Abstract 3665: COL4A1 and COL4A2 Mutations cause Genetically Modifiable Cerebrovascular Diseases

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Marion Jeanne ◽  
Yi-Chinn Weng ◽  
Michelle de Leau ◽  
Cassandre Labelle-Dumais ◽  
Berkeley W Kauffman ◽  
...  
Keyword(s):  
Er Stress ◽  
Cell Biology ◽  
Phenotypic Variability ◽  
Cerebrovascular Diseases ◽  
Basement Membranes ◽  
Mutant Mice ◽  
Genetic Modifiers ◽  
Cellular Mechanisms ◽  
Cerebral Magnetic Resonance Imaging ◽  
Genetic Context

Mutations in the type IV collagen alpha 1 gene (COL4A1) cause Cerebrovascular Diseases (CVDs) in mice and human patients. Patients with COL4A1 mutations suffer from a broad range of CVDs, from infantile porencephaly to debilitating or fatal intracerebral hemorrhage (ICH), to subclinical cerebral microbleeds, suggesting that environmental and other genetic factors may influence their phenotypes. COL4A1 is one of the most abundant proteins in basement membranes and forms heterotrimers with COL4A2. Among possible pathogenic mechanisms are cellular stress due to the toxic intracellular aggregation of the COL4A1 and COL4A2 proteins and/or their absence in the basement membrane. Our first goal is to identify the relative contributions of COL4A1 and COL4A2 mutations to sporadic ICH and to understand the cellular mechanisms and genetic complexity underlying the disease. We identified novel COL4A1 mutations and for the first time, we discovered COL4A2 mutations in a cohort of 96 patients with sporadic ICH. Using a cell-based assay we determined that the mutations impair COL4A1 and COL4A2 secretion. We showed that mutant COL4A1 or COL4A2 proteins accumulate within the cell where they titrate normal COL4A1 and COL4A2 proteins. Interestingly, we found that some of the mutations can ultimately result in endoplasmic reticulum (ER) stress and activation of the Unfolded Protein Response. Our second goal was to test the hypothesis that differences in genetic context could contribute to phenotypic variability in human patients. Thus, we characterized CVD in Col4a1 mutant mice with two different genetic backgrounds. Using cerebral magnetic resonance imaging and histological analysis, we show that one or more genetic modifiers from the CAST/EiJ strain significantly reduce the size and frequency of ICHs detected in Col4a1 mutant mice on a C57BL/6J background. In conclusion, we found that both COL4A1 and COL4A2 mutations cause ICH in human patients, our results support that ER stress could be involved in the pathogenesis and we showed that genetic context is crucial for expressivity and severity of the CVD. We predict that ongoing experiments to better understand the cell biology of COL4A1 and COL4A2 mutations and the mechanisms of genetic modification could lead to targeted therapeutics to reduce the risk of CVD in patients with COL4A1 or COL4A2 mutations.

scholarly journals Macropinocytosis and Clathrin-Dependent Endocytosis Play Pivotal Roles for the Infectious Entry of Puumala Virus

2019 ◽  
Author(s):  
Sandy Bauherr ◽  
Filip Larsberg ◽  
Annett Petrich ◽  
Hannah Sabeth Sperber ◽  
Victoria Klose ◽  
...  
Keyword(s):  
Rna Interference ◽  
Cell Biology ◽  
Mammalian Cells ◽  
Case Fatality ◽  
Hemorrhagic Fever ◽  
Puumala Virus ◽  
Virus Species ◽  
Global Public Health ◽  
Emerging Pathogens ◽  
Cellular Mechanisms

AbstractViruses from the taxonomic familyHantaviridaeare encountered as emerging pathogens causing two life-threatening human zoonoses: hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) with case fatalities of up to 50%. Here we comprehensively investigated entry of the Old-World Hantavirus, Puumala virus (PUUV), into mammalian cells, showing that upon treatment with pharmacological inhibitors of macropinocytosis and clathrin-mediated endocytosis, PUUV infections are significantly reduced. We demonstrated that the inhibitors did not interfere with viral replication and that RNA interference, targeting cellular mediators of macropinocytosis, is able to decrease PUUV infection levels significantly. Moreover, we established lipophilic tracer staining of PUUV virus particles and showed co-localization of stained virions and markers of macropinocytic uptake. Cells treated with lysosomotrophic agents were shown to exhibit an increased resistance to infection, confirming previous data suggesting that a low pH-dependent step is involved in PUUV infection. Finally, we observed a significant increase in the fluid-phase uptake of cell infected with PUUV, indicative of a virus-triggered promotion of macropinocytosis.Author SummaryTheHantaviridaefamily comprises a very diverse group of virus species and is considered an emerging global public health threat. Human pathogenic hantaviruses are primarily rodent-borne. Zoonosis is common with more than 150,000 annually registered cases and a case fatality index of up to 50%. Individual hantavirus species differ significantly in terms of their pathogenicity, but also their cell biology and host-pathogen interactions. In this study, we focused on the most prevalent pathogenic hantavirus in Europe, Puumala virus (PUUV), and investigated the entry and internalization of PUUV virions into mammalian cells. We showed that both, clathrin-mediated endocytosis and macropinocytosis, are cellular pathways exploited by the virus to establish productive infections and demonstrated that pharmacological inhibition of macropinocytosis or its targeted knockdown using RNA interference significantly reduced viral infections. We also found indications for an increase of macropinocytic uptake upon PUUV infections, suggesting that the virus triggers specific cellular mechanisms in order to promote its own internalization and facilitate infections.

