DOCSLIB.ORG

Familial Neonatal Isolated Cardiomyopathy Caused by a Mutation in the flavoprotein Subunit of Succinate Dehydrogenase

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Familial Neonatal Isolated Cardiomyopathy Caused by a Mutation in the flavoprotein Subunit of Succinate Dehydrogenase European Journal of Human Genetics (2010) 18, 1160–1165 & 2010 Macmillan Publishers Limited All rights reserved 1018-4813/10 www.nature.com/ejhg ARTICLE Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase Aviva Levitas1,2,8, Emad Muhammad1,3,8, Gali Harel1,3,8, Ann Saada4, Vered Chalifa Caspi5, Esther Manor1,6, John C Beck7, Val Sheffield7 and Ruti Parvari*,1,3,5 Cardiomyopathies are common disorders resulting in heart failure; the most frequent form is dilated cardiomyopathy (DCM), which is characterized by dilatation of the left or both ventricles and impaired systolic function. DCM causes considerable morbidity and mortality, and is one of the major causes of sudden cardiac death. Although about one-third of patients are reported to have a genetic form of DCM, reported mutations explain only a minority of familial DCM. Moreover, the recessive neonatal isolated form of DCM has rarely been associated with a mutation. In this study, we present the association of a mutation in the SDHA gene with recessive neonatal isolated DCM in 15 patients of two large consanguineous Bedouin families. The cardiomyopathy is presumably caused by the significant tissue-specific reduction in SDH enzymatic activity in the heart muscle, whereas substantial activity is retained in the skeletal muscle and lymphoblastoid cells. Notably, the same mutation was previously reported to cause a multisystemic failure leading to neonatal death and Leigh’s syndrome. This study contributes to the molecular characterization of a severe form of neonatal cardiomyopathy and highlights extreme phenotypic variability resulting from a specific missense mutation in a nuclear gene encoding a protein of the mitochondrial respiratory chain. European Journal of Human Genetics (2010) 18, 1160–1165; doi:10.1038/ejhg.2010.83; published online 16 June 2010 Keywords: neonatal isolated cardiomyopathy; recessive inheritance; SDHA;mutation INTRODUCTION (FKTN). Defects in this gene also cause additional types of muscular Cardiomyopathies are the most common disorders resulting in heart dystrophies: the Fukuyama-type congenital muscular dystrophy, limb- failure. Dilated cardiomyopathy (DCM; MIM 115200) is characterized girdle muscular dystrophy type 2M, and the Walker–Warburg by cardiac dilatation and reduced systolic function. DCM is the most syndrome. (3) CMD2A (OMIM 611880) was reported in one family; frequent form of cardiomyopathy and the major cause of cardiac the disease appeared in the second decade of life and is caused by transplantation in children, accounting for 450% of all cardiac a mutation in the gene encoding the cardiac structural component transplantations performed in patients between 1 and 10 years of troponin I (TNNI3). (4). A myopathy with fatal cardiomyopathy age. Many factors may contribute to the development of this disorder, (OMIM 611705) reported in one family is caused by mutation in the although most commonly the etiology is unknown. A heritable gene encoding titin (TTN). Mitochondrial dysfunction frequently pattern is present in 20–30% of the cases;1 however, reported muta- affects the heart and may cause both hypertrophic cardiomyopathy tions explain only a minority of familial DCM.2 Although diverse and DCM.3 Nuclear encoded genes affecting mitochondrial functions modes of inheritance have been demonstrated, most familial DCM are known to cause DCM. For example, a rare genetic disorder of the pedigrees show an autosomal dominant pattern of inheritance, usually fatty acid b-oxidation cycle caused by mutations in both alleles of the presenting in the second or third decade of life. DCM with recessive a-subunit (HADHA) of the mitochondrial trifunctional protein may inheritance has been described five times and the affected genes result in a severe neonatal cardiomyopathy with hypoketotic hypo- identified in four of the cases: (1) CMD3a, a fatal congenital DCM glycemia and hepatic encephalopathy, often progressing to coma and reported in one family (OMIM 300069) (Online Mendelian Inheri- neonatal death.4,5 Another example is the recent finding of a nonsense tance in Man (OMIM) http://www.ncbi.nlm.nih.gov/OMIM)), is mutation in Coenzyme Q10, a mobile lipophilic electron carrier caused by mutations in tafazin (the