title: Dymeclin deficiency causes postnatal microcephaly, hypomyelination and reticulum-to-Golgi trafficking defects in mice and humans.
abstract: Dymeclin is a Golgi-associated protein whose deficiency causes Dyggve-Melchior-Clausen syndrome (DMC, MIM #223800), a rare recessively inherited spondyloepimetaphyseal dysplasia consistently associated with postnatal microcephaly and intellectual disability. While the skeletal phenotype of DMC patients has been extensively described, very little is known about their cerebral anomalies, which result in brain growth defects and cognitive dysfunction. We used Dymeclin-deficient mice to determine the cause of microcephaly and to identify defective mechanisms at the cellular level. Brain weight and volume were reduced in all mutant mice from postnatal day 5 onward. Mutant mice displayed a narrowing of the frontal cortex, although cortical layers were normally organized. Interestingly, the corpus callosum was markedly thinner, a characteristic we also identified in DMC patients. Consistent with this, the myelin sheath was thinner, less compact and not properly rolled, while the number of mature oligodendrocytes and their ability to produce myelin basic protein were significantly decreased. Finally, cortical neurons from mutant mice and primary fibroblasts from DMC patients displayed substantially delayed endoplasmic reticulum to Golgi trafficking, which could be fully rescued upon Dymeclin re-expression. These findings indicate that Dymeclin is crucial for proper myelination and anterograde neuronal trafficking, two processes that are highly active during postnatal brain maturation.
authors: Inserm, U1141, Paris, France, Sorbonne Paris Cité, Univ Paris Diderot, UMRS 1141, Paris, France.
authors: Nina
authors: N
authors: Dupuis
authors: Inserm, U1141, Paris, France, Sorbonne Paris Cité, Univ Paris Diderot, UMRS 1141, Paris, France.
authors: Assia
authors: A
authors: Fafouri
authors: Inserm, U1141, Paris, France, Sorbonne Paris Cité, Univ Paris Diderot, UMRS 1141, Paris, France.
authors: Aurélien
authors: A
authors: Bayot
authors: Inserm, U1141, Paris, France, Sorbonne Paris Cité, Univ Paris Diderot, UMRS 1141, Paris, France.
authors: Manoj
authors: M
authors: Kumar
authors: Inserm, U1141, Paris, France, Sorbonne Paris Cité, Univ Paris Diderot, UMRS 1141, Paris, France.
authors: Tifenn
authors: T
authors: Lecharpentier
authors: Centre for the Developing Brain, Department of Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, UK.
authors: Gareth
authors: G
authors: Ball
authors: Centre for the Developing Brain, Department of Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, UK.
authors: David
authors: D
authors: Edwards
authors: CNRS UMR7224, Inserm, U952, Paris, France, Univ Pierre et Marie Curie, Paris, France.
authors: Véronique
authors: V
authors: Bernard
authors: Inserm, U1141, Paris, France, Sorbonne Paris Cité, Univ Paris Diderot, UMRS 1141, Paris, France.
authors: Pascal
authors: P
authors: Dournaud
authors: Inserm, U1141, Paris, France, Sorbonne Paris Cité, Univ Paris Diderot, UMRS 1141, Paris, France, Service de Génétique Clinique, AP-HP, Hôpital Robert Debré, Paris, France.
authors: Séverine
authors: S
authors: Drunat
authors: Service de Neuropédiatrie, Hôpital Roger Salengro, Lille, France.
authors: Marie
authors: M
authors: Vermelle-Andrzejewski
authors: Medical Genetics Department, Hôpital Erasme, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors: Catheline
authors: C
authors: Vilain
authors: Medical Genetics Department, Hôpital Erasme, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors: Marc
authors: M
authors: Abramowicz
authors: Medical Genetics Department, Hôpital Erasme, Université Libre de Bruxelles (ULB), Brussels, Belgium, Institut de Pathologie et de Génétique, Gosselies, Belgium.
authors: Julie
authors: J
authors: Désir
authors: CNRS UMR3347, Orsay, France, Institut Curie, Centre de Recherche, Paris, France.
authors: Jacky
authors: J
authors: Bonaventure
authors: CNRS UMR144, Paris, France and Institut Curie, Centre de Recherche, Paris, France.
authors: Nelly
authors: N
authors: Gareil
authors: CNRS UMR144, Paris, France and Institut Curie, Centre de Recherche, Paris, France.
authors: Gaelle
authors: G
authors: Boncompain
authors: Inserm, U1141, Paris, France, Sorbonne Paris Cité, Univ Paris Diderot, UMRS 1141, Paris, France.
authors: Zsolt
authors: Z
authors: Csaba
authors: CNRS UMR144, Paris, France and Institut Curie, Centre de Recherche, Paris, France.
authors: Franck
authors: F
authors: Perez
authors: Inserm, U1141, Paris, France, Sorbonne Paris Cité, Univ Paris Diderot, UMRS 1141, Paris, France, Service de Génétique Clinique, AP-HP, Hôpital Robert Debré, Paris, France.
authors: Sandrine
authors: S
authors: Passemard
authors: Inserm, U1141, Paris, France, Sorbonne Paris Cité, Univ Paris Diderot, UMRS 1141, Paris, France, Centre for the Developing Brain, Department of Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, UK.
authors: Pierre
authors: P
authors: Gressens
authors: Inserm, U1141, Paris, France, Sorbonne Paris Cité, Univ Paris Diderot, UMRS 1141, Paris, France, vincent.elghouzzi@inserm.fr.
authors: Vincent
authors: V
authors: El Ghouzzi
mesh_terms: D000818:Animals; D002675:Child, Preschool; D015536:Down-Regulation; D004392:Dwarfism / Q000235:genetics*; D018870:Endoplasmic Reticulum, Rough / Q000378:metabolism; D005260:Female; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D008831:Microcephaly / Q000235:genetics*; D009154:Mutation; D009186:Myelin Sheath / Q000235:genetics / Q000502:physiology; D010009:Osteochondrodysplasias / Q000151:congenital* / Q000235:genetics; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D011506:Proteins / Q000235:genetics*
chemical_list: C477370:DYM protein, human; C532993:Dym protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011506:Proteins