 12(10), 1590; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101590 - 09 Oct 2021
Viewed by 642
Abstract
The frequency of mitochondrial diseases (MD) has been scarcely documented, and only a few studies have reported data in certain specific geographical areas. In this study, we arranged a nationwide call in Spain to obtain a global estimate of the number of cases. [...] Read more.
The frequency of mitochondrial diseases (MD) has been scarcely documented, and only a few studies have reported data in certain specific geographical areas. In this study, we arranged a nationwide call in Spain to obtain a global estimate of the number of cases. A total of 3274 cases from 49 Spanish provinces were reported by 39 centres. Excluding duplicated and unsolved cases, 2761 patients harbouring pathogenic mutations in 140 genes were recruited between 1990 and 2020. A total of 508 patients exhibited mutations in nuclear DNA genes (75% paediatric patients) and 1105 in mitochondrial DNA genes (33% paediatric patients). A further 1148 cases harboured mutations in the MT-RNR1 gene (56% paediatric patients). The number of reported cases secondary to nuclear DNA mutations increased in 2014, owing to the implementation of next-generation sequencing technologies. Between 2014 and 2020, excepting MT-RNR1 cases, the incidence was 6.34 (95% CI: 5.71–6.97) cases per million inhabitants at the paediatric age and 1.36 (95% CI: 1.22–1.50) for adults. In conclusion, this is the first study to report nationwide epidemiological data for MD in Spain. The lack of identification of a remarkable number of mitochondrial genes necessitates the systematic application of high-throughput technologies in the routine diagnosis of MD. Full article
(This article belongs to the Special Issue Expanding the Genetic Landscape of Mitochondrial Diseases)
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Article
Mitochondrial Genetic Heterogeneity in Leber’s Hereditary Optic Neuropathy: Original Study with Meta-Analysis
Genes 2021, 12(9), 1300; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091300 - 24 Aug 2021
Viewed by 833
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Expanding the Genetic Landscape of Mitochondrial Diseases)
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Article
Application of Genome Sequencing from Blood to Diagnose Mitochondrial Diseases
Genes 2021, 12(4), 607; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12040607 - 20 Apr 2021
Viewed by 636
Abstract
Mitochondrial diseases can be caused by pathogenic variants in nuclear or mitochondrial DNA-encoded genes that often lead to multisystemic symptoms and can have any mode of inheritance. Using a single test, Genome Sequencing (GS) can effectively identify variants in both genomes, but it [...] Read more.
Mitochondrial diseases can be caused by pathogenic variants in nuclear or mitochondrial DNA-encoded genes that often lead to multisystemic symptoms and can have any mode of inheritance. Using a single test, Genome Sequencing (GS) can effectively identify variants in both genomes, but it has not yet been universally used as a first-line approach to diagnosing mitochondrial diseases due to related costs and challenges in data analysis. In this article, we report three patients with mitochondrial disease molecularly diagnosed through GS performed on DNA extracted from blood to demonstrate different diagnostic advantages of this technology, including the detection of a low-level heteroplasmic pathogenic variant, an intragenic nuclear DNA deletion, and a large mtDNA deletion. Current technical improvements and cost reductions are likely to lead to an expanded routine diagnostic usage of GS and of the complementary “Omic” technologies in mitochondrial diseases. Full article
(This article belongs to the Special Issue Expanding the Genetic Landscape of Mitochondrial Diseases)
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Article
Leigh Syndrome Due to NDUFV1 Mutations Initially Presenting as LBSL
Genes 2020, 11(11), 1325; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11111325 - 09 Nov 2020
Cited by 1 | Viewed by 697
Abstract
Leigh syndrome (LS) is most frequently characterized by the presence of focal, bilateral, and symmetric brain lesions Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare condition, characterized by progressive pyramidal, cerebellar, and dorsal column dysfunction. We describe [...] Read more.