function of this gene is not located in the inner mitochondrial membrane. The mutation results known). Mutations in this gene also cause Barth’s syndrome (OMIM in multisystem disease, including cardiomyopathy.6 302060). (2) CMD1X (OMIM 611615) with or without mild proximal Succinate dehydrogenase (SDH, E.C. 1.3.5.1) deficiency is a rare muscle weakness, caused by mutations in the gene encoding fukutin condition in humans, representing 2% of mitochondrial respiratory 1Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; 2Pediatric Cardiology Department, Soroka Medical Center, Beer-Sheva, Israel; 3Faculty of Health Sciences, Department of Virology and Developmental Genetics, Ben-Gurion University of the Negev, Beer-Sheva, Israel; 4Department of Human Genetics and Metabolic Diseases, Hadassah–Hebrew University Medical Center, Jerusalem, Israel; 5National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel; 6Institute of Genetics, Soroka Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel; 7Division of Medical Genetics, Department of Pediatrics, Howard Hughes Medical Institute, University of Iowa, Iowa City, IA, USA *Correspondence: Professor R Parvari, Faculty of Health Sciences, Department of Virology and Developmental Genetics, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. Tel: +972 8 647 9967; Fax: +972 8 627 6215; E-mail: [email protected] 8These authors contributed equally to this work. Received 28 January 2010; accepted 21 April 2010; published online 16 June 2010 SDHA mutation in isolated neonatal cardiomyopathy ALevitaset al 1161 chain (RC) disorders.7 Its clinical presentation is highly variable, alkaline phosphatase 0.6U and 6U Exonuclease I (both from Fermentas, ranging from early-onset encephalomyopathies to tumor susceptibility Vilnius, Lithuania). in adults.8,9 SDH catalyzes the conversion of succinate to fumarate and The mutation was identified on genomic DNA by direct sequencing of a is a component of the mitochondrial RC (complex II) and the Krebs PCR product using primers, forward: GTGCACACTGTTGGGCCCTT and cycle. SDH is composed of four subunits, all encoded in the nuclear reverse: GCCCCGTGACTCCTTCCGT, which amplify exon 13, the mutation changing the first nucleotide in this exon. The 3¢ first nucleotide and two DNA – two soluble proteins, the flavoprotein (Fp, SDHA), and the Fe-S nucleotides of the forward and reverse primers, respectively, are unique to protein (SDHB) – which are anchored to the inner membrane by chromosome 5 and do not exist on the pseudogene SDHA gene on chromo- 8,9 subunits SDHC and SDHD. Pathogenic mutations in the SDHA gene some 3. Under the amplification conditions of 30 cycles of 941 1¢,601 1¢,and have rarely been documented in children, and all but one case have 721 1¢, only the sequence of chromosome 5 is amplified. This was validated by been reported in patients with Leigh’s syndrome.7,10–12 The single case BLAST analysis revealing 100% identity to chromosome 5 and the 11 nucleo- not presenting with Leigh’s syndrome describes death at infancy, before tides differences form the sequence of chromosome 3. any sign of the syndrome could be detected, following a respiratory infection and severe hypoglycemia.13 A late-onset neurodegenerative RESULTS disease with progressive optic atrophy, ataxia, and myopathy was Patients tentatively ascribed to a heterozygous mutation in a conserved region In all, 15 Bedouin patients of one tribe who presented with cardio- of the SDHA protein.14 In this report, we present the association of a myopathy, between the ages of 32 weeks in utero to 10 years of age, mutation in the SDHA gene with the clinical manifestation and were enrolled. The laboratory indices were normal except for mildly interfamilial variability of 15 patients diagnosed with DCM. increased lactate of 3.7 mmol/l. The electrocardiogram of all patients was sinus rhythm with LV hypertrophy and normal QTC interval. METHODS Cardiomyopathies were categorized according to World Health 27 Patients Organization cardiomyopathy classification. At presentation, all The study was approved by the Soroka Medical Center Review Board. The patients had normal growth (30th–50th percentile) and a normal patients’ medical records were carefully reviewed, and details of their somatic neuromuscular examination, including muscle bulk and strength, growth, psychomotor development, clinical course, hospitalizations, and reflexes, and gait. The psychomotor development was appropriate laboratory results were recorded. Their parents and siblings were interviewed for age. During follow-up visits, the neuromuscular examinations and underwent a complete physical examination (particularly focused on the remained normal and none of the patients had seizures. In two cardiac and neuromuscular systems). The patients’ evaluation included: echo- patients, a brain MRI was performed without any evidence of cardiology: transthoracic two-dimensional and Doppler echocardiography focal lesions in the basal ganglia or grey matter or cortex or performed using a System Vivid 7 echocardiograph (GE Medical Systems, brainstem, ruling out Leigh’s syndrome. Eight infants were diagnosed Saskatchewan,
