1. Mutations in BCAP31 Cause a Severe X-Linked Phenotype with Deafness, Dystonia, and Central Hypomyelination and Disorganize the Golgi Apparatus
- Author
-
Odile Boespflug-Tanguy, Jean-Pierre Desvignes, Ana Borges-Correia, Imen Dorboz, Marc Delepine, Nadine Girard, Laurent Villard, Pierre Sarda, Jean-Christophe Roux, Catherine Badens, Pierre Cacciagli, Pierre Cau, Julie Sutera-Sardo, Mark Lathrop, Nicolas Lévy, Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Centre de référence maladie rare Thalassémie, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Département de génétique médicale [Hôpital de la Timone - APHM], Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de Génotypage (CNG), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU de Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Villard, Laurent, and Medical Genomics - - GENMED2010 - ANR-10-LABX-0013 - LABX - VALID
- Subjects
Male ,Programmed cell death ,Golgi Apparatus ,Deafness ,[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics ,Biology ,Young Adult ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Report ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetics(clinical) ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Child ,Cell Shape ,Myelin Sheath ,Genetics (clinical) ,030304 developmental biology ,Dystonia ,0303 health sciences ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Endoplasmic reticulum ,Infant ,Membrane Proteins ,Genetic Diseases, X-Linked ,Fibroblasts ,Golgi apparatus ,16. Peace & justice ,medicine.disease ,Phenotype ,Pedigree ,Crosstalk (biology) ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Membrane protein ,Child, Preschool ,Mutation ,Unfolded protein response ,symbols ,Female ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,030217 neurology & neurosurgery - Abstract
International audience; BAP31 is one of the most abundant endoplasmic reticulum (ER) membrane proteins. It is a chaperone protein involved in several pathways , including ER-associated degradation, export of ER proteins to the Golgi apparatus, and programmed cell death. BAP31 is encoded by BCAP31, located in human Xq28 and highly expressed in neurons. We identified loss-of-function mutations in BCAP31 in seven individuals from three families. These persons suffered from motor and intellectual disabilities, dystonia, sensorineural deafness, and white-matter changes, which together define an X-linked syndrome. In the primary fibroblasts of affected individuals, we found that BCAP31 deficiency altered ER morphology and caused a disorganization of the Golgi apparatus in a significant proportion of cells. Contrary to what has been described with transient-RNA-interference experiments, we demonstrate that constitutive BCAP31 deficiency does not activate the unfolded protein response or cell-death effectors. Rather, our data demonstrate that the lack of BAP31 disturbs ER metabolism and impacts the Golgi apparatus, highlighting an important role for BAP31 in ER-to-Golgi crosstalk. These findings provide a molecular basis for a Mendelian syndrome and link intracellular protein trafficking to severe congenital brain dysfunction and deafness.
- Published
- 2013
- Full Text
- View/download PDF