Dataset Information

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.

SUBMITTER: Cacciagli P

PROVIDER: S-EPMC3769969 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mutations in BCAP31 cause a severe X-linked phenotype with deafness, dystonia, and central hypomyelination and disorganize the Golgi apparatus.

Cacciagli Pierre P Sutera-Sardo Julie J Borges-Correia Ana A Roux Jean-Christophe JC Dorboz Imen I Desvignes Jean-Pierre JP Badens Catherine C Delepine Marc M Lathrop Mark M Cau Pierre P Lévy Nicolas N Girard Nadine N Sarda Pierre P Boespflug-Tanguy Odile O Villard Laurent L

American journal of human genetics 20130901 3

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, sen ...[more]

PMID: 24011989

Similar Datasets

Project description:Autosomal-dominant, early-onset DYT1 dystonia is associated with an in-frame deletion of a glutamic acid codon (?E) in the TOR1A gene. The gene product, torsinA, is an evolutionarily conserved AAA+ ATPase. The fact that constitutive secretion from patient fibroblasts is suppressed indicates that the ?E-torsinA protein influences the cellular secretory machinery. However, which component is affected remains unclear. Prompted by recent reports that abnormal protein trafficking through the Golgi apparatus, the major protein-sorting center of the secretory pathway, is sometimes associated with a morphological change in the Golgi, we evaluated the influence of ?E-torsinA on this organelle. Specifically, we examined its structure by confocal microscopy, in cultures of striatal, cerebral cortical and hippocampal neurons obtained from wild-type, heterozygous and homozygous ?E-torsinA knock-in mice. In live neurons, the Golgi was assessed following uptake of a fluorescent ceramide analog, and in fixed neurons it was analyzed by immuno-fluorescence staining for the Golgi-marker GM130. Neither staining method indicated genotype-specific differences in the size, staining intensity, shape or localization of the Golgi. Moreover, no genotype-specific difference was observed as the neurons matured in vitro. These results were supported by a lack of genotype-specific differences in GM130 expression levels, as assessed by Western blotting. The Golgi was also disrupted by treatment with brefeldin A, but no genotype-specific differences were found in the immuno-fluorescence staining intensity of GM130. Overall, our results demonstrate that the ?E-torsinA protein does not drastically influence Golgi morphology in neurons, irrespective of genotype, brain region (among those tested), or maturation stage in culture. While it remains possible that functional changes in the Golgi exist, our findings imply that any such changes are not severe enough to influence its morphology to a degree detectable by light microscopy.

Dataset Information

Mutations in BCAP31 cause a severe X-linked phenotype with deafness, dystonia, and central hypomyelination and disorganize the Golgi apparatus.

Publications

Mutations in BCAP31 cause a severe X-linked phenotype with deafness, dystonia, and central hypomyelination and disorganize the Golgi apparatus.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets