Genetics, Gene Therapy & Genetic Disease
- How much does a disrupted mitochondrial network influence neuronal dysfunction?
Mitochondria are organelles that are present in all nucleated cells in the body. They have manifold functions but famously generate ATP efficiently through the process of oxidative phosphorylation. This ensures all tissues have an adequate energy supply and underlines the need for a fully functional mitochondrial network. Since mitochondrial biogenesis and maintenance require components from two genetic sources, mitochondrial diseases can result from mutations in either the nuclear or the mitochondrial genome (mtDNA). Enigmatically, mitochondrial disease can affect individuals at any age and in any tissue (Lightowlers et al, 2015). For a subset of mutations, the genotype can be ascribed to a clinical phenotype and a number of mutations are associated with remarkable tissue selectivity (Boczonadi et al, 2018). However, the gene expression pathways governing this tissue‐specific presentation are far from clear. In this issue of EMBO Molecular Medicine, Sprenger et al (2018) use mouse models to investigate the consequences of deleting a mitochondrial protease, YME1L, in neuronal/glial precursors. The loss causes multiple defects at both cell and tissue level, including a marked fragmentation of the mitochondrial network. Tandem depletion of a second mitochondrial protease, Oma1, successfully restored the mitochondrial connectivity, but did not rescue the ocular defects and caused an earlier onset of neurological dysfunction. Thus, in addition to other findings, the authors conclude that a fragmented mitochondrial network contributes less to the disease phenotype than the disruption of mitochondrial proteostasis.
See also: HG Sprenger et al
Chrzanowska‐Lightowlers and Lightowlers discuss the work of Sprenger et al who examined in mice the consequences of deleting a mitochondrial protease, YME1L, in neuronal/glial precursors and how a fragmented mitochondrial network contributes to the disruption of mitochondrial proteostasis.
EMBO Mol Med (2018) e9899
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- APOPT1/COA8 assists COX assembly and is oppositely regulated by UPS and ROS
- Alba Signes1,
- Raffaele Cerutti1,
- Anna S Dickson2,
- Cristiane Benincá1,
- Elizabeth C Hinchy1,
- Daniele Ghezzi3,4,
- Rosalba Carrozzo5,
- Enrico Bertini5,
- Michael P Murphy1,
- James A Nathan2,
- Carlo Viscomi1,
- Erika Fernandez‐Vizarra (emfvb2{at}mrc-mbu.cam.ac.uk)*,1 and
- Massimo Zeviani (mdz21{at}mrc-mbu.cam.ac.uk)*,1
- 1MRC‐Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
- 2Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
- 3Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Milan, Italy
- 4Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
- 5Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Research Hospital, IRCCS, Rome, Italy
- ↵*
Corresponding author. Tel: +44 1223 252846; E‐mail: emfvb2{at}mrc-mbu.cam.ac.uk
Corresponding author. Tel: +44 1223 252704; E‐mail: mdz21{at}mrc-mbu.cam.ac.uk
APOPT1 loss‐of‐function causes a leukoencephalopathy associated with mitochondrial cytochrome c oxidase (COX) deficiency in patients. APOPT1 does not play a role in apoptosis, but contributes to the biogenesis of COX, which is part of the mitochondrial respiratory chain.
Synopsis
APOPT1 loss‐of‐function causes a leukoencephalopathy associated with mitochondrial cytochrome c oxidase (COX) deficiency in patients. APOPT1 does not play a role in apoptosis, but contributes to the biogenesis of cytochrome c oxidase (COX), which is part of the mitochondrial respiratory chain.
Isolated COX deficiency in multiple tissues was caused by ablation of Apopt1 in mice.
Mature APOPT1 is localized in the inner compartment of mitochondria participating in the intermediate stages of COX assembly.
APOPT1 precursor is degraded by the Ubiquitin‐Proteasome System in non‐stress conditions.
Under oxidative stress, the amount of intra‐mitochondrial APOPT1 was found to increase and to protect assembly COX intermediates from oxidative‐induced degradation.
A new term for APOPT1 is proposed: COA8, for COX assembly 8th factor.
EMBO Mol Med (2018) e9582
- Received July 20, 2018.