Load more

Recommended publications
  • Metabolic Targets of Coenzyme Q10 in Mitochondria
    antioxidants Review Metabolic Targets of Coenzyme Q10 in Mitochondria Agustín Hidalgo-Gutiérrez 1,2,*, Pilar González-García 1,2, María Elena Díaz-Casado 1,2, Eliana Barriocanal-Casado 1,2, Sergio López-Herrador 1,2, Catarina M. Quinzii 3 and Luis C. López 1,2,* 1 Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, 18016 Granada, Spain; [email protected] (P.G.-G.); [email protected] (M.E.D.-C.); [email protected] (E.B.-C.); [email protected] (S.L.-H.) 2 Centro de Investigación Biomédica, Instituto de Biotecnología, Universidad de Granada, 18016 Granada, Spain 3 Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA; [email protected] * Correspondence: [email protected] (A.H.-G.); [email protected] (L.C.L.); Tel.: +34-958-241-000 (ext. 20197) (L.C.L.) Abstract: Coenzyme Q10 (CoQ10) is classically viewed as an important endogenous antioxidant and key component of the mitochondrial respiratory chain. For this second function, CoQ molecules seem to be dynamically segmented in a pool attached and engulfed by the super-complexes I + III, and a free pool available for complex II or any other mitochondrial enzyme that uses CoQ as a cofactor. This CoQ-free pool is, therefore, used by enzymes that link the mitochondrial respiratory chain to other pathways, such as the pyrimidine de novo biosynthesis, fatty acid β-oxidation and amino acid catabolism, glycine metabolism, proline, glyoxylate and arginine metabolism, and sulfide oxidation Citation: Hidalgo-Gutiérrez, A.; metabolism. Some of these mitochondrial pathways are also connected to metabolic pathways González-García, P.; Díaz-Casado, in other compartments of the cell and, consequently, CoQ could indirectly modulate metabolic M.E.; Barriocanal-Casado, E.; López-Herrador, S.; Quinzii, C.M.; pathways located outside the mitochondria.
    [Show full text]
  • Human Mitochondrial Pathologies of the Respiratory Chain and ATP Synthase: Contributions from Studies of Saccharomyces Cerevisiae
    life Review Human Mitochondrial Pathologies of the Respiratory Chain and ATP Synthase: Contributions from Studies of Saccharomyces cerevisiae Leticia V. R. Franco 1,2,* , Luca Bremner 1 and Mario H. Barros 2 1 Department of Biological Sciences, Columbia University, New York, NY 10027, USA; [email protected] 2 Department of Microbiology,Institute of Biomedical Sciences, Universidade de Sao Paulo, Sao Paulo 05508-900, Brazil; [email protected] * Correspondence: [email protected] Received: 27 October 2020; Accepted: 19 November 2020; Published: 23 November 2020 Abstract: The ease with which the unicellular yeast Saccharomyces cerevisiae can be manipulated genetically and biochemically has established this organism as a good model for the study of human mitochondrial diseases. The combined use of biochemical and molecular genetic tools has been instrumental in elucidating the functions of numerous yeast nuclear gene products with human homologs that affect a large number of metabolic and biological processes, including those housed in mitochondria. These include structural and catalytic subunits of enzymes and protein factors that impinge on the biogenesis of the respiratory chain. This article will review what is currently known about the genetics and clinical phenotypes of mitochondrial diseases of the respiratory chain and ATP synthase, with special emphasis on the contribution of information gained from pet mutants with mutations in nuclear genes that impair mitochondrial respiration. Our intent is to provide the yeast mitochondrial specialist with basic knowledge of human mitochondrial pathologies and the human specialist with information on how genes that directly and indirectly affect respiration were identified and characterized in yeast. Keywords: mitochondrial diseases; respiratory chain; yeast; Saccharomyces cerevisiae; pet mutants 1.
