title: Mutations in BCAP31 cause a severe X-linked phenotype with deafness, dystonia, and central hypomyelination and disorganize the Golgi apparatus.
abstract: 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.
authors.affiliation: INSERM UMR-S 910, Faculté de Médecine Timone, Aix-Marseille Universite, Marseille, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cacciagli
authors.forename: Julie
authors.initials: J
authors.lastname: Sutera-Sardo
authors.forename: Ana
authors.initials: A
authors.lastname: Borges-Correia
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Roux
authors.forename: Imen
authors.initials: I
authors.lastname: Dorboz
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Desvignes
authors.forename: Catherine
authors.initials: C
authors.lastname: Badens
authors.forename: Marc
authors.initials: M
authors.lastname: Delepine
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Pierre
authors.initials: P
authors.lastname: Cau
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lévy
authors.forename: Nadine
authors.initials: N
authors.lastname: Girard
authors.forename: Pierre
authors.initials: P
authors.lastname: Sarda
authors.forename: Odile
authors.initials: O
authors.lastname: Boespflug-Tanguy
authors.forename: Laurent
authors.initials: L
authors.lastname: Villard
mesh_terms: D048430:Cell Shape; D002648:Child; D002675:Child, Preschool; D003638:Deafness / Q000150:complications / Q000235:genetics*; D004421:Dystonia / Q000150:complications / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000473:pathology / Q000648:ultrastructure; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006056:Golgi Apparatus / Q000473:pathology* / Q000648:ultrastructure; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009186:Myelin Sheath / Q000473:pathology* / Q000648:ultrastructure; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
chemical_list: C091247:BCAP31 protein, human; D008565:Membrane Proteins