The gene responsible for Dyggve-Melchior-Clausen syndrome encodes a novel peripheral membrane protein dynamically associated with the Golgi apparatus

Autor: Graça Raposo, Zsolt Csaba, Ariane Dimitrov, Ole Vielemeyer, Pierre Gressens, Pierre Rustin, Valérie Cormier-Daire, Franck Perez, Charles Gueudry, Vincent Paupe, Tania Attié-Bitach, Jean-Baptiste Sibarita, Thierry Gilbert, Vincent El Ghouzzi
Přispěvatelé: Compartimentation et dynamique cellulaires (CDC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), Roper Scientific SARL, Roper Scientific, Interdisciplinary Institute for Neuroscience (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche, Institut Curie [Paris], Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), El Ghouzzi, Vincent
Rok vydání: 2008
Předmět:
[SDV]Life Sciences [q-bio]
Dwarfism
[SDV.GEN] Life Sciences [q-bio]/Genetics
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics
Biology
Cell Line
Green fluorescent protein
03 medical and health sciences
symbols.namesake
Cytosol
0302 clinical medicine
Genetics
Humans
[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
[SDV.BC] Life Sciences [q-bio]/Cellular Biology
Molecular Biology
Genetics (clinical)
Secretory pathway
030304 developmental biology
[SDV.GEN]Life Sciences [q-bio]/Genetics
0303 health sciences
myristoylation
Peripheral membrane protein
Intracellular Signaling Peptides and Proteins
Brain
Membrane Proteins
Proteins
General Medicine
Golgi apparatus
Embryo
Mammalian
Molecular biology
Transmembrane protein
Transport protein
[SDV] Life Sciences [q-bio]
Protein Transport
Transmembrane domain
nocodazole
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics
Membrane protein
Dymeclin
Mutation
DMC syndrome
FRAP
symbols
[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
030217 neurology & neurosurgery
Zdroj: Human Molecular Genetics
Human Molecular Genetics, Oxford University Press (OUP), 2009, 18 (3), pp.440-453. ⟨10.1093/hmg/ddn371⟩
Human Molecular Genetics, 2009, 18 (3), pp.440-453. ⟨10.1093/hmg/ddn371⟩
ISSN: 1460-2083
0964-6906
DOI: 10.1093/hmg/ddn371
Popis: International audience; Dyggve-Melchior-Clausen dysplasia (DMC) is a rare inherited dwarfism with severe mental retardation due to mutations in the DYM gene which encodes Dymeclin, a 669-amino acid protein of yet unknown function. Despite a high conservation across species and several predicted transmembrane domains, Dymeclin could not be ascribed to any family of proteins. Here we show, using in situ hybridization, that DYM is widely expressed in human embryos, especially in the cortex, the hippocampus and the cerebellum. Both the endogenous and the recombinant protein fused to green fluorescent protein co-localized with Golgi apparatus markers. Electron microscopy revealed that Dymeclin associates with the Golgi apparatus and with transitional vesicles of the reticulum-Golgi interface. Moreover, permeabilization assays revealed that Dymeclin is not a transmembrane but a peripheral protein of the Golgi apparatus as it can be completely released from the Golgi after permeabilization of the plasma membrane. Time lapse confocal microscopy experiments on living cells further showed that the protein shuttles between the cytosol and the Golgi apparatus in a highly dynamic manner and recognizes specifically a subset of mature Golgi membranes. Finally, we found that DYM mutations associated with DMC result in mis-localization and subsequent degradation of Dymeclin. These data indicate that DMC results from a loss-of-function of Dymeclin, a novel peripheral membrane protein which shuttles rapidly between the cytosol and mature Golgi membranes and point out a role of Dymeclin in cellular trafficking.
Databáze: OpenAIRE
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