scholarly journals Mycobacterium tuberculosis infection of host cells in space and time

2019 ◽  
Vol 43 (4) ◽  
pp. 341-361 ◽  
Author(s):  
Claudio Bussi ◽  
Maximiliano G Gutierrez
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Host Cell ◽  
Cell Biology ◽  
Current Knowledge ◽  
Bacterial Pathogen ◽  
Infectious Agent ◽  
Host Cells ◽  
Cellular Mechanisms ◽  
Mycobacterium Tuberculosis Infection ◽  
Human Host

ABSTRACTTuberculosis (TB) caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb) remains one of the deadliest infectious diseases with over a billion deaths in the past 200 years (Paulson 2013). TB causes more deaths worldwide than any other single infectious agent, with 10.4 million new cases and close to 1.7 million deaths in 2017. The obstacles that make TB hard to treat and eradicate are intrinsically linked to the intracellular lifestyle of Mtb. Mtb needs to replicate within human cells to disseminate to other individuals and cause disease. However, we still do not completely understand how Mtb manages to survive within eukaryotic cells and why some cells are able to eradicate this lethal pathogen. Here, we summarise the current knowledge of the complex host cell-pathogen interactions in TB and review the cellular mechanisms operating at the interface between Mtb and the human host cell, highlighting the technical and methodological challenges to investigating the cell biology of human host cell-Mtb interactions.

scholarly journals Occludin protects secretory cells from ER stress by facilitating SNARE-dependent apical protein exocytosis

2020 ◽  
Vol 117 (9) ◽  
pp. 4758-4769 ◽  
Author(s):  
Tao Zhou ◽  
Yunzhe Lu ◽  
Chongshen Xu ◽  
Rui Wang ◽  
Liye Zhang ◽  
...  
Keyword(s):  
Er Stress ◽  
Protein Secretion ◽  
Milk Proteins ◽  
Late Pregnancy ◽  
Mutant Mice ◽  
Snare Proteins ◽  
Secretory Cells ◽  
Tissue Polarity ◽  
Pregnancy And Lactation ◽  
Dependent Protein

Tight junctions (TJs) are fundamental features of both epithelium and endothelium and are indispensable for vertebrate organ formation and homeostasis. However, mice lackingOccludin(Ocln) develop relatively normally to term. Here we show thatOclnis essential for mammary gland physiology, as mutant mice fail to produce milk. Surprisingly,Oclnnull mammary glands showed intact TJ function and normal epithelial morphogenesis, cell differentiation, and tissue polarity, suggesting thatOclnis not required for these processes. Using single-cell transcriptomics, we identified milk-producing cells (MPCs) and found they were progressively more prone to endoplasmic reticulum (ER) stress as protein production increased exponentially during late pregnancy and lactation. Importantly,Oclnloss in MPCs resulted in greatly heightened ER stress; this in turn led to increased apoptosis and acute shutdown of protein expression, ultimately leading to lactation failure in the mutant mice. We show that the increased ER stress was caused by a secretory failure of milk proteins inOclnnull cells. Consistent with an essential role in protein secretion, Occludin was seen to reside on secretory vesicles and to be bound to SNARE proteins. Taken together, our results demonstrate thatOclnprotects MPCs from ER stress by facilitating SNARE-dependent protein secretion and raise the possibility that other TJ components may participate in functions similar toOcln.

scholarly journals Auxin cell biology in plant pattern formation

Botany ◽  
2017 ◽  
Vol 95 (4) ◽  
pp. 357-368 ◽  
Author(s):  
Adriana E. Caragea ◽  
Thomas Berleth
Keyword(s):  
Pattern Formation ◽  
Plant Development ◽  
Plant Tissue ◽  
Cell Biology ◽  
Cellular Mechanisms ◽  
Detailed Understanding ◽  
Vast Array ◽  
Genetics And Genomics ◽  
Resolution Cell ◽  
Early Establishment

Auxin has been implicated in a vast array of plant processes, and concomitant with a more detailed understanding of the cellular mechanisms underlying its biosynthesis, transport, and perception, it has become increasingly clear that auxin also has instructive roles in plant pattern formation. Moreover, it turns out that in a multitude of instances, from the early establishment of body axes to organogenesis in shoot and root, plant tissue patterns owe their robust flexibility in part to feedback interactions involving auxin. Higher resolution cell biology, molecular genetics, and genomics, as well as live imaging are now used together to define the parameters needed to generate more detailed and precise mathematical models of plant development.

