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  1. Article ; Online: Recent advances in understanding the molecular genetic basis of mitochondrial disease.

    Thompson, Kyle / Collier, Jack J / Glasgow, Ruth I C / Robertson, Fiona M / Pyle, Angela / Blakely, Emma L / Alston, Charlotte L / Oláhová, Monika / McFarland, Robert / Taylor, Robert W

    Journal of inherited metabolic disease

    2019  Volume 43, Issue 1, Page(s) 36–50

    Abstract: Mitochondrial disease is hugely diverse with respect to associated clinical presentations and underlying genetic causes, with pathogenic variants in over 300 disease genes currently described. Approximately half of these have been discovered in the last ... ...

    Abstract Mitochondrial disease is hugely diverse with respect to associated clinical presentations and underlying genetic causes, with pathogenic variants in over 300 disease genes currently described. Approximately half of these have been discovered in the last decade due to the increasingly widespread application of next generation sequencing technologies, in particular unbiased, whole exome-and latterly, whole genome sequencing. These technologies allow more genetic data to be collected from patients with mitochondrial disorders, continually improving the diagnostic success rate in a clinical setting. Despite these significant advances, some patients still remain without a definitive genetic diagnosis. Large datasets containing many variants of unknown significance have become a major challenge with next generation sequencing strategies and these require significant functional validation to confirm pathogenicity. This interface between diagnostics and research is critical in continuing to expand the list of known pathogenic variants and concomitantly enhance our knowledge of mitochondrial biology. The increasing use of whole exome sequencing, whole genome sequencing and other "omics" techniques such as transcriptomics and proteomics will generate even more data and allow further interrogation and validation of genetic causes, including those outside of coding regions. This will improve diagnostic yields still further and emphasizes the integral role that functional assessment of variant causality plays in this process-the overarching focus of this review.
    MeSH term(s) Genome, Mitochondrial ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Mitochondrial Diseases/diagnosis ; Mitochondrial Diseases/genetics ; Molecular Diagnostic Techniques ; Sequence Analysis, RNA ; Transcriptome ; Whole Exome Sequencing/methods
    Language English
    Publishing date 2019-05-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 438341-2
    ISSN 1573-2665 ; 0141-8955
    ISSN (online) 1573-2665
    ISSN 0141-8955
    DOI 10.1002/jimd.12104
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1508: Show issues Location:
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  2. Article ; Online: Novel compound mutations in the mitochondrial translation elongation factor (TSFM) gene cause severe cardiomyopathy with myocardial fibro-adipose replacement.

    Perli, Elena / Pisano, Annalinda / Glasgow, Ruth I C / Carbo, Miriam / Hardy, Steven A / Falkous, Gavin / He, Langping / Cerbelli, Bruna / Pignataro, Maria Gemma / Zacara, Elisabetta / Re, Federica / Della Monica, Paola Lilla / Morea, Veronica / Bonnen, Penelope E / Taylor, Robert W / d'Amati, Giulia / Giordano, Carla

    Scientific reports

    2019  Volume 9, Issue 1, Page(s) 5108

    Abstract: Primary mitochondrial dysfunction is an under-appreciated cause of cardiomyopathy, especially when cardiac symptoms are the unique or prevalent manifestation of disease. Here, we report an unusual presentation of mitochondrial cardiomyopathy, with ... ...