    [Show full text]
  • Disorders of Human Coenzyme Q10 Metabolism: an Overview
    International Journal of Molecular Sciences Review Disorders of Human Coenzyme Q10 Metabolism: An Overview Iain Hargreaves 1,*, Robert A. Heaton 1 and David Mantle 2 1 School of Pharmacy, Liverpool John Moores University, L3 5UA Liverpool, UK; [email protected] 2 Pharma Nord (UK) Ltd., Telford Court, Morpeth, NE61 2DB Northumberland, UK; [email protected] * Correspondence: [email protected] Received: 19 August 2020; Accepted: 11 September 2020; Published: 13 September 2020 Abstract: Coenzyme Q10 (CoQ10) has a number of vital functions in all cells, both mitochondrial and extramitochondrial. In addition to its key role in mitochondrial oxidative phosphorylation, CoQ10 serves as a lipid soluble antioxidant, plays an important role in fatty acid, pyrimidine and lysosomal metabolism, as well as directly mediating the expression of a number of genes, including those involved in inflammation. In view of the central role of CoQ10 in cellular metabolism, it is unsurprising that a CoQ10 deficiency is linked to the pathogenesis of a range of disorders. CoQ10 deficiency is broadly classified into primary or secondary deficiencies. Primary deficiencies result from genetic defects in the multi-step biochemical pathway of CoQ10 synthesis, whereas secondary deficiencies can occur as result of other diseases or certain pharmacotherapies. In this article we have reviewed the clinical consequences of primary and secondary CoQ10 deficiencies, as well as providing some examples of the successful use of CoQ10 supplementation in the treatment of disease. Keywords: coenzyme Q10; mitochondria; oxidative stress; antioxidant; deficiencies 1. Introduction Coenzyme Q10 (CoQ10) is a lipid-soluble molecule comprising a central benzoquinone moiety, to which is attached a 10-unit polyisoprenoid lipid tail [1] (Figure1).
    [Show full text]
  • Mutations in Ubiquinone Deficiency and Oxidative Phosphorylation Disorders
    Prenyldiphosphate synthase, subunit 1 (PDSS1) and OH- benzoate polyprenyltransferase (COQ2) mutations in ubiquinone deficiency and oxidative phosphorylation disorders Julie Mollet, … , Arnold Munnich, Agnès Rötig J Clin Invest. 2007;117(3):765-772. https://doi.org/10.1172/JCI29089. Research Article Coenzyme Q10 (CoQ10) plays a pivotal role in oxidative phosphorylation (OXPHOS), as it distributes electrons among the various dehydrogenases and the cytochrome segments of the respiratory chain. We have identified 2 novel inborn errors of CoQ10 biosynthesis in 2 distinct families. In both cases, enzymologic studies showed that quinone-dependent OXPHOS activities were in the range of the lowest control values, while OXPHOS enzyme activities were normal. CoQ10 deficiency was confirmed by restoration of normal OXPHOS activities after addition of quinone. A genome-wide search for homozygosity in family 1 identified a region of chromosome 10 encompassing the gene prenyldiphosphate synthase, subunit 1 (PDSS1), which encodes the human ortholog of the yeastC OQ1 gene, a key enzyme of CoQ10 synthesis. Sequencing of PDSS1 identified a homozygous nucleotide substitution modifying a conserved amino acid of the protein (D308E). In the second family, direct sequencing of OH-benzoate polyprenyltransferase (COQ2), the human ortholog of the yeast COQ2 gene, identified a single base pair frameshift deletion resulting in a premature stop codon (c.1198delT, N401fsX415). Transformation of yeast Δcoq1 and Δcoq2 strains by mutant yeast COQ1 and mutant human COQ2
    [Show full text]
  • Mevalonate Pathway Provides Ubiquinone to Maintain Pyrimidine