- Revision received November 20, 2018.
- Accepted November 21, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Alternative oxidase‐mediated respiration prevents lethal mitochondrial cardiomyopathy
- Jayasimman Rajendran1,2,
- Janne Purhonen1,2,
- Saara Tegelberg1,3,4,
- Olli‐Pekka Smolander5,
- Matthias Mörgelin6,
- Jan Rozman7,8,
- Valerie Gailus‐Durner7,
- Helmut Fuchs7,
- Martin Hrabe de Angelis7,8,9,
- Petri Auvinen5,
- Eero Mervaala10,
- Howard T Jacobs5,11,
- Marten Szibor5,11,
- Vineta Fellman1,3,12 and
- Jukka Kallijärvi (jukka.kallijarvi{at}helsinki.fi)*,1,2
- 1Folkhälsan Research Center, Helsinki, Finland
- 2Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- 3Department of Clinical Sciences, Lund, Pediatrics, Lund University, Lund, Sweden
- 4Molecular Neurology Research Program and Neuroscience Center, University of Helsinki, Helsinki, Finland
- 5Institute of Biotechnology, University of Helsinki, Helsinki, Finland
- 6Division of Infection Medicine, Clinical Sciences, Lund University, Lund, Sweden
- 7German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- 8German Center for Diabetes Research (DZD), Neuherberg, Germany
- 9Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, TU Munich, Freising‐Weihenstephan, Germany
- 10Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- 11Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
- 12Children's Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- ↵*Corresponding author. Tel: +358 504487006; E‐mail: jukka.kallijarvi{at}helsinki.fi
Bcs1l mutant mice show respiratory chain cIII dysfunction resulting in poor electron and proton transfer, and quinol oxidation. This study makes use of alternative oxidase (AOX), an enzyme that shunts electrons from quinols directly to oxygen, thus restoring electron flow upstream of cIII.
Synopsis
Bcs1l mutant mice show respiratory chain cIII dysfunction resulting in poor electron and proton transfer, and quinol oxidation. This study makes use of alternative oxidase (AOX), an enzyme that shunts electrons from quinols directly to oxygen, thus restoring electron flow upstream of cIII.
Broadly expressed transgenic AOX prevents lethal cardiomyopathy in Bcs1lp.S78G knock‐in mice and extends their median survival from 210 to 590 days.
Restoration of electron flow upstream of cIII by AOX is sufficient to prevent the cardiac decompensation.
AOX prevents pathological changes in the expression of central transcriptional regulators of substrate utilization and metabolic stress in the heart.
Analyses of reactive oxygen species (ROS) production and damage suggest that ROS are not instrumental in the rescue.
EMBO Mol Med (2018) e9456
- Received August 8, 2018.
- Revision received November 8, 2018.
- Accepted November 12, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Sea squirt alternative oxidase bypasses fatal mitochondrial heart disease
Mitochondrial diseases are a diverse group of inborn disorders affecting cellular energy production by oxidative phosphorylation (OXPHOS) via the five (CI‐CV) mitochondrial respiratory chain (MRC) complexes. The sea squirt alternative oxidase (AOX) is able to bypass the distal part of the MRC and was shown to alleviate the consequences of CIII and CIV defects in several cellular and Drosophila models. In this issue of EMBO Molecular Medicine, Rajendran et al (2018) demonstrate the first proof of concept in mammals, by showing that AOX is capable to extend lifespan and prevent heart failure in a CIII deficient mouse model, raising the possibility of future human AOX bypass treatment.
See also: J Rajendran et al (2018)
A. Saada discusses the proof‐of‐concept study by Rajendran et al (in this issue of EMBO Molecular Medicine) that indicates that AOX bypass expands lifespan in a relevant genetic mouse model of a human mitochondrial disorder.
EMBO Mol Med (2018) e9962
- © 2018 The Author. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Murine MPDZ‐linked hydrocephalus is caused by hyperpermeability of the choroid plexus
- Junning Yang1,
- Claire Simonneau1,
- Robert Kilker1,
- Laura Oakley2,
- Matthew D Byrne2,
- Zuzana Nichtova3,
- Ioana Stefanescu1,
- Fnu Pardeep‐Kumar4,
- Sushil Tripathi4,
- Eric Londin5,
- Pascale Saugier‐Veber6,
- Belinda Willard7,
- Mathew Thakur4,
- Stephen Pickup8,
- Hiroshi Ishikawa9,
- Horst Schroten10,
- Richard Smeyne2 and
- Arie Horowitz (arie.horowitz{at}jefferson.edu)*,1,11
- 1Cardeza Center for Vascular Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
- 2Department of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
- 3Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
- 4Department of Radiology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
- 5Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
- 6Department of Genetics, University of Rouen, Rouen, France
- 7Proteomics Core Facility, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
- 8Department of Radiology, University of Pennsylvania Medical School, Philadelphia, PA, USA
- 9Department of NDU Life Sciences, School of Life Dentistry, Nippon Dental University, Chiyoda‐ku, Tokyo, Japan
- 10Pediatric Infectious Diseases, University Children's Hospital Mannheim, Heidelberg University, Mannheim, Germany
- 11Department of Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
- ↵*Corresponding author. Tel: +1 215 955 8017; E‐mail: arie.horowitz{at}jefferson.edu
Dysfunction of the choroid plexus (CP) is a likely cause of hydrocephalus, but the underlying pathophysiological and molecular mechanisms remain unclear. Depletion of Mpdz, a cell junction protein, is shown here to induce paracellular and transcellular hyperpermeability of the CP in mice.
Synopsis
Dysfunction of the choroid plexus (CP) is a likely cause of hydrocephalus, but the underlying pathophysiological and molecular mechanisms remain unclear. Depletion of Mpdz, a cell junction protein, is shown here to induce paracellular and transcellular hyperpermeability of the CP in mice.
Contrast medium leaks from the choroid plexus into the lateral ventricles of Mpdz−/− mice.
Transmitted electron microscopy (TEM) of the CP of Mpdz−/− mice shows that intercellular junctions between the CP epithelial cells (CPECs) are structurally defective.
The receptor to low‐density lipoprotein is overabundant in CPECs of Mpdz−/− mice by approximately 40%, and its constitutive transcytosis higher by more than 50% compared to CPECs of Mpdz+/+ mice.
Fluid‐phase uptake is approximately two‐fold higher than Mpdz+/+ mice.
Comparative proteomic analysis of the cerebrospinal fluid of Mpdz+/+ and Mpdz−/− mice finds protein overabundance in the latter, including more than 50‐fold abundance of ApoE.
EMBO Mol Med (2018) e9540
- Received July 11, 2018.
- Revision received November 6, 2018.
- Accepted November 9, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- A dual‐AAV approach restores fast exocytosis and partially rescues auditory function in deaf otoferlin knock‐out mice
- Hanan Al‐Moyed1,2,
- Andreia P Cepeda1,2,
- SangYong Jung3,4,
- Tobias Moser2,3,4,
- Sebastian Kügler (sebastian.kuegler{at}med.uni-goettingen.de)*,5 and
- Ellen Reisinger (ellen.reisinger{at}med.uni-goettingen.de)*,1
- 1Molecular Biology of Cochlear Neurotransmission Group, Department of Otorhinolaryngology, University Medical Center Göttingen, and Collaborative Research Center 889, University of Göttingen, Göttingen, Germany
- 2Göttingen Graduate School for Neurosciences, Biophysics, and Molecular Biosciences, University of Göttingen, Göttingen, Germany
- 3Institute for Auditory Neurosciences and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany
- 4Synaptic Nanophysiology Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
- 5Center Nanoscale Microscopy and Physiology of the Brain (CNMPB), Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
- ↵*
Corresponding author. Tel: +49 551 39 8351; E‐mail: sebastian.kuegler{at}med.uni-goettingen.de
Corresponding author. Tel: +49 551 39 9688; E‐mail: ellen.reisinger{at}med.uni-goettingen.de
Gene delivery of large genes exceeding the packing capacity of a single adeno‐associated virus (AAV) is challenging. Split‐AAV vectors can bypass this problem. This work offers the first application of split‐AAV gene therapy to the inner ear to restore hearing in a genetically deaf mouse model.
