DOCSLIB.ORG

Imaging Patterns Characterizing Mitochondrial Leukodystrophies

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Imaging Patterns Characterizing Mitochondrial Leukodystrophies Published April 1, 2021 as 10.3174/ajnr.A7097 ORIGINAL RESEARCH PEDIATRICS Imaging Patterns Characterizing Mitochondrial Leukodystrophies S.D. Roosendaal, T. van de Brug, C.A.P.F. Alves, S. Blaser, A. Vanderver, N.I. Wolf, and M.S. van der Knaap ABSTRACT BACKGROUND AND PURPOSE: Achieving a specific diagnosis in leukodystrophies is often difficult due to clinical and genetic heter- ogeneity. Mitochondrial defects cause 5%–10% of leukodystrophies. Our objective was to define MR imaging features commonly shared by mitochondrial leukodystrophies and to distinguish MR imaging patterns related to specific genetic defects. MATERIALS AND METHODS: One hundred thirty-two patients with a mitochondrial leukodystrophy with known genetic defects were identified in the data base of the Amsterdam Leukodystrophy Center. Numerous anatomic structures were systematically assessed on brain MR imaging. Additionally, lesion characteristics were scored. Statistical group analysis was performed for 57 MR imaging features by hierarchic testing on clustered genetic subgroups. RESULTS: MR imaging features indicative of mitochondrial disease that were frequently found included white matter rarefaction (n ¼ 50 patients), well-delineated cysts (n ¼ 20 patients), T2 hyperintensity of the middle blade of the corpus callosum (n ¼ 85 patients), and symmetric abnormalities in deep gray matter structures (n ¼ 42 patients). Several disorders or clusters of disorders had characteristic features. The combination of T2 hyperintensity in the brain stem, middle cerebellar peduncles, and thalami was associated with complex 2 deficiency. Predominantly periventricular localization of T2 hyperintensities and cystic lesions with a dis- tinct border was associated with defects in complexes 3 and 4. T2-hyperintense signal of the cerebellar cortex was specifically associated with variants in the gene NUBPL. T2 hyperintensities predominantly affecting the directly subcortical cerebral white mat- ter, globus pallidus, and substantia nigra were associated with Kearns-Sayre syndrome. CONCLUSIONS: In a large group of patients with a mitochondrial leukodystrophy, general MR imaging features suggestive of mitochon- drial disease were found. Additionally, we identified several MR imaging patterns correlating with specific genotypes. Recognition of these patterns facilitates the diagnosis in future patients. ABBREVIATIONS: KSS ¼ Kearns-Sayre syndrome; SDH ¼ Succinate dehydrogenase; MELAS ¼ mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome; MNGIE ¼ mitochondrial neurogastrointestinal encephalopathy eukodystrophies are genetic disorders predominantly involv- characterized by a specific combination of affected structures on Ling the white matter of the CNS.1 Clinical and genetic hetero- MR imaging, constituting a recognizable pattern. Recent diagnos- geneity complicate establishing a specific molecular diagnosis, tic algorithms for leukodystrophies acknowledge the central role which becomes more effective when clinical, radiologic, and of MR imaging pattern recognition.1,2 genetic parameters are combined.1 Most leukodystrophies are A subset of leukodystrophies, involving 5%–10%, is caused by mitochondrial defects.3,4 Mitochondrial diseases comprise a group Received November 17, 2020; accepted after revision January 14, 2021. of disorders with genetic defects in mitochondrial oxidative energy From the Departments of Radiology (S.D.R.) and Epidemiology and Biostatistics metabolism. Mitochondria are cellular organelles that produce (T.v.d.B.), Amsterdam UMC, Amsterdam, the Netherlands; Division of Neuroradiology (C.A.P.F.A.), and Department of Radiology and Division of energy via oxidative phosphorylation (Online Supplemental Data). Neurology (A.V.), The Children's Hospital of Philadelphia, Philadelphia, The oxidative phosphorylation system consists of 5 respiratory Pennsylvania; Division of Neuroradiology (S.B.), Department of Diagnostic Imaging, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Please address correspondence to Stefan D. Roosendaal, MD, PhD, Amsterdam Department of Pediatric Neurology (M.S.v.d.K., N.I.W.), Emma Children’s Hospital, UMC, Department of Radiology, Meibergdreef 9, 1105 AZ Amsterdam, the Amsterdam Leukodystrophy Center, Amsterdam UMC, Vrije Universiteit and Netherlands: e-mail: [email protected] Amsterdam Neuroscience, Amsterdam, the Netherlands; and Department of Functional Genomics (M.S.v.d.K.), Center for Neurogenomics and Cognitive Indicates open access to non-subscribers at www.ajnr.org Research, VU University, Amsterdam, the Netherlands. The following authors are members of the European Reference Network for Rare Indicates article with online supplemental data. Neurological Disorders, project ID 739510: M.S. van der Knaap and N.I. Wolf. http://dx.doi.org/10.3174/ajnr.A7097 AJNR Am J Neuroradiol :2021 www.ajnr.org 1 Copyright 2021 by American Society of Neuroradiology. chain complexes in the mitochondrial membrane. Human cells deficiency was present in 10 patients, all with variants in LYRM7. possess 2 different genomes: the nuclear genome, containing Some were part of a previous study on LYRM7.14 Complex 4 defi- approximately 20,000 genes, and the mitochondrial genome, con- ciency was present in 9 patients: 7 with variants in APOPT1,1 taining 37 genes. Although mitochondria have functions in addi- with variants in COX6B,and1withvariantsinCOX10.Most tion to energy metabolism, mitochondrial diseases are typically patients with APOPT1 variants were part of a previous study on regarded as disorders of oxidative phosphorylation.5 They are APOPT1.12 Iron-sulfur cluster assembly pathway variants were caused by variants in either mitochondrial genes or, much more present in 33 patients: 9 with variants in NUBPL, 8inIBA57,7in frequently, nuclear genes encoding proteins necessary for mito- ISCA2,5inFDX1L,3inBOLA3,and1inCDK5RAP1. chondrial function.5 Concerning the high number of associated Descriptions of some of the patients with NUBPL,11 IBA57,20 and gene defects, it is not surprising that mitochondrial disorders have a FDX1L21 variants were published before. A large mitochondrial striking clinical heterogeneity;5 the high energy demand of the CNS DNA deletion was present in 6 patients, all presenting with the explains it being the most commonly affected organ.5 KSS phenotype. Additionally, 4 patients had TYMP variants, in- Some mitochondrial encephalopathies predominantly manifest dicative of MNGIE, and 5 patients had CLPP variants; descrip- with lesions of gray matter structures (eg, mitochondrial encephal- tions of some of the latter have been published before.13 opathy, lactic acidosis, and stroke-like episodes syndrome (MELAS); Alpers syndrome; and Leigh syndrome).6 Another category mani- MR Imaging Evaluation festsasleukodystrophy.7 The leukoencephalopathy in Kearns-Sayre At least 1 brain MR imaging was available for each patient. syndrome (KSS)8 and mitochondrial neurogastrointestinal ence- When multiple MRIs were available, the first was used for phalopathy syndrome (MNGIE)9 has been known for a long time, analysis. MR sequences and image quality were variable but more recently, next-generation genetic sequencing techniques because the MRIs were acquired at multiple institutions. T2- have revealed that numerous unsolved cases of leukodystrophy have weighted and nonenhanced T1-weighted sequences were a