    Author Manuscript Published OnlineFirst on November 19, 2019; DOI: 10.1158/0008-5472.CAN-19-0650 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Mevalonate pathway provides ubiquinone to maintain pyrimidine 2 synthesis and survival in p53-deficient cancer cells exposed to metabolic 3 stress 4 5 Irem, Kaymak1, Carina, R., Maier1, Werner, Schmitz1, Andrew, D., Campbell2, 6 Beatrice, Dankworth1, Carsten, P., Ade1, Susanne, Walz3, Madelon, Paauwe2, 7 Charis, Kalogirou4, Hecham, Marouf1, Mathias, T., Rosenfeldt5,6, David, M., 8 Gay2,7, Grace, H., McGregor2,7, Owen, J., Sansom2 and Almut, Schulze1,6$# 9 10 1 Theodor-Boveri-Institute, Biocenter, Am Hubland, 97074 Würzburg, Germany 11 2 Cancer Research UK Beatson Institute, Garscube Estate Switchback Road 12 Bearsden Glasgow, G61 1BD 13 3 ComPrehensive Cancer Center Mainfranken, Core Unit Bioinformatics, 14 Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany 15 4 DePartment of Urology, University Hospital Würzburg, Josef-Schneider-Str. 2, 16 97080 Würzburg 17 5 DePartment of Pathology, University HosPital Würzburg, Josef-Schneider-Str. 18 2, 97080 Würzburg 19 6 ComPrehensive Cancer Center Mainfranken, Josef-Schneider-Str.6, 97080 20 Würzburg, Germany 21 7Institute of Cancer Sciences, University of Glasgow, Garscube Estate, 22 Switchback Road, Bearsden, Glasgow, G61 1QH 23 24 #Corresponding author 25 email: [email protected] 26 $Current address: Division of Tumor Metabolism and Microenvironment, 27 German Cancer Research Center, Im Neuenheimer Feld 281, 69120 28 Heidelberg, Germany ([email protected]) 29 Phone: +49 6221 42 3423 30 31 Running Title: Mevalonate pathway supports ubiquinone synthesis in cancer 32 Conflict of interest: The authors declare no competing financial interests.
    [Show full text]
  • Molecular Diagnostic Testing Requisition
    BAYLOR GENETICS PHONE CONNECT 2450 HOLCOMBE BLVD. 1.800.411.4363 GRAND BLVD. RECEIVING DOCK FAX HOUSTON, TX 77021-2024 1.800.434.9850 MOLECULAR DIAGNOSTIC TESTING REQUISITION PATIENT INFORMATION (COMPLETE ONE FORM FOR EACH PERSON TESTED) / / Patient Last Name Patient First Name MI Date of Birth (MM / DD / YYYY) Address City State Zip Phone Patient discharged from Biological Sex: the hospital/facility: Female Male Unknown Accession # Hospital / Medical Record # Yes No Gender identity (if diff erent from above): REPORTING RECIPIENTS Ordering Physician Institution Name Email (Required for International Clients) Phone Fax ADDITIONAL RECIPIENTS Name Email Fax Name Email Fax PAYMENT (FILL OUT ONE OF THE OPTIONS BELOW) SELF PAYMENT Pay With Sample Bill To Patient INSTITUTIONAL BILLING Institution Name Institution Code Institution Contact Name Institution Phone Institution Contact Email INSURANCE Do Not Perform Test Until Patient is Aware of Out-Of-Pocket Costs (excludes prenatal testing) REQUIRED ITEMS 1. Copy of the Front/Back of Insurance Card(s) 2. ICD10 Diagnosis Code(s) 3. Name of Ordering Physician 4. Insured Signature of Authorization / / / / Name of Insured Insured Date of Birth (MM / DD / YYYY) Name of Insured Insured Date of Birth (MM / DD / YYYY) Patient's Relationship to Insured Phone of Insured Patient's Relationship to Insured Phone of Insured Address of Insured Address of Insured City State Zip City State Zip Primary Insurance Co. Name Primary Insurance Co. Phone Secondary Insurance Co. Name Secondary Insurance Co. Phone Primary Member Policy # Primary Member Group # Secondary Member Policy # Secondary Member Group # By signing below, I hereby authorize Baylor Genetics to provide my insurance carrier any information necessary, including test results, for processing my insurance claim.