Synopsis
Gene delivery of large genes exceeding the packing capacity of a single adeno‐associated virus (AAV) is challenging. Split‐AAV vectors can bypass this problem. This work offers the first application of split‐AAV gene therapy to the inner ear to restore hearing in a genetically deaf mouse model.
The 6 kb‐long otoferlin coding sequence was split into two fragments and packaged into two separate AAV2/6 viruses which were co‐injected into cochleae of otoferlin knock‐out mice.
Both the dual‐AAV trans‐splicing and the hybrid strategy led to re‐assembly of the two otoferlin cDNA fragments and expression of full‐length otoferlin.
Otoferlin expression from dual‐AAVs was restricted to hair cells and reached ˜30% of wild type otoferlin protein levels in inner hair cells.
In inner hair cells, fast exocytosis of the readily releasable pool of vesicles was fully recovered, and vesicle replenishment was restored to 35–50% of wild‐type controls.
Auditory brainstem responses were present albeit with reduced wave amplitudes in dual‐AAV transduced otoferlin knock‐out mice and indicated hearing thresholds of 40–60 dB.
EMBO Mol Med (2018) e9396
- Received June 3, 2018.
- Revision received November 9, 2018.
- Accepted November 12, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- β‐RA reduces DMQ/CoQ ratio and rescues the encephalopathic phenotype in Coq9R239X mice
- Agustín Hidalgo‐Gutiérrez1,2,
- Eliana Barriocanal‐Casado1,2,
- Mohammed Bakkali3,
- M Elena Díaz‐Casado1,2,
- Laura Sánchez‐Maldonado1,2,
- Miguel Romero4,
- Ramy K Sayed2,5,
- Cornelia Prehn6,
- Germaine Escames1,2,7,
- Juan Duarte4,
- Darío Acuña‐Castroviejo1,2,7 and
- Luis C López (luisca{at}ugr.es)*,1,2,7
- 1Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain
- 2Instituto de Biotecnología, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain
- 3Departamento de Genética, Facultad de Ciencias, Universidad de Granada, Granada, Spain
- 4Departamento de Farmacología, Facultad de Farmacia, Universidad de Granada, Granada, Spain
- 5Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Sohag University, Sohag, Egypt
- 6Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg, Germany
- 7Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Granada, Spain
- ↵*Corresponding author. Tel: +34 958241000 ext. 20197; E‐mail: luisca{at}ugr.es
This study proposes a powerful therapy for COQ9 or COQ7 deficiencies. The novel therapeutic strategy is based on oral administration of β‐RA, showing superior outcomes to those obtained after oral CoQ10 supplementation, as demonstrated in the mitochondrial encephalopathy Coq9R239X mouse model.
Synopsis
This study proposes a powerful therapy for COQ9 or COQ7 deficiencies. The novel therapeutic strategy is based on oral administration of β‐RA, showing superior outcomes to those obtained after oral CoQ10 supplementation, as demonstrated in the mitochondrial encephalopathy Coq9R239X mouse model.
The DMQ/CoQ ratio was revealed as an important factor in the pathologic features of CoQ deficiency syndrome.
A powerful therapy was provided for patients with mutations in COQ9 or COQ7.
The specific therapeutic mechanisms of β‐RA in the Coq9R239X mouse model were demonstrated, opening the potential application of 4‐HB analogs to other forms of CoQ deficiencies.
Potential endocrine interactions were suggested as crucial factors in mitochondrial encephalopathies.
EMBO Mol Med (2018) e9466
- Received June 23, 2018.
- Revision received October 23, 2018.
