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TK2 Depletion Mitochondrial Disorders

Caterina Garone, Robert W Taylor, Andrés Nascimento, Joanna Poulton, Carl Fratter, Cristina Domínguez-González, Julie C Evans, Mariana Loos, Pirjo Isohanni, Anu Suomalainen, Dipak Ram, M Imelda Hughes, Robert McFarland, Emanuele Barca, Carlos Lopez Gomez, Sandeep Jayawant, Neil D Thomas, Adnan Y Manzur, Karin Kleinsteuber, Miguel A Martin, Timothy Kerr, Grainne S Gorman, Ewen W Sommerville, Patrick F Chinnery, Monika Hofer, Christoph Karch, Jeffrey Ralph, Yolanda Cámara, Marcos Madruga-Garrido, Jana Domínguez-Carral, Carlos Ortez, Sonia Emperador, Julio Montoya, Anupam Chakrapani, Joshua F Kriger, Robert Schoenaker, Bruce Levin, John L P Thompson, Yuelin Long, Shamima Rahman, Maria Alice Donati, Salvatore DiMauro, Michio Hirano
BACKGROUND: Thymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive TK2 mutations cause a spectrum of disease from infantile onset to adult onset manifesting primarily as myopathy. OBJECTIVE: To perform a retrospective natural history study of a large cohort of patients with TK2 deficiency. METHODS: The study was conducted by 42 investigators across 31 academic medical centres...
March 30, 2018: Journal of Medical Genetics
Stephanie E Siegmund, Hua Yang, Rohit Sharma, Martin Javors, Owen Skinner, Vamsi Mootha, Michio Hirano, Eric A Schon
Mitochondrial disorders affecting oxidative phosphorylation (OxPhos) are caused by mutations in both the nuclear and mitochondrial genomes. One promising candidate for treatment is the drug rapamycin, which has been shown to extend lifespan in multiple animal models, and which was previously shown to ameliorate mitochondrial disease in a knock-out mouse model lacking a nuclear-encoded gene specifying an OxPhos structural subunit (Ndufs4). In that model, relatively high-dose intraperitoneal rapamycin extended lifespan and improved markers of neurological disease, via an unknown mechanism...
December 1, 2017: Human Molecular Genetics
Charlotte L Alston, Andrew M Schaefer, Pravrutha Raman, Nicola Solaroli, Kim J Krishnan, Emma L Blakely, Langping He, Kate Craig, Mark Roberts, Aashish Vyas, John Nixon, Rita Horvath, Douglass M Turnbull, Anna Karlsson, Grainne S Gorman, Robert W Taylor
Mutations in nuclear genes involved in the maintenance of mitochondrial DNA (mtDNA) are associated with an extensive spectrum of clinical phenotypes, manifesting as either mtDNA depletion syndromes or multiple mtDNA deletion disorders.(1.)
December 3, 2013: Neurology
Ayman W El-Hattab, Fernando Scaglia
Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. MDS are due to defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mitochondrial nucleotide synthesis (TK2, SUCLA2, SUCLG1, RRM2B, DGUOK, and TYMP) or mtDNA replication (POLG and C10orf2). MDS are phenotypically heterogeneous and usually classified as myopathic, encephalomyopathic, hepatocerebral or neurogastrointestinal...
April 2013: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
Victor Venegas, Michelle C Halberg
Mitochondrial disorders are complex and heterogeneous diseases that may be caused by molecular defects in either the nuclear or mitochondrial genome. The biosynthesis and maintenance of the integrity of the mitochondrial genome is solely dependent on a number of nuclear proteins. Defects in these nuclear genes can lead to mitochondrial DNA (mtDNA) depletion (Spinazzola et al. Biosci Rep 27:39-51, 2007). The mitochondrial DNA (mtDNA) depletion syndromes (MDDSs) are autosomal recessive disorders characterized by a significant reduction in mtDNA content...