mitochondrial cause, and MR imaging patterns of new mitochon- available for every patient; FLAIR was available for 115 drial leukodystrophies were added.10 Patient selection by specific MR patients. These images were used to systematically score imaging patterns was pivotal in the detection of the novel leukody- numerous white and gray matter structures as normal or strophies caused by defects in the genes LYRM7, APOPT1, NUBPL, abnormal, and specific features of the abnormalities were and CLPP.11-14 However, systematic studies on MR imaging patterns scored, as described in van der Knaap et al.22 More salient in larger groups of patients with different mitochondrial leukodystro- features of this scoring system were as follows: The white phies are lacking, and information on the associated MR imaging matter was divided into 3 zones—directly subcortical white patterns is lacking in recent leukodystrophy diagnostic algorithms.1,2 matter (ie, arcuate fibers), deep white matter, and periven- In the current study, we systematically analyzed MRIs of a tricular white matter. The corpus callosum was divided into large group of patients with mitochondrial leukodystrophy. In all inner, middle, and outer blades (or layers) and anterior, mid- patients, the causative gene defect was known. The study aims dle, and posterior parts. Cysts were strictly scored as lesions were to describe MR imaging features suggesting a mitochondrial with a signal intensity identical to that of CSF on FLAIR leukodystrophy in general and to distinguish MR imaging pat- images, whereas lesions having a signal intensity on FLAIR terns related to particular gene defects. intermediate between normal white matter and CSF were defined as rarefaction. The caudate nucleus, putamen, globus MATERIALS AND METHODS pallidus, thalamus, dentate nucleus, substantia nigra, cerebral Patients cortex, and cerebellar cortex were individually evaluated. In the MR imaging data base of the Amsterdam Leukodystrophy Center, comprising more than 4000 patients, 132 patients with a Statistical Analysis mitochondrial leukodystrophy and a known gene defect
Load more

Recommended publications
  • Supplementary Information ADC Mar 2017
    Supplementary Material for Diagnosing Childhood-onset Inborn Errors of Metabolism by Next Generation Sequencing Clinical Proforma ! CLINICAL&PROFORMA&FOR&MANCHESTER&METABOLIC&NGS&PANELS& ! Patient!Name:!! ! Sex:!Male! !Female! ! ! Date!of!Birth!(D/M/Y):! !! Reference!Number:! !! ! Clinical&Information& ! ! Clinical!features! ! ! ! Age!of!onset! ! ! ! Details!of!relevant!biochemical! ! testing! ! ! Likely!mode!of!inheritance! Dominant! !!!!!XHlinked! !!!!!!Recessive! !!!!!!Sporadic! !!!!!!Information!not!available! ! Parental!consanguinity!H!!!!!!!Yes! !!!!!!!!!!!!!!!!!!!!!No! !!!!!!!!!!!!!!!!!!!Information!not!available! !!!! Relevant!family!history!! ! (draw!brief!pedigrees!if!needed)! ! and!any!other!relevant! !!!!!!!!!!!!!!!!!!!!!!!!!! information! ! Possible!or!likely!diagnosis!or! ! disease!group! ! Is!the!patient!known!to!any! ! Consultants!in!Manchester! ! Genetics!department?! ! (If!yes,!give!name)!! ! & Gene&panel&request& AA!+!NT! ! Key:&&AA!Disorders!of!amino!acid!metabolism!and!cerebral!organic!acid! AMN!+!FAOD!+!KET! ! disorders;!NT!Disorders!of!neurotransmission;!AMN!Disorders!associated! with!hyperammonaemia;!FAOD(Fatty!acid!oxidation!defects;!KET!Disorders! OA!+!VIT! ! of!ketogenesis!or!ketolysis;!OA!Organic!acidaemias,!including!disorders!of! CHO! & branched!chain!amino!acid!catabolism,!3>methylglutaconic!acidurias;!VIT! LSD!+!NCL! & Folate!and!cobalamin!defects,!also!riboflavin!transport!defects,!and!biotin> PER! ! responsive!disorders;!CHO!Disorders!of!carbohydrate!metabolism;!LSD! Lysosomal!disorders;!NCL!Neuronal!ceroid!lipofuscinoses;!PER!Peroxisomal!