- Accepted October 26, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Rescuing ocular development in an anophthalmic pig by blastocyst complementation
- Hongyong Zhang1,2,3,†,
- Jiaojiao Huang1,2,3,†,
- Zechen Li4,†,
- Guosong Qin1,2,3,
- Nan Zhang1,
- Tang Hai1,2,3,
- Qianlong Hong1,
- Qiantao Zheng1,2,3,
- Ying Zhang1,2,3,
- Ruigao Song1,2,3,
- Jing Yao1,2,3,
- Chunwei Cao1,2,3,
- Jianguo Zhao (zhaojg{at}ioz.ac.cn)*,1,2,3 and
- Qi Zhou (qzhou{at}ioz.ac.cn)*,1,2,3
- 1State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- 2Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
- 3Institute of Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- 4College of Life Sciences Qufu Normal University, Qufu, China
- ↵*
Corresponding author. Tel: +86 10 64806259; E‐mail: zhaojg{at}ioz.ac.cn
Corresponding author. Tel: +86 10 64806299; E‐mail: qzhou{at}ioz.ac.cn
↵† These authors contributed equally to this work
Blastocyst complementation is a new route for regenerating allogeneic organs in pigs for xenotransplantation, but reconstituting complicated organs, like a whole eye, was never done up to now. This strategy offers potentials for generating personalized human patient‐specific organs in large animals.
Synopsis
Blastocyst complementation is a new route for regenerating allogeneic organs in pigs for xenotransplantation, but reconstituting complicated organs, like a whole eye, was never done up to now. This strategy offers potentials for generating personalized human patient‐specific organs in large animals.
Intact allogenic eyes can be regenerated using exogenous blastocyst complementation in an anophthalmic pig model.
Porcine RPEs are isolated and cultured in vitro from 60‐day chimeric foetuses.
The chimeric pig with regenerated eyes was derived from the somatic cloned blastocyst complementation and developed to full term.
EMBO Mol Med (2018) 10: e8861
- Received January 11, 2018.
- Revision received October 8, 2018.
- Accepted October 11, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- TUBB1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology
- Athanasia Stoupa1,2,3,4,
- Frédéric Adam5,
- Dulanjalee Kariyawasam3,4,
- Catherine Strassel6,
- Sanjay Gawade7,
- Gabor Szinnai7,8,
- Alexandre Kauskot5,
- Dominique Lasne5,9,
- Carsten Janke10,11,
- Kathiresan Natarajan10,11,20,
- Alain Schmitt1,
- Christine Bole‐Feysot12,
- Patrick Nitschke13,
- Juliane Léger3,14,15,16,
- Fabienne Jabot‐Hanin13,
- Frédéric Tores13,
- Anita Michel6,
- Arnold Munnich17,18,
- Claude Besmond17,
- Raphaël Scharfmann1,
- François Lanza6,
- Delphine Borgel5,9,
- Michel Polak1,2,3,4,19 and
- Aurore Carré (aurore.carre{at}inserm.fr)*,1,2,3
- 1INSERM U1016, Faculté de Médecine, Cochin Institute, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
- 2IMAGINE Institute Affiliate, Paris, France
- 3RARE Disorder Center: Centre des Maladies Endocriniennes Rares de la Croissance et du Développement, Paris, France
- 4Pediatric Endocrinology, Gynecology and Diabetology Unit, Hôpital Universitaire Necker‐Enfants Malades, AP‐HP, Paris, France
- 5INSERM UMR_S1176, Paris‐Sud University, Université Paris‐Saclay, Le Kremlin‐Bicêtre, France
- 6INSERM, EFS Grand Est, BPPS UMR‐S 1255, FMTS, Université de Strasbourg, Strasbourg, France
- 7Department of Biomedicine, Pediatric Immunology, University of Basel, Basel, Switzerland
- 8Pediatric Endocrinology, University Children's Hospital Basel, University of Basel, Basel, Switzerland
- 9Necker Children's Hospital, Biological Hematology Service, Assistance Publique—Hôpitaux de Paris, Paris, France
- 10Institut Curie, CNRS UMR3348, PSL Research University, Orsay, France
- 11Institut Curie, CNRS UMR3348, Université Paris Sud, Université Paris‐Saclay, Orsay, France
- 12Genomic Platform, INSERM UMR 1163, IMAGINE Institute, Paris Descartes University, Sorbonne Paris Cité, Paris, France
- 13Bioinformatics Platform, IMAGINE Institute, Paris Descartes University, Paris, France
- 14Pediatric Endocrinology Unit, Hôpital Universitaire Robert Debré, AP‐HP, Paris, France
- 15Paris Diderot University, Sorbonne Paris Cité, Paris, France
- 16INSERM UMR 1141, DHU Protect, Paris, France
- 17INSERM U1163, IMAGINE Institute, Translational Genetics, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
- 18Department of Genetics, Hôpital Universitaire Necker‐Enfants Malades, AP‐HP, Paris, France
- 19Fédération Parisienne pour le Dépistage et la Prévention des Handicaps de l'Enfant (FPDPHE), Paris, France
- 20Present Address: Physiology and Biomedical Engineering Department, Mayo Clinic, Rochester, MN, USA
- ↵*Corresponding author. Tel: +33 1 76 53 55 71; E‐mail: aurore.carre{at}inserm.fr
Whole‐exome sequencing in a consanguineous family with Congenital Hypothyroidism (CH) revealed a novel homozygous mutation in TUBB1, encoding for a member of beta‐tubulins, essential for microtubule organisation. Until now, TUBB1 mutations were only known to be involved in platelet disorders.