2012: Methods in Molecular Biology
William C Copeland
Mitochondrial DNA (mtDNA) is replicated by the DNA polymerase g in concert with accessory proteins such as the mtDNA helicase, single stranded DNA binding protein, topoisomerase, and initiating factors. Nucleotide precursors for mtDNA replication arise from the mitochondrial salvage pathway originating from transport of nucleosides, or alternatively from cytoplasmic reduction of ribonucleotides. Defects in mtDNA replication or nucleotide metabolism can cause mitochondrial genetic diseases due to mtDNA deletions, point mutations, or depletion which ultimately cause loss of oxidative phosphorylation...
January 2012: Critical Reviews in Biochemistry and Molecular Biology
Henna Tyynismaa, Ren Sun, Sofia Ahola-Erkkilä, Henrikki Almusa, Rosanna Pöyhönen, Mari Korpela, Jari Honkaniemi, Pirjo Isohanni, Anders Paetau, Liya Wang, Anu Suomalainen
Autosomal-inherited progressive external ophthalmoplegia (PEO) is an adult-onset disease characterized by the accumulation of multiple mitochondrial DNA (mtDNA) deletions in post-mitotic tissues. Mutations in six different genes have been described to cause the autosomal dominant form of the disease, but only mutations in the DNA polymerase gamma gene are known to cause autosomal recessive PEO (arPEO), leaving the genetic background of arPEO mostly unknown. Here we used whole-exome sequencing and identified compound heterozygous mutations, leading to two amino acid alterations R225W and a novel T230A in thymidine kinase 2 (TK2) in arPEO patients...
January 1, 2012: Human Molecular Genetics
Victor Venegas, Jing Wang, David Dimmock, Lee-Jun Wong
Mitochondrial disorders are a group of complex and heterogeneous diseases that may be caused by molecular defects in the nuclear or mitochondrial genome. The biosynthesis and integrity of the small 16.6-kb mitochondrial genome require a group of nuclear encoded genes. The mitochondrial DNA (mtDNA) depletion syndromes (MDDSs) are autosomal recessive disorders caused by molecular defects in nuclear genes, and characterized by a reduction in mtDNA content. To date, mutations in at least nine genes (POLG, DGUOK, TK2, TYMP, MPV17, SUCLA2, SUCLG1, RRM2B, and C10orf2) have been reported to cause various forms of MDDSs...
January 2011: Current Protocols in Human Genetics
Joanna D Stewart, Susanne Schoeler, Kamil S Sitarz, Rita Horvath, Kerstin Hallmann, Angela Pyle, Patrick Yu-Wai-Man, Robert W Taylor, David C Samuels, Wolfram S Kunz, Patrick F Chinnery
Disorders of mitochondrial DNA (mtDNA) maintenance have emerged as an important cause of human genetic disease, but demonstrating the functional consequences of de novo mutations remains a major challenge. We studied the rate of depletion and repopulation of mtDNA in human fibroblasts exposed to ethidium bromide in patients with heterozygous POLG mutations, POLG2 and TK2 mutations. Ethidium bromide induced mtDNA depletion occurred at the same rate in human fibroblasts from patients and healthy controls. By contrast, the restoration of mtDNA levels was markedly delayed in fibroblasts from patients with compound heterozygous POLG mutations...
March 2011: Biochimica et Biophysica Acta
Bruce H Cohen, Robert K Naviaux
Disorders of oxidative phosphorylation and mitochondrial function can be caused from mutations involving both mitochondrial DNA (mtDNA) or mitochondrial-targeted nuclear DNA genes. Progressive depletion of mtDNA is one mechanism of mitochondrial dysfunction leading to human disease, which is the end result of loss of the sufficient mtDNA-encoded proteins for normal electron transport chain function. Mitochondrial DNA depletion is caused by germline deletions and duplications of segments within the mtDNA as well as germline mutations in the nuclear genes responsible for mtDNA duplication (the polymerase apparatus including POLG, POLG2 and PEO1) and mtDNA maintenance (those genes that regulate the deoxynucleotide triphosphate pools and other functions including TP1, TK2, DGUOK, SUCLA1, SUCLA2, ANT1, RRM2B and MPV17)...