    [Show full text]
  • Enhancing Mitochondrial Activity in Neurons Protects Against
    RESEARCH ARTICLE Enhancing mitochondrial activity in neurons protects against neurodegeneration in a mouse model of multiple sclerosis Sina C Rosenkranz1, Artem A Shaposhnykov1, Simone Tra¨ ger1, Jan Broder Engler1, Maarten E Witte2,3, Vanessa Roth1, Vanessa Vieira1, Nanne Paauw3, Simone Bauer1, Celina Schwencke-Westphal1, Charlotte Schubert1, Lukas Can Bal1, Benjamin Schattling1, Ole Pless4, Jack van Horssen3, Marc Freichel5, Manuel A Friese1* 1Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 2Department of Pathology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands; 3Department of Molecular Cell Biology and Immunology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands; 4Fraunhofer ITMP ScreeningPort, Hamburg, Germany; 5Institute of Pharmacology, Heidelberg University, Heidelberg, Germany Abstract While transcripts of neuronal mitochondrial genes are strongly suppressed in central nervous system inflammation, it is unknown whether this results in mitochondrial dysfunction and whether an increase of mitochondrial function can rescue neurodegeneration. Here, we show that predominantly genes of the electron transport chain are suppressed in inflamed mouse neurons, resulting in impaired mitochondrial complex IV activity. This was associated with post-translational inactivation of the transcriptional co-regulator proliferator-activated receptor gamma coactivator 1- *For correspondence: alpha (PGC-1a).
    [Show full text]
  • COQ9 (N-17): Sc-83392
    SAN TA C RUZ BI OTEC HNOL OG Y, INC . COQ9 (N-17): sc-83392 BACKGROUND PRODUCT Coenzyme Q (COQ), also referred to as ubiquinone, is a fat-soluble component Each vial contains 200 µg IgG in 1.0 ml of PBS with < 0.1% sodium azide of the electron transport chain that participates in aerobic cellular respiration and 0.1% gelatin. within mitochondria and is essential for ATP-dependent energy production. Blocking peptide available for competition studies, sc-83392 P, (100 µg COQ9 (coenzyme Q9 homolog) is a 318 amino acid protein that localizes to peptide in 0.5 ml PBS containing < 0.1% sodium azide and 0.2% BSA). the mitochondrion and is involved in the synthesis of coenzyme Q. Multiple isoforms of COQ9 exist due to alternative splicing events. The gene encoding APPLICATIONS COQ9 maps to human chromosome 16, which encodes over 900 genes and comprises nearly 3% of the human genome. The GAN gene is located on COQ9 (N-17) is recommended for detection of COQ9 of mouse, rat and chromosome 16 and, with mutation, may lead to giant axonal neuropathy, a human origin by Western Blotting (starting dilution 1:200, dilution range nervous system disorder characterized by increasing malfunction with growth . 1:100-1:1000), immunofluorescence (starting dilution 1:50, dilution range The rare disorder Rubinstein-Taybi syndrome is also associated with chro - 1:50-1:500) and solid phase ELISA (starting dilution 1:30, dilution range mo some 16, as is Crohn’s disease, which is a gastrointestinal inflammatory 1:30- 1:3000); non cross-reactive with other COQ family members.