    [Show full text]
  • Roles of Mitochondrial Respiratory Complexes During Infection Pedro Escoll, Lucien Platon, Carmen Buchrieser
    Roles of Mitochondrial Respiratory Complexes during Infection Pedro Escoll, Lucien Platon, Carmen Buchrieser To cite this version: Pedro Escoll, Lucien Platon, Carmen Buchrieser. Roles of Mitochondrial Respiratory Complexes during Infection. Immunometabolism, Hapres, 2019, Immunometabolism and Inflammation, 1, pp.e190011. 10.20900/immunometab20190011. pasteur-02593579 HAL Id: pasteur-02593579 https://hal-pasteur.archives-ouvertes.fr/pasteur-02593579 Submitted on 15 May 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License ij.hapres.com Review Roles of Mitochondrial Respiratory Complexes during Infection Pedro Escoll 1,2,*, Lucien Platon 1,2,3, Carmen Buchrieser 1,2,* 1 Institut Pasteur, Unité de Biologie des Bactéries Intracellulaires, 75015 Paris, France 2 CNRS-UMR 3525, 75015 Paris, France 3 Faculté des Sciences, Université de Montpellier, 34095 Montpellier, France * Correspondence: Pedro Escoll, Email: [email protected]; Tel.: +33-0-1-44-38-9540; Carmen Buchrieser, Email: [email protected]; Tel.: +33-0-1-45-68-8372. ABSTRACT Beyond oxidative phosphorylation (OXPHOS), mitochondria have also immune functions against infection, such as the regulation of cytokine production, the generation of metabolites with antimicrobial proprieties and the regulation of inflammasome-dependent cell death, which seem in turn to be regulated by the metabolic status of the organelle.
    [Show full text]
  • Severe Respiratory Complex III Defect Prevents Liver Adaptation To
    Severe respiratory complex III defect prevents liver adaptation to prolonged fasting Laura Kremer, Caroline L ’Hermitte-Stead, Pierre Lesimple, Mylène Gilleron, Sandrine Filaut, Claude Jardel, Tobias Haack, Tim Strom, Thomas Meitinger, Hatem Azzouz, et al. To cite this version: Laura Kremer, Caroline L ’Hermitte-Stead, Pierre Lesimple, Mylène Gilleron, Sandrine Filaut, et al.. Severe respiratory complex III defect prevents liver adaptation to prolonged fasting. Journal of Hepatology, Elsevier, 2016, 65 (2), pp.377-85. 10.1016/j.jhep.2016.04.017. inserm-01321215 HAL Id: inserm-01321215 https://www.hal.inserm.fr/inserm-01321215 Submitted on 25 May 2016 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. 1 Severe respiratory complex III defect prevents liver adaptation to prolonged fasting Laura S Kremer1,2, Caroline L’hermitte- Stead3,4,5, Pierre Lesimple3,4,5, Mylène Gilleron3,4,5,6, Sandrine Filaut6, Claude Jardel3,4,5,6, Tobias B Haack1,2, Tim M Strom1,2, Thomas Meitinger1,2, Hatem Azzouz7, Neji Tebib7, Hélène Ogier de Baulny8, Guy Touati9, Holger Prokisch1,
    [Show full text]
  • C20orf7 (NDUFAF5) (NM 001039375) Human Recombinant Protein Product Data
    OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for TP760234 C20orf7 (NDUFAF5) (NM_001039375) Human Recombinant Protein Product data: Product Type: Recombinant Proteins Description: Recombinant protein of human chromosome 20 open reading frame 7 (C20orf7), nuclear gene encoding mitochondrial protein, transcript variant 2, full length, with N-terminal HIS tag, expressed in E.Coli, 50ug Species: Human Expression Host: E. coli Tag: N-His Predicted MW: 35.9 kDa Concentration: >50 ug/mL as determined by microplate BCA method Purity: > 80% as determined by SDS-PAGE and Coomassie blue staining Buffer: 25mM Tris, pH8.0, 150 mM NaCl, 10% glycerol, 1 % Sarkosyl Storage: Store at -80°C. Stability: Stable for 12 months from the date of receipt of the product under proper storage and handling conditions. Avoid repeated freeze-thaw cycles. RefSeq: NP_001034464 Locus ID: 79133 UniProt ID: Q5TEU4 RefSeq Size: 2227 Cytogenetics: 20p12.1 RefSeq ORF: 951 Synonyms: bA526K24.2; C20orf7; dJ842G6.1; MC1DN16 Summary: The NADH-ubiquinone oxidoreductase complex (complex I) of the mitochondrial respiratory chain catalyzes the transfer of electrons from NADH to ubiquinone, and consists of at least 43 subunits. The complex is located in the inner mitochondrial membrane. This gene encodes a mitochondrial protein that is associated with the matrix face of the mitochondrial inner membrane and is required for complex I assembly. A mutation in this gene results in mitochondrial complex I deficiency. Multiple transcript variants encoding different isoforms have been found for this gene.