Leigh syndrome (LS) is most frequently characterized by the presence of focal, bilateral, and symmetric brain lesions Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare condition, characterized by progressive pyramidal, cerebellar, and dorsal column dysfunction. We describe a case with infantile-onset neurodegeneration, psychomotor retardation, irritability, hypotonia, and nystagmus. Brain MRI demonstrated signal abnormalities in the deep cerebral white matter, corticospinal and dorsal column tracts, and pyramids, which resemble the MRI pattern of a severe form of LBSL, and involvement of basal ganglia and thalamus that resemble the radiological features of LS. We identified biallelic loss-of-function mutations, one novel (c.756delC, p.Thr253Glnfs*44) and another reported (c.1156C > T, p.Arg386Cys), in NDUFV1 (NADH:Ubiquinone Oxidoreductase Core Subunit V1) by exome sequencing. Biochemical and functional analyses revealed lactic acidosis, complex I (CI) assembly and enzyme deficiency, and a loss of NDUFV1 protein. Complementation assays restored the NDUFV1 protein, CI assembly, and CI enzyme levels. The clinical and radiological features of this case are compatible with the phenotype of LS and LBSL associated with NDUFV1 mutations. Full article
(This article belongs to the Special Issue Expanding the Genetic Landscape of Mitochondrial Diseases)
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Review

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Review
Interrogating Mitochondrial Biology and Disease Using CRISPR/Cas9 Gene Editing
Genes 2021, 12(10), 1604; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101604 (registering DOI) - 12 Oct 2021
Viewed by 217
Abstract
Mitochondrial disease originates from genetic changes that impact human bodily functions by disrupting the mitochondrial oxidative phosphorylation system. MitoCarta is a curated and published inventory that sheds light on the mitochondrial proteome, but the function of some mitochondrially-localised proteins remains poorly characterised. Consequently, [...] Read more.
Mitochondrial disease originates from genetic changes that impact human bodily functions by disrupting the mitochondrial oxidative phosphorylation system. MitoCarta is a curated and published inventory that sheds light on the mitochondrial proteome, but the function of some mitochondrially-localised proteins remains poorly characterised. Consequently, various gene editing systems have been employed to uncover the involvement of these proteins in mitochondrial biology and disease. CRISPR/Cas9 is an efficient, versatile, and highly accurate genome editing tool that was first introduced over a decade ago and has since become an indispensable tool for targeted genetic manipulation in biological research. The broad spectrum of CRISPR/Cas9 applications serves as an attractive and tractable system to study genes and pathways that are essential for the regulation and maintenance of mitochondrial health. It has opened possibilities of generating reliable cell and animal models of human disease, and with further exploitation of the technology, large-scale genomic screenings have uncovered a wealth of fundamental mechanistic insights. In this review, we describe the applications of CRISPR/Cas9 system as a genome editing tool to uncover new insights into pathomechanisms of mitochondrial diseases and/or biological processes involved in mitochondrial function. Full article
(This article belongs to the Special Issue Expanding the Genetic Landscape of Mitochondrial Diseases)
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Review
Molecular Insights into Mitochondrial Protein Translocation and Human Disease
Genes 2021, 12(7), 1031; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12071031 - 01 Jul 2021
Viewed by 729
Abstract
In human mitochondria, mtDNA encodes for only 13 proteins, all components of the OXPHOS system. The rest of the mitochondrial components, which make up approximately 99% of its proteome, are encoded in the nuclear genome, synthesized in cytosolic ribosomes and imported into mitochondria. [...] Read more.
In human mitochondria, mtDNA encodes for only 13 proteins, all components of the OXPHOS system. The rest of the mitochondrial components, which make up approximately 99% of its proteome, are encoded in the nuclear genome, synthesized in cytosolic ribosomes and imported into mitochondria. Different import machineries translocate mitochondrial precursors, depending on their nature and the final destination inside the organelle. The proper and coordinated function of these molecular pathways is critical for mitochondrial homeostasis. Here, we will review molecular details about these pathways, which components have been linked to human disease and future perspectives on the field to expand the genetic landscape of mitochondrial diseases. Full article
(This article belongs to the Special Issue Expanding the Genetic Landscape of Mitochondrial Diseases)
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