Skip to Main content Skip to Navigation
Journal articles

Mutations in BCAP31 Cause a Severe X-Linked Phenotype with Deafness, Dystonia, and Central Hypomyelination and Disorganize the Golgi Apparatus

Pierre Cacciagli 1 Julie Sutera-Sardo 1 Ana Borges-Correia 1 Jean-Christophe Roux 1 Imen Dorboz 2 Jean-Pierre Desvignes 1 Catherine Badens 3, 1, 4 Marc Délépine 5 Mark Lathrop 6 Pierre Cau 1 Nicolas Lévy 1, 4 Nadine Girard 7 Pierre Sarda 8 Odile Boespflug-Tanguy 9 Laurent Villard 1, *
* Corresponding author
1 GMGF - Génétique Médicale et Génomique Fonctionnelle
2 PROTECT - Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies
3 Centre de référence maladie rare Thalassémie
4 Département de génétique médicale [Hôpital de la Timone - APHM]
5 CEA - Commissariat à l'énergie atomique et aux énergies alternatives
6 CNG - Centre National de Génotypage
7 TIMONE - Hôpital de la Timone [CHU - APHM]
8 CHU de Montpellier
9 GReD - Génétique, Reproduction et Développement
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.
Document type :
Journal articles
Complete list of metadata

Cited literature [18 references]  Display  Hide  Download
https://hal-amu.archives-ouvertes.fr/hal-01668665
Contributor : Laurent Villard Connect in order to contact the contributor
Submitted on : Friday, March 23, 2018 - 4:52:06 PM
Last modification on : Tuesday, April 20, 2021 - 11:22:02 AM
Long-term archiving on: : Tuesday, September 11, 2018 - 9:28:25 AM

File

Vignette du document
PIIS0002929713003431_biffé.p...
Files produced by the author(s)

Identifiers

Collections

UNIV-AMU | GRED | CEA-DRF | JACOB | PRES_CLERMONT | MMG | USPC | CEA | UNIV-PARIS7 | CNRS | ACL-SVSAE | INSERM | PHARMA-AMU | UNIV-PARIS

Citation

Pierre Cacciagli, Julie Sutera-Sardo, Ana Borges-Correia, Jean-Christophe Roux, Imen Dorboz, et al.. Mutations in BCAP31 Cause a Severe X-Linked Phenotype with Deafness, Dystonia, and Central Hypomyelination and Disorganize the Golgi Apparatus. American Journal of Human Genetics, Elsevier (Cell Press), 2013, 93, pp.579-586. ⟨10.1016/j.ajhg.2013.07.023⟩. ⟨hal-01668665⟩

Export

BibTeX TEI DC DCterms EndNote

Share

Metrics

Record views

1204

Files downloads

1032