Synopsis
Whole‐exome sequencing in a consanguineous family with congenital hypothyroidism (CH) revealed a novel homozygous mutation in TUBB1, encoding for a member of beta‐tubulins, essential for microtubule organisation. Until now, TUBB1 mutations were only known to be involved in platelet disorders.
Two more mutations were identified in two distinct families with thyroid dysgenesis (TD) and abnormal platelet physiology, reinforcing the link between TUBB1 mutations and thyroid disease.
TUBB1 is expressed in the developing and adult thyroid in humans and mice.
Tubb1−/− mice have large platelets and show hypothyroidism with early thyroid progenitors proliferation defects, altered thyroid migration and failure of thyroid hormone synthesis.
Platelet findings concerned basal activation and increased aggregation.
These results expand our knowledge on genetic background of CH and TD.
EMBO Mol Med (2018) 10: e9569
- Received July 19, 2018.
- Revision received October 18, 2018.
- Accepted October 19, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Loss of the mitochondrial i‐AAA protease YME1L leads to ocular dysfunction and spinal axonopathy
- Hans‐Georg Sprenger1,2,
- Gulzar Wani2,
- Annika Hesseling2,
- Tim König2,4,
- Maria Patron1,2,
- Thomas MacVicar1,2,
- Sofia Ahola1,2,
- Timothy Wai2,5,6,
- Esther Barth2,
- Elena I Rugarli2,
- Matteo Bergami2,3 and
- Thomas Langer (langer{at}age.mpg.de)*,1,2,3
- 1Max‐Planck‐Institute for Biology of Ageing, Cologne, Germany
- 2Institute of Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging‐Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- 3Center for Molecular Medicine, University of Cologne, Cologne, Germany
- 4Present Address: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
- 5Present Address: Institut Pasteur, CNRS UMR 3691, Mitochondrial Biology Group, Paris, France
- 6Present Address: Sorbonne Paris Cité, Paris Descartes University, Paris, France
- ↵*Corresponding author. Tel: +49 221 37 970 500; E‐mail: langer{at}age.mpg.de
Novel mouse models demonstrate the importance of mitochondrial proteostasis for eye development and axonal maintenance in the spinal cord. Loss of the mitochondrial protease YME1L induces cell‐specific neurodegeneration independently of respiratory chain defects and mitochondria fragmentation.
Synopsis
Novel mouse models demonstrate the importance of mitochondrial proteostasis for eye development and axonal maintenance in the spinal cord. Loss of the mitochondrial protease YME1L induces cell‐specific neurodegeneration independently of respiratory chain defects and mitochondria fragmentation.
Mice lacking YME1L in the nervous system (NYKO mice) show microphthalmia with cataracts and late‐onset degeneration of spinal cord axons involved in proprioception.
YME1L regulates anterograde axonal transport of mitochondria in cultured neurons.
Loss of the mitochondrial protease OMA1 in NYKO mice suppresses aberrant OPA1 processing and mitochondrial fragmentation, but not neurodegeneration in absence of YME1L.
OMA1 exerts pro‐survival functions and delays the degeneration of YME1L‐ deficient neurons.
EMBO Mol Med (2018) e9288
- Received May 1, 2018.
- Revision received October 4, 2018.
- Accepted October 8, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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