    Abstract Primary mitochondrial dysfunction is an under-appreciated cause of cardiomyopathy, especially when cardiac symptoms are the unique or prevalent manifestation of disease. Here, we report an unusual presentation of mitochondrial cardiomyopathy, with dilated phenotype and pathologic evidence of biventricular fibro-adipose replacement, in a 33-year old woman who underwent cardiac transplant. Whole exome sequencing revealed two novel compound heterozygous variants in the TSFM gene, coding for the mitochondrial translation elongation factor EF-Ts. This protein participates in the elongation step of mitochondrial translation by binding and stabilizing the translation elongation factor Tu (EF-Tu). Bioinformatics analysis predicted a destabilization of the EF-Ts variants complex with EF-Tu, in agreement with the dramatic steady-state level reduction of both proteins in the clinically affected myocardium, which demonstrated a combined respiratory chain enzyme deficiency. In patient fibroblasts, the decrease of EF-Ts was paralleled by up-regulation of EF-Tu and induction of genes involved in mitochondrial biogenesis, along with increased expression of respiratory chain subunits and normal oxygen consumption rate. Our report extends the current picture of morphologic phenotypes associated with mitochondrial cardiomyopathies and confirms the heart as a main target of TSFM dysfunction. The compensatory response detected in patient fibroblasts might explain the tissue-specific expression of TSFM-associated disease.
    MeSH term(s) Cardiomyopathies/etiology ; Cardiomyopathies/genetics ; Humans ; Male ; Mitochondrial Proteins/genetics ; Mutation/genetics ; Peptide Elongation Factor Tu/genetics ; Peptide Elongation Factors/genetics ; Protein Binding ; Protein Biosynthesis
    Chemical Substances Mitochondrial Proteins ; Peptide Elongation Factors ; TSFM protein, human ; elongation factor Ts ; Peptide Elongation Factor Tu (EC 3.6.1.-)
    Language English
    Publishing date 2019-03-25
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-019-41483-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Novel GFM2 variants associated with early-onset neurological presentations of mitochondrial disease and impaired expression of OXPHOS subunits.

    Glasgow, Ruth I C / Thompson, Kyle / Barbosa, Inês A / He, Langping / Alston, Charlotte L / Deshpande, Charu / Simpson, Michael A / Morris, Andrew A M / Neu, Axel / Löbel, Ulrike / Hall, Julie / Prokisch, Holger / Haack, Tobias B / Hempel, Maja / McFarland, Robert / Taylor, Robert W

    Neurogenetics

    2017  Volume 18, Issue 4, Page(s) 227–235

    Abstract: Mitochondrial diseases are characterised by clinical, molecular and functional heterogeneity, reflecting their bi-genomic control. The nuclear gene GFM2 encodes mtEFG2, a protein with an essential role during the termination stage of mitochondrial ... ...

    Abstract Mitochondrial diseases are characterised by clinical, molecular and functional heterogeneity, reflecting their bi-genomic control. The nuclear gene GFM2 encodes mtEFG2, a protein with an essential role during the termination stage of mitochondrial translation. We present here two unrelated patients harbouring different and previously unreported compound heterozygous (c.569G>A, p.(Arg190Gln); c.636delA, p.(Glu213Argfs*3)) and homozygous (c.275A>C, p.(Tyr92Ser)) recessive variants in GFM2 identified by whole exome sequencing (WES) together with histochemical and biochemical findings to support the diagnoses of pathological GFM2 variants in each case. Both patients presented similarly in early childhood with global developmental delay, raised CSF lactate and abnormalities on cranial MRI. Sanger sequencing of familial samples confirmed the segregation of bi-allelic GFM2 variants with disease, while investigations into steady-state mitochondrial protein levels revealed respiratory chain subunit defects and loss of mtEFG2 protein in muscle. These data demonstrate the effects of defective mtEFG2 function, caused by previously unreported variants, confirming pathogenicity and expanding the clinical phenotypes associated with GFM2 variants.
    MeSH term(s) Child ; Exome/genetics ; Female ; Homozygote ; Humans ; Male ; Mitochondria/genetics ; Mitochondria/metabolism ; Mitochondrial Diseases/genetics ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism ; Mutation/genetics ; Pedigree ; Peptide Elongation Factor G/genetics ; Phenotype
    Chemical Substances GFM2 protein, human ; Mitochondrial Proteins ; Peptide Elongation Factor G
    Language English
    Publishing date 2017-10-26
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1339887-8
    ISSN 1364-6753 ; 1364-6745
    ISSN (online) 1364-6753
    ISSN 1364-6745
    DOI 10.1007/s10048-017-0526-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5295: Show issues Location:
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  4. Article ; Online: Bi-allelic Mutations in NDUFA6 Establish Its Role in Early-Onset Isolated Mitochondrial Complex I Deficiency.