    [Show full text]
  • Identification of a Novel Biogenesis Factor for Mitochondrial Complex I Using Chlamydomonas Reinhardtii As a Model System
    Identification of a novel biogenesis factor for mitochondrial Complex I using Chlamydomonas reinhardtii as a model system DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Nitya Subrahmanian Graduate Program in Plant Cellular and Molecular Biology The Ohio State University 2015 Dissertation Committee: Patrice P. Hamel, Advisor Anita K. Hopper Venkat Gopalan R. Keith Slotkin Copyright by Nitya Subrahmanian 2015 ABSTRACT Mitochondria, the “powerhouse” of the cell, produce energy through the mitochondrial respiratory chain, which comprises five major complexes. Complex I is the first and most complicated enzyme required in this process. With more than 40 subunits, one FMN molecule and eight Fe-S clusters, the assembly of mitochondrial Complex I is highly intricate. Complex I deficiency in humans causes severe metabolic defects leading to fatal diseases such as encephalomyopathy and Parkinson’s disease. In 60% of the patients presenting Complex I dysfunction, there is no molecular explanation and it is assumed that defects in yet-to-be discovered assembly factors are responsible for the Complex I deficiency. In this study, we present the identification of a novel factor required for the biogenesis of Complex I in a green alga. Study of Complex I biogenesis in humans is very limited due to the lethality of patients with Complex I-related diseases and associated ethical concerns. Chlamydomonas reinhardtii, a unicellular photosynthetic alga, is an ideal model organism for the study of Complex I assembly and function. Chlamydomonas is genetically tractable and it’s Complex I subunit composition is similar to its human counterpart.
    [Show full text]
  • Blueprint Genetics Leukodystrophy and Leukoencephalopathy Panel
    Leukodystrophy and Leukoencephalopathy Panel Test code: NE2001 Is a 118 gene panel that includes assessment of non-coding variants. In addition, it also includes the maternally inherited mitochondrial genome. Is ideal for patients with a clinical suspicion of leukodystrophy or leukoencephalopathy. The genes on this panel are included on the Comprehensive Epilepsy Panel. About Leukodystrophy and Leukoencephalopathy Leukodystrophies are heritable myelin disorders affecting the white matter of the central nervous system with or without peripheral nervous system myelin involvement. Leukodystrophies with an identified genetic cause may be inherited in an autosomal dominant, an autosomal recessive or an X-linked recessive manner. Genetic leukoencephalopathy is heritable and results in white matter abnormalities but does not necessarily meet the strict criteria of a leukodystrophy (PubMed: 25649058). The mainstay of diagnosis of leukodystrophy and leukoencephalopathy is neuroimaging. However, the exact diagnosis is difficult as phenotypes are variable and distinct clinical presentation can be present within the same family. Genetic testing is leading to an expansion of the phenotypic spectrum of the leukodystrophies/encephalopathies. These findings underscore the critical importance of genetic testing for establishing a clinical and pathological diagnosis. Availability 4 weeks Gene Set Description Genes in the Leukodystrophy and Leukoencephalopathy Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD ABCD1*
    [Show full text]
  • Mrna-Binding Protein Tristetraprolin Is Essential for Cardiac Response To
    mRNA-binding protein tristetraprolin is essential for PNAS PLUS cardiac response to iron deficiency by regulating mitochondrial function Tatsuya Satoa,1, Hsiang-Chun Changa,1, Marina Bayevaa, Jason S. Shapiroa, Lucia Ramos-Alonsob, Hidemichi Kouzua, Xinghang Jianga, Ting Liua, Sumeyye Yara, Konrad T. Sawickia, Chunlei Chena, María Teresa Martínez-Pastorc, Deborah J. Stumpod, Paul T. Schumackere, Perry J. Blacksheard, Issam Ben-Sahraf, Sergi Puigb, and Hossein Ardehalia,2 aFeinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; bDepartamento de Biotecnología, Instituto de Agroquímica y Tecnología de Alimentos, Consejo Superior de Investigaciones Científicas, 46980 Paterna, Valencia, Spain; cDepartamento de Bioquímica y Biología Molecular, Universitat de València, 46100 Burjassot, Valencia, Spain; dSignal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709; eDepartment of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; and fDepartment of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611 Edited by J. G. Seidman, Harvard Medical School, Boston, MA, and approved May 23, 2018 (received for review March 23, 2018) Cells respond to iron deficiency by activating iron-regulatory electron transport chain (ETC) (11). However, energy pro- proteins to increase cellular iron uptake and availability. However, duction by oxidative phosphorylation in mitochondria is non- it is not clear how cells adapt to conditions when cellular iron essential for survival, at least in the short term, as demonstrated uptake does not fully match iron demand. Here, we show that the by a switch to anaerobic respiration and heavy reliance on gly- mRNA-binding protein tristetraprolin (TTP) is induced by iron colysis in muscle during vigorous exercise, when oxygen demand deficiency and degrades mRNAs of mitochondrial Fe/S-cluster- outmatches its supply (12).