August 2010: Methods: a Companion to Methods in Enzymology
David Dimmock, Lin-Ya Tang, Eric S Schmitt, Lee-Jun C Wong
BACKGROUND: The mitochondrial DNA (mtDNA) depletion syndromes (MDDSs) are autosomal recessive disorders characterized by a reduction in cellular mtDNA content. Mutations in at least 9 genes [POLG, polymerase (DNA directed), gamma; DGUOK, deoxyguanosine kinase; TK2, thymidine kinase, mitochondrial; TYMP, thymidine phosphorylase; MPV17, MpV17 mitochondrial inner membrane protein; SUCLA2, succinate-CoA ligase, ADP-forming, beta subunit; SUCLG1, succinate-CoA ligase, alpha subunit; RRM2B, RRM2B, ribonucleotide reductase M2 B (TP53 inducible); and C10orf2, chromosome 10 open reading frame 2 (also known as TWINKLE)] have been reported to cause mtDNA depletion...
July 2010: Clinical Chemistry
Ramon Martí, Andrés Nascimento, Jaume Colomer, Mari C Lara, Ester López-Gallardo, Eduardo Ruiz-Pesini, Julio Montoya, Antoni L Andreu, Paz Briones, Mercè Pineda
Mitochondrial DNA (mtDNA) depletion syndrome (MDS) is a devastating disorder of infancy caused by a significant reduction of the number of copies of mitochondrial DNA in one or more tissues. We report a Spanish patient with the myopathic form of MDS, harboring two mutations in the thymidine kinase 2 gene (TK2): a previously reported deletion (p.K244del) and a novel nucleotide duplication in the exon 2, generating a frameshift and premature stop codon. Sensorineural hearing loss was a predominant symptom in the patient and a novel feature of MDS due to TK2 mutations...
August 2010: Pediatric Research
Stefano Bartesaghi, Joanne Betts-Henderson, Kelvin Cain, David Dinsdale, Xiaoshan Zhou, Anna Karlsson, Paolo Salomoni, Pierluigi Nicotera
Mutations of thymidine kinase 2 (TK2), an essential component of the mitochondrial nucleotide salvage pathway, can give rise to mitochondrial DNA (mtDNA) depletion syndromes (MDS). These clinically heterogeneous disorders are characterized by severe reduction in mtDNA copy number in affected tissues and are associated with progressive myopathy, hepatopathy and/or encephalopathy, depending in part on the underlying nuclear genetic defect. Mutations of TK2 have previously been associated with an isolated myopathic form of MDS (OMIM 609560)...
May 1, 2010: Human Molecular Genetics
J Poulton, M Hirano, A Spinazzola, M Arenas Hernandez, C Jardel, A Lombès, B Czermin, R Horvath, J W Taanman, A Rotig, M Zeviani, C Fratter
These tables list both published and a number of unpublished mutations in genes associated with early onset defects in mitochondrial DNA (mtDNA) maintenance including C10orf2, SUCLG1, SUCLA2, TYMP, RRM2B, MPV17, DGUOK and TK2. The list should not be taken as evidence that any particular mutation is pathogenic. We have included genes known to cause mtDNA depletion, excluding POLG1, because of the existing database ( We have also excluded mutations in C10orf2 associated with dominant adult onset disorders...
December 2009: Biochimica et Biophysica Acta
James Collins, Kevin E Bove, David Dimmock, Paula Morehart, Lee-Jun Wong, Brenda Wong
The mitochondrial DNA depletion syndromes (MDS) are autosomal recessive disorders with a decreased mitochondrial DNA copy number. Mutations in thymidine kinase 2 (TK2) have been responsible for the myopathic form of MDS. We describe a child with congenital muscle weakness who had a progressive mitochondrial myopathy associated with extensive fibro-fatty replacement of myofibers resembling muscular dystrophy. MDS was suspected based upon findings in the initial muscle biopsy. Sequence analysis of the TK2 gene revealed two novel heterozygous mutations: the frame shift mutation, c...