    Alston, Charlotte L / Heidler, Juliana / Dibley, Marris G / Kremer, Laura S / Taylor, Lucie S / Fratter, Carl / French, Courtney E / Glasgow, Ruth I C / Feichtinger, René G / Delon, Isabelle / Pagnamenta, Alistair T / Dolling, Helen / Lemonde, Hugh / Aiton, Neil / Bjørnstad, Alf / Henneke, Lisa / Gärtner, Jutta / Thiele, Holger / Tauchmannova, Katerina /
    Quaghebeur, Gerardine / Houstek, Josef / Sperl, Wolfgang / Raymond, F Lucy / Prokisch, Holger / Mayr, Johannes A / McFarland, Robert / Poulton, Joanna / Ryan, Michael T / Wittig, Ilka / Henneke, Marco / Taylor, Robert W

    American journal of human genetics

    2018  Volume 103, Issue 4, Page(s) 592–601

    Abstract: Isolated complex I deficiency is a common biochemical phenotype observed in pediatric mitochondrial disease and often arises as a consequence of pathogenic variants affecting one of the ∼65 genes encoding the complex I structural subunits or assembly ... ...

    Abstract Isolated complex I deficiency is a common biochemical phenotype observed in pediatric mitochondrial disease and often arises as a consequence of pathogenic variants affecting one of the ∼65 genes encoding the complex I structural subunits or assembly factors. Such genetic heterogeneity means that application of next-generation sequencing technologies to undiagnosed cohorts has been a catalyst for genetic diagnosis and gene-disease associations. We describe the clinical and molecular genetic investigations of four unrelated children who presented with neuroradiological findings and/or elevated lactate levels, highly suggestive of an underlying mitochondrial diagnosis. Next-generation sequencing identified bi-allelic variants in NDUFA6, encoding a 15 kDa LYR-motif-containing complex I subunit that forms part of the Q-module. Functional investigations using subjects' fibroblast cell lines demonstrated complex I assembly defects, which were characterized in detail by mass-spectrometry-based complexome profiling. This confirmed a marked reduction in incorporated NDUFA6 and a concomitant reduction in other Q-module subunits, including NDUFAB1, NDUFA7, and NDUFA12. Lentiviral transduction of subjects' fibroblasts showed normalization of complex I. These data also support supercomplex formation, whereby the ∼830 kDa complex I intermediate (consisting of the P- and Q-modules) is in complex with assembled complex III and IV holoenzymes despite lacking the N-module. Interestingly, RNA-sequencing data provided evidence that the consensus RefSeq accession number does not correspond to the predominant transcript in clinically relevant tissues, prompting revision of the NDUFA6 RefSeq transcript and highlighting not only the importance of thorough variant interpretation but also the assessment of appropriate transcripts for analysis.
    MeSH term(s) Alleles ; Amino Acid Sequence ; Electron Transport Complex I/deficiency ; Electron Transport Complex I/genetics ; Female ; Fibroblasts/pathology ; Genetic Heterogeneity ; Humans ; Infant ; Male ; Mitochondria/genetics ; Mitochondrial Diseases/genetics ; Mitochondrial Proteins/genetics ; Mutation/genetics ; Phenotype ; Sequence Alignment
    Chemical Substances Mitochondrial Proteins ; Electron Transport Complex I (EC 7.1.1.2)
    Language English
    Publishing date 2018-09-20
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 219384-x
    ISSN 1537-6605 ; 0002-9297
    ISSN (online) 1537-6605
    ISSN 0002-9297
    DOI 10.1016/j.ajhg.2018.08.013
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 107: Show issues Location:
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