Search results for "Vesicular Transport Proteins"
showing 10 items of 28 documents
Neuronal inhibition of the autophagy nucleation complex extends life span in post-reproductive C. elegans
2017
Autophagy is a ubiquitous catabolic process that causes cellular bulk degradation of cytoplasmic components and is generally associated with positive effects on health and longevity. Inactivation of autophagy has been linked with detrimental effects on cells and organisms. The antagonistic pleiotropy theory postulates that some fitness-promoting genes during youth are harmful during aging. On this basis, we examined genes mediating post-reproductive longevity using an RNAi screen. From this screen, we identified 30 novel regulators of post-reproductive longevity, including pha-4. Through downstream analysis of pha-4, we identified that the inactivation of genes governing the early stages of…
A TRAPPC6B splicing variant associates to restless legs syndrome
2016
Abstract INTRODUCTION: RLS is a common movement disorders with a strong genetic component in its pathophysiology, but, up to now, no causative mutation has been reported. METHODS: We re-evaluated the previously described RLS2 family by exome sequencing. RESULTS: We identified fifteen variations in the 14q critical region. The c.485G > A transition of the TRAPPC6B gene segregates with the RLS2 haplotype, is absent in 200 local controls and is extremely rare in 12988 exomes from the Exome Variant Server (EVS). This variant alters a splicing site and hampers the normal transcript processing by promoting exon 3-skipping as demonstrated by minigene transfection and by patient transcripts. CON…
Hepatitis B Virus Exploits ERGIC-53 in Conjunction with COPII to Exit Cells.
2020
Several decades after its discovery, the hepatitis B virus (HBV) still displays one of the most successful pathogens in human populations worldwide. The identification and characterization of interactions between cellular and pathogenic components are essential for the development of antiviral treatments. Due to its small-sized genome, HBV highly depends on cellular functions to produce and export progeny particles. Deploying biochemical-silencing methods and molecular interaction studies in HBV-expressing liver cells, we herein identified the cellular ERGIC-53, a high-mannose-specific lectin, and distinct components of the endoplasmic reticulum (ER) export machinery COPII as crucial factor…
Small Rab GTPases in Intracellular Vesicle Trafficking: The Case of Rab3A/Raphillin-3A Complex in the Kidney
2021
Small Rab GTPases, the largest group of small monomeric GTPases, regulate vesicle trafficking in cells, which are integral to many cellular processes. Their role in neurological diseases, such as cancer and inflammation have been extensively studied, but their implication in kidney disease has not been researched in depth. Rab3a and its effector Rabphillin-3A (Rph3A) expression have been demonstrated to be present in the podocytes of normal kidneys of mice rats and humans, around vesicles contained in the foot processes, and they are overexpressed in diseases with proteinuria. In addition, the Rab3A knockout mice model induced profound cytoskeletal changes in podocytes of high glucose fed a…
Cohen Syndrome-Associated Cataract Is Explained by VPS13B Functions in Lens Homeostasis and Is Modified by Additional Genetic Factors
2020
International audience; Purpose: Cohen syndrome (CS) is a rare genetic disorder caused by variants of the VPS13B gene. CS patients are affected with a severe form of retinal dystrophy, and in several cases cataracts also develop. The purpose of this study was to investigate the mechanisms and risk factors for cataract in CS, as well as to report on cataract surgeries in CS patients.Methods: To understand how VPS13B is associated with visual impairments in CS, we generated the Vps13b∆Ex3/∆Ex3 mouse model. Mice from 1 to 3 months of age were followed by ophthalmoscopy and slit-lamp examinations. Phenotypes were investigated by histology, immunohistochemistry, and western blot. Literature anal…
Sporadic ALS is not associated with VAPB gene mutations in Southern Italy
2006
Abstract Mutations in the Cu/Zn superoxide dismutase (Sod1) gene have been reported to cause adult-onset autosomal dominant Amyotrophic Lateral Sclerosis (FALS). In sporadic cases (SALS) de novo mutations in the Sod1 gene have occasionally been observed. The recent finding of a mutation in the VAMP/synaptobrevin-associated membrane protein B (VAPB) gene as the cause of amyotrophic lateral sclerosis (ALS8), prompted us to investigate the entire coding region of this gene in SALS patients. One hundred twenty-five unrelated patients with adult-onset ALS and 150 healthy sex-age-matched subjects with the same genetic background were analyzed. Genetic analysis for all exons of the VAPB gene by DH…
Congenital neutropenia with retinopathy, a new phenotype without intellectual deficiency or obesity secondary toVPS13Bmutations
2013
Over one hundred VPS13B mutations are reported in Cohen syndrome (CS). Most cases exhibit a homogeneous phenotype that includes intellectual deficiency (ID), microcephaly, facial dysmorphism, slender extremities, truncal obesity, progressive chorioretinal dystrophy, and neutropenia. We report on a patient carrying two VPS13B splicing mutations with an atypical phenotype that included microcephaly, retinopathy, and congenital neutropenia, but neither obesity nor ID. RNA analysis of the IVS34+2T_+3AinsT mutation did not reveal any abnormal splice fragments but mRNA quantification showed a significant decrease in VPS13B expression. RNA sequencing analysis up- and downstream from the IVS57+2T>C…
Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas
2007
AbstractIntegrative genomic and gene-expression analyses have identified amplified oncogenes in B-cell non-Hodgkin lymphoma (B-NHL), but the capability of such technologies to localize tumor suppressor genes within homozygous deletions remains unexplored. Array-based comparative genomic hybridization (CGH) and gene-expression microarray analysis of 48 cell lines derived from patients with different B-NHLs delineated 20 homozygous deletions at 7 chromosome areas, all of which contained tumor suppressor gene targets. Further investigation revealed that only a fraction of primary biopsies presented inactivation of these genes by point mutation or intragenic deletion, but instead some of them w…
Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy
2013
Vici syndrome is a recessively inherited multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. To investigate the molecular basis of Vici syndrome, we carried out exome and Sanger sequence analysis in a cohort of 18 affected individuals. We identified recessive mutations in EPG5 (previously KIAA1632), indicating a causative role in Vici syndrome. EPG5 is the human homolog of the metazoan-specific autophagy gene epg-5, encoding a key autophagy regulator (ectopic P-granules autophagy protein 5) implicated in the formation of autolysosomes. Further studies showed a severe block in autophagosomal clearance in muscle a…
Soluble N-ethylmaleimide-sensitive-factor attachment protein and N-ethylmaleimide-insensitive factors are required for Ca2+-stimulated exocytosis of …
1996
Ca2+ stimulates exocytosis in permeabilized insulin-secreting cells. To investigate the putative cytosolic components involved in the Ca2+ response, HIT-T15 cells (a pancreatic B-cell line) were permeabilized with streptolysin-O, a procedure that allows rapid exchange of soluble components including macromolecules. We found that in this cell preparation the secretory response to Ca2+ but not to guanosine 5'-[gamma-thio]triphosphate was lost as a function of time and could be restored by rat brain cytosol in a concentration-dependent manner. Reconstitutive activity of rat brain cytosol was found in a high-molecular-mass heat-labile partially N-ethylmaleimide(NEM)-sensitive fraction. The NEM-…