    [Show full text]
  • Rescue of Primary Ubiquinone Deficiency Due to a Novel COQ7 Defect Using 2,4–Dihydroxybensoic Acid
    Therapeutics J Med Genet: first published as 10.1136/jmedgenet-2015-102986 on 17 June 2015. Downloaded from SHORT REPORT Rescue of primary ubiquinone deficiency due to a novel COQ7 defect using 2,4–dihydroxybensoic acid Christoph Freyer,1,2 Henrik Stranneheim,1,3 Karin Naess,1,4 Arnaud Mourier,5 Andrea Felser,4 Camilla Maffezzini,2 Nicole Lesko,1,4 Helene Bruhn,1,4 Martin Engvall,1,6 Rolf Wibom,1,4 Michela Barbaro,1,6 Yvonne Hinze,5 Måns Magnusson,3 Robin Andeer,3 Rolf H Zetterström,1,6 Ulrika von Döbeln,1,4 Anna Wredenberg,1,2 Anna Wedell1,2,3 ▸ Additional material is ABSTRACT other mitochondrial dehydrogenases, and functions in published online only. To view Background Coenzyme Q is an essential mitochondrial lysosomes, endoplasmic reticulum and plasma mem- please visit the journal online electron carrier, redox cofactor and a potent antioxidant branes. Furthermore, CoQ is the only lipid-soluble (http://dx.doi.org/10.1136/ 2 jmedgenet-2015-102986). in the majority of cellular membranes. Coenzyme Q antioxidant synthesised entirely by animal cells. deficiency has been associated with a range of CoQ levels naturally diminish with age,2 but For numbered affiliations see 10 end of article. metabolic diseases, as well as with some drug can also be decreased due to treatments with, for treatments and ageing. example, statins due to a shared biosynthesis 3 Correspondence to Methods We used whole exome sequencing (WES) to pathway with cholesterol. Additionally, CoQ10 Dr Anna Wredenberg, Division investigate patients with inherited metabolic diseases deficiencies (MIM 607426, 614651, 614652, for Metabolic Diseases, and applied a novel ultra-pressure liquid chromatography 612016, 614654, 614650) have been reported in a Department of Laboratory — Medicine, Karolinska Institutet, mass spectrometry approach to measure coenzyme Q range of patients with inborn errors of metabol- 4 Stockholm, Sweden; in patient samples.
    [Show full text]
  • A Genome Wide Copper-Sensitized Screen Identifies Novel Regulators of Mitochondrial Cytochrome C Oxidase Activity
    bioRxiv preprint doi: https://doi.org/10.1101/2020.12.31.424969; this version posted January 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Genetic regulators of mitochondrial copper A genome wide copper-sensitized screen identifies novel regulators of mitochondrial cytochrome c oxidase activity Natalie M. Garza1, Aaron T. Griffin1,2, Mohammad Zulkifli1, Chenxi Qiu1,3, Craig D. Kaplan1,4, Vishal M. Gohil*1 1Department of Biochemistry and Biophysics, MS 3474, Texas A&M University, College Station, TX 77843, USA 2Present Address: Department of Systems Biology, Columbia University, New York, NY 10032, USA 3Present Address: Department of Medicine, Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA 4Present Address: Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA *To whom the correspondence should be addressed: Vishal M. Gohil, 301 Old Main Drive, MS 3474, Texas A&M University, College Station, TX 77843 USA; Email: [email protected]; Tel: (979) 847-6138; Fax: (979) 845-9274 Running Title: Genetic regulators of mitochondrial copper Keywords: Copper, mitochondria, vacuole, cytochrome c oxidase, pH, AP-3, Rim20, Rim21 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.12.31.424969; this version posted January 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
    [Show full text]
  • Mitochondrial DNA (Mtdna) Test Requisition