    [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]
  • Deltex3 Inhibits Epithelial Mesenchymal Transition In
    Journal of Cancer 2021, Vol. 12 860 Ivyspring International Publisher Journal of Cancer 2021; 12(3): 860-873. doi: 10.7150/jca.48141 Research Paper Deltex3 inhibits Epithelial Mesenchymal Transition in Papillary Thyroid Carcinoma via promoting ubiquitination of XRCC5 to regulate the AKT signal pathway Lidong Wang1, Yonglian Huang1, Chenxi Liu1, Mingyue Guo1, Zhennan Ma1, Jingni He1, Ailian Wang2, Xiaodan Sun3, Zhen Liu1 1. Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China. 2. Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, China. 3. Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China. Corresponding author: Zhen Liu, PhD, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China. E-mail: [email protected]. Zip code: 110004. Telephone number: +86018940254591. © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2020.05.13; Accepted: 2020.11.02; Published: 2021.01.01 Abstract Background: Papillary thyroid carcinoma (PTC) is one of the most common endocrine malignant tumors. Poor prognoses such as high recurrence rate always appear in PTC patients with cervical lymph node metastasis. The process of ubiquitination plays important roles in PTC. As ubiquitin E3 ligases, Deltex (DTX) family proteins were reported to associate with multiple cancers. However, functions and mechanisms of DTX3 in PTC are currently unknown. Methods: In this study, DTX3 expressions were examined in 114 PTC and paired paracancerous normal tissues through quantitative real-time polymerase chain reaction and western blot.
    [Show full text]
  • Mitochondrial Disease and Endocrine Dysfunction
    Mitochondrial Disease and Endocrine Dysfunction Jasmine Chow1, Joyeeta Rahman2, John C Achermann2, Mehul Dattani2,3, Shamima Rahman2,4,* 1Department of Paediatrics, Queen Elizabeth Hospital, Hong Kong 2Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK 3Endocrinology Unit, Great Ormond Street Hospital, London WC1N 3JH, UK 4Metabolic Unit, Great Ormond Street Hospital, London WC1N 3JH, UK * Author for correspondence Address for correspondence: Mitochondrial Research Group Genetics and Genomic Medicine UCL Institute of Child Health 30 Guilford Street London WC1N 1EH UK Tel: +44(0)207 905 2608, Fax: +44(0)207 404 6191 Email: [email protected] 1 Abstract: Mitochondria are critical organelles for endocrine health, housing steroid hormone biosynthesis and providing energy in the form of ATP for hormone production and trafficking. Mitochondrial diseases are multisystem disorders of oxidative phosphorylation that are characterised by enormous clinical, biochemical and genetic heterogeneity. Currently mitochondrial disease has been linked to greater than 200 monogenic defects encoded on two genomes, the nuclear genome and the ancient circular mitochondrial genome located within the mitochondria themselves. Endocrine dysfunction is often observed in genetic mitochondrial disease and reflects decreased intracellular production or extracellular secretion of hormones. Diabetes mellitus is the most frequently described endocrine disturbance in patients with inherited mitochondrial disease, but other endocrine manifestations in these patients may include growth hormone deficiency, hypogonadism, adrenal dysfunction, hypoparathyroidism and thyroid disease. Whilst mitochondrial endocrine dysfunction is frequently in the context of multisystem disease, some mitochondrial disorders are characterised by isolated endocrine involvement, and it is anticipated that further monogenic mitochondrial endocrine diseases will be revealed by genome-wide next generation sequencing approaches.