November 2009: Neuromuscular Disorders: NMD
Joan Villarroya, Carme de Bolós, Anna Meseguer, Michio Hirano, Maya R Vilà
Mitochondrial DNA (mtDNA) depletion syndrome (MDS) is an autosomal recessive disorder characterized by a reduced amount of mtDNA, which impairs synthesis of respiratory chain complexes. MDS has been classified into two main groups, the hepatocerebral form affecting liver and the central nervous system, and the myopathic form targeting the skeletal muscle. We have compared the molecular genetic characteristics of fibroblasts derived from two patients harboring TK2 mutations with two harboring mutations in DGUOK gene...
May 1, 2009: Experimental Cell Research
A Spinazzola, F Invernizzi, F Carrara, E Lamantea, A Donati, M Dirocco, I Giordano, M Meznaric-Petrusa, E Baruffini, I Ferrero, M Zeviani
Mitochondrial DNA depletion syndromes (MDSs) form a group of autosomal recessive disorders characterized by profoundly decreased mitochondrial DNA copy numbers in affected tissues. Three main clinical presentations are known: myopathic, encephalomyopathic and hepatocerebral. The first is associated with mutations in thymidine kinase 2 (TK2) and p53-induced ribonucleotide reductase B subunit (RRM2B); the second with mutations in succinate synthase A (SUCLA2) and B (SUCLG1); the third with mutations in Twinkle (PEO1), pol-gammaA (POLG1), deoxyguanosine kinase (DGUOK) and MPV17 (MPV17)...
April 2009: Journal of Inherited Metabolic Disease
Emma Blakely, Langping He, Julie L Gardner, Gavin Hudson, John Walter, Imelda Hughes, Douglass M Turnbull, Robert W Taylor
Mitochondrial DNA depletion syndromes are a heterogeneous group of childhood neurological disorders characterised by a quantitative abnormality of mitochondrial DNA. We describe two siblings who presented at 8 months and 14 months with myopathy, which rapidly progressed and resulted in death by respiratory failure at age 14 and 18 months, respectively. Muscle biopsy revealed marked respiratory chain defects, with real-time PCR confirming a dramatic depletion of mitochondrial DNA. Sequencing of the thymidine kinase 2 (TK2) gene revealed two, novel heterozygous mutations (p...
July 2008: Neuromuscular Disorders: NMD
María-Jesús Pérez-Pérez, Eva-María Priego, Ana-Isabel Hernández, Olga Familiar, María-José Camarasa, Ana Negri, Federico Gago, Jan Balzarini
Human mitochondrial thymidine kinase (TK2) is a pyrimidine deoxynucleoside kinase (dNK) that catalyzes the phosphorylation of pyrimidine deoxynucleosides to their corresponding deoxynucleoside 5'-monophosphates by gamma-phosphoryl transfer from ATP. In resting cells, TK2 is suggested to play a key role in the mitochondrial salvage pathway to provide pyrimidine nucleotides for mitochondrial DNA (mtDNA) synthesis and maintenance. However, recently the physiological role of TK2turned out to have direct clinical relevance as well...
September 2008: Medicinal Research Reviews
Xiaoshan Zhou, Nicola Solaroli, Mia Bjerke, James B Stewart, Björn Rozell, Magnus Johansson, Anna Karlsson
Deficient enzymatic activity of the mitochondrial deoxyribonucleoside kinases deoxyguanosine kinase (DGUOK) or thymidine kinase 2 (TK2) cause mitochondrial DNA (mtDNA)-depletion syndromes in humans. Here we report the generation of a Tk2-deficient mouse strain and show that the mice develop essentially normally for the first week but from then on exhibit growth retardation and die within 2-4 weeks of life. Several organs including skeletal muscle, heart, liver and spleen showed progressive loss of mtDNA without increased mtDNA mutations or structural alterations...
August 1, 2008: Human Molecular Genetics
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