    SHIP TO: Medical Genetics Laboratories BCM-MEDICAL GENETICS LABORATORIES Baylor College of Medicine PHONE: 800-411-GENE | FAX: 713-798-2787 | www.bcmgeneticlabs.org 2450 Holcombe, Grand Blvd. -Receiving Dock Houston, TX 77021-2024 MITOCHONDRIAL DNA (mtDNA) TEST REQUISITION Phone: 713-798-6555 PATIENT INFORMATION INDICATION FOR STUDY NAME: DATE OF COLLECTION: / / LAST NAME FIRST NAME MI MM DD YY HOSPITAL#: ACCESSION#: DATE OF BIRTH: / / GENDER (Please select one): FEMALE MALE MM DD YY SAMPLE TYPE (Please select one): ETHNIC BACKGROUND (Select all that apply): UNKNOWN BLOOD AFRICAN AMERICAN SKELETAL MUSCLE ASIAN DNA (Specify Source): ASHKENAZIC JEWISH EUROPEAN CAUCASIAN -OR- HISPANIC OTHER (Specify): NATIVE AMERICAN INDIAN PLACE PATIENT STICKER HERE OTHER JEWISH OTHER (Please specify): REPORTING INFORMATION ADDITIONAL PROFESSIONAL REPORT RECIPIENTS PHYSICIAN: NAME: INSTITUTION: PHONE: *FAX: PHONE: *FAX: NAME: EMAIL (INTERNATIONAL CLIENT REQUIREMENT): PHONE: *FAX: *BCM-MEDICAL GENETIC LABORATORIES HAS A FAX ONLY POLICY FOR REPORTING INDICATION FOR STUDY SYMPTOMATIC (Summarize below.): *FAMILIAL MUTATION/VARIANT ANALYSIS: Complete all fields below and attach the proband's report. GENE NAME: ASYMPTOMATIC/POSITIVE FAMILY HISTORY: (ATTACH FAMILY HISTORY) MUTATION/UNCLASSIFIED VARIANT: RELATIONSHIP TO PROBAND: THIS INDIVIDUAL IS CURRENTLY: SYMPTOMATIC ASYMPTOMATIC *If family mutation is known, complete the FAMILIAL MUTATION/ VARIANT ANALYSIS section. NAME OF PROBAND: ASYMPTOMATIC/POPULATION SCREENING RELATIONSHIP TO PROBAND: OTHER (Specify clinical findings below.): BCM LAB#: A COPY OF ORIGINAL RESULTS ATTACHED IF PROBAND TESTING WAS PERFORMED AT ANOTHER LAB, CALL TO DISCUSS PRIOR TO SENDING SAMPLE. A POSITIVE CONTROL MAY BE REQUIRED IN SOME CASES. REQUIRED: NEW YORK STATE PHYSICIAN SIGNATURE OF CONSENT I certify that the patient specified above and/or their legal guardian has been informed of the benefits, risks, and limitations of the laboratory test(s) requested.
    [Show full text]
  • A Personalized Model of COQ2 Nephropathy Rescued by the Wild-Type COQ2 Allele Or Dietary Coenzyme Q10 Supplementation
    BASIC RESEARCH www.jasn.org A Personalized Model of COQ2 Nephropathy Rescued by the Wild-Type COQ2 Allele or Dietary Coenzyme Q10 Supplementation † ‡ Jun-yi Zhu,* Yulong Fu,* Adam Richman,* Zhanzheng Zhao, Patricio E. Ray, § and Zhe Han*§ Centers for *Cancer and Immunology Research and ‡Genetic Medicine Research, Children’s National Health System, Washington, DC; †Department of Nephrology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; and §Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC ABSTRACT Clinical studies have identified patients with nephrotic syndrome caused by mutations in genes involved in the biosynthesis of coenzyme Q10 (CoQ10), a lipid component of the mitochondrial electron transport chain and an important antioxidant. However, the cellular mechanisms through which these mutations induce podocyte injury remain obscure. Here, we exploited the striking similarities between Drosophila nephrocytes and human podocytes to develop a Drosophila model of these renal diseases, and performed a systematic in vivo analysis assessing the role of CoQ10 pathway genes in renal function. Nephrocyte-specific silencing of Coq2, Coq6,andCoq8, which are genes involved in the CoQ10 pathway that have been associated with genetic nephrotic syndrome in humans, induced dramatic adverse changes in these cells. In particular, silencing of Coq2 led to an abnormal localization of slit diaphragms, collapse of lacunar channels, and more dysmorphic mitochondria. In addition, Coq2-deficient nephrocytes showed elevated levels of autophagy and mitophagy, increased levels of reactive oxygen species, and increased sensitivity to oxidative stress. Dietary supplementation with CoQ10 at least partially rescued these defects. Furthermore, expressing the wild-type human COQ2 gene specifically in nephrocytes rescued the de- fective protein uptake, but expressing the mutant allele derived from a patient with COQ2 nephropathy did not.
    [Show full text]