    [Show full text]
  • Transcriptomic and Proteomic Landscape of Mitochondrial
    TOOLS AND RESOURCES Transcriptomic and proteomic landscape of mitochondrial dysfunction reveals secondary coenzyme Q deficiency in mammals Inge Ku¨ hl1,2†*, Maria Miranda1†, Ilian Atanassov3, Irina Kuznetsova4,5, Yvonne Hinze3, Arnaud Mourier6, Aleksandra Filipovska4,5, Nils-Go¨ ran Larsson1,7* 1Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne, Germany; 2Department of Cell Biology, Institute of Integrative Biology of the Cell (I2BC) UMR9198, CEA, CNRS, Univ. Paris-Sud, Universite´ Paris-Saclay, Gif- sur-Yvette, France; 3Proteomics Core Facility, Max Planck Institute for Biology of Ageing, Cologne, Germany; 4Harry Perkins Institute of Medical Research, The University of Western Australia, Nedlands, Australia; 5School of Molecular Sciences, The University of Western Australia, Crawley, Australia; 6The Centre National de la Recherche Scientifique, Institut de Biochimie et Ge´ne´tique Cellulaires, Universite´ de Bordeaux, Bordeaux, France; 7Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden Abstract Dysfunction of the oxidative phosphorylation (OXPHOS) system is a major cause of human disease and the cellular consequences are highly complex. Here, we present comparative *For correspondence: analyses of mitochondrial proteomes, cellular transcriptomes and targeted metabolomics of five [email protected] knockout mouse strains deficient in essential factors required for mitochondrial DNA gene (IKu¨ ); expression, leading to OXPHOS dysfunction. Moreover,
    [Show full text]
  • Thesis Reference
    Thesis C11orf83, a mitochondrial cardiolipin-binding protein involved in bc1 complex assembly and supercomplex stabilization DESMURS-ROUSSEAU, Marjorie Abstract Cette thèse a permis d'identifier C11orf83, désormais appelé UQCC3, comme étant une protéine mitochondriale ancrée dans la membrane interne. Nous avons constaté l'implication de C11orf83 dans l'assemblage du complexe III de la chaîne respiratoire via la stabilisation du complexe intermédiaire MT-CYB/UQCRB/UQCRQ. Nous avons également prouvé que C11orf83 était associée avec le dimère de complexe III et était détectée dans le supercomplexe III2/IV. Son absence induit une baisse significative de ce supercomplexe et du respirasome (I/III2/IV). La capacité de C11orf83 de lier les cardiolipines, connues pour être impliquées dans la formation et la stabilisation de ces supercomplexes, pourrait expliquer ces résultats. Ainsi, ce travail de thèse en lien avec une récente étude clinique mettant en évidence une déficience du complexe III chez un patient atteint d'une mutation du gène C11orf83 (Wanschers et al., 2014) permet d'améliorer les connaissances sur l'assemblage du complexe III et la compréhension d'une maladie mitochondriale. Reference DESMURS-ROUSSEAU, Marjorie. C11orf83, a mitochondrial cardiolipin-binding protein involved in bc1 complex assembly and supercomplex stabilization. Thèse de doctorat : Univ. Genève, 2015, no. Sc. 4857 DOI : 10.13097/archive-ouverte/unige:108015 URN : urn:nbn:ch:unige-1080158 Available at: http://archive-ouverte.unige.ch/unige:108015 Disclaimer: layout of this document may differ from the published version. 1 / 1 UNIVERSITÉ DE GENÈVE Département de Biologie Cellulaire FACULTÉ DES SCIENCES Professeur Jean-Claude Martinou Département de Science des Protéines Humaines FACULTÉ DE MEDECINE Professeur Amos Bairoch C11orf83, a mitochondrial cardiolipin-binding protein involved in bc1 complex assembly and supercomplex stabilization.
    [Show full text]