scholarly journals Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 574
Author(s):  
Thomas Grange ◽  
Mélodie Aubart ◽  
Maud Langeois ◽  
Louise Benarroch ◽  
Pauline Arnaud ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Clinical Features ◽  
Familial Aggregation ◽  
Phenotypic Variability ◽  
Connective Tissue Disorder ◽  
Clinical Feature ◽  
Phenotypic Variance ◽  
Genetic Modifiers ◽  
Clinical Variability ◽  
New Strategy

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with considerable inter- and intra-familial clinical variability. The contribution of inherited modifiers to variability has not been quantified. We analyzed the distribution of 23 clinical features in 1306 well-phenotyped MFS patients carrying FBN1 mutations. We found strong correlations between features within the same system (i.e., ophthalmology vs. skeletal vs. cardiovascular) suggesting common underlying determinants, while features belonging to different systems were largely uncorrelated. We adapted a classical quantitative genetics model to estimate the heritability of each clinical feature from phenotypic correlations between relatives. Most clinical features showed strong familial aggregation and high heritability. We found a significant contribution by the major locus on the phenotypic variance only for ectopia lentis using a new strategy. Finally, we found evidence for the “Carter effect” in the MFS cardiovascular phenotype, which supports a polygenic model for MFS cardiovascular variability and indicates additional risk for children of MFS mothers with an aortic event. Our results demonstrate that an important part of the phenotypic variability in MFS is under the control of inherited modifiers, widely shared between features within the same system, but not among different systems. Further research must be performed to identify genetic modifiers of MFS severity.

Hemoglobin E Syndromes

Hematology ◽  
2007 ◽  
Vol 2007 (1) ◽  
pp. 79-83 ◽  
Author(s):  
Elliott Vichinsky
Keyword(s):  
Iron Overload ◽  
Clinical Course ◽  
Phenotypic Variability ◽  
Thalassemia Major ◽  
Screening Tests ◽  
Genetic Modifiers ◽  
Hemoglobin E ◽  
Mild Anemia ◽  
Hb E ◽  
Nitric Oxide Deficiency

Abstract Hemoglobin (Hb) E is one of the world’s most common and important mutations. It results in a heterogeneous group of disorders whose phenotype range from asymptomatic to severe. Hb E trait and Hb EE are mild disorders. The combination of Hb E and Hb S (Hb SE) results in a sickle cell disease syndrome similar to sickle β+ thalassemia. It is important to distinguish Hb E disorders diagnostically because of this marked difference in clinical course among different genotypes. Screening tests, including hemoglobin electrophoresis and high-pressure liquid chromatography (HPLC), may suggest other mutations, unless one is familiar with the findings. E β-thalassemia, the most serious form of E syndromes, affects a million people worldwide and is increasing in North America. Its phenotype ranges from mild anemia to severe transfusion-dependent thalassemia major. Several genetic modifiers affect the phenotype, including the type of β-thalassemia mutation, Hb F levels, and co-inheritance of α-thalassemia. However, the cause of the phenotypic variability is largely unknown. A prospective natural history study of E β-thalassemia in Sri Lanka suggests that environmental modifiers are prognostically important. The clinical course of E β-thalassemia is punctuated by acute and chronic complications that may cause serious morbidity and mortality. Recent studies indicate these patients are at high risk for thromboembolism secondary to a hypercoagulable state increased by splenectomy. Morbidity from iron overload in nontransfused patients secondary to increased gastrointestinal iron absorption is common. Cardiopulmonary disease, including pulmonary hypertension, requires ongoing monitoring and is secondary to iron overload, thromboembolism, and hemolysis-induced nitric oxide deficiency. These patients are excellent candidates for Hb F–modulating agents because moderate changes in hemoglobin may result in marked improvement in phenotype. Recent studies with hydroxyurea indicate 40% of patients will clinically improve with hydroxyurea.

scholarly journals The untapped cell biology of neglected tropical diseases

2016 ◽  
Vol 27 (5) ◽  
pp. 739-743 ◽  
Author(s):  
William Sullivan
Keyword(s):  
World Health Organization ◽  
Cell Biology ◽  
High Probability ◽  
Neglected Tropical Diseases ◽  
World Health ◽  
Tropical Diseases ◽  
Cellular Mechanisms ◽  
The World ◽  
Health Organization

The World Health Organization lists a constellation of 17 tropical diseases that afflict approximately one in six individuals on the planet and, until recently, few resources have been devoted to the treatment and eradication of those diseases. They are often referred to as the diseases of the “bottom billion,” because they are most prevalent among the poorest individuals in impoverished tropical nations. However, the few studies that have been performed reveal an extraordinary world of molecular and cellular adaptations that facilitate the pathogens’ survival in hosts ranging from insects to humans. A compelling case can be made that even a modest investment toward understanding the basic molecular and cell biology of these neglected pathogens has a high probability of yielding exciting new cellular mechanisms and insights into novel ways of combating these diseases.

Historical perspectives in fat cell biology: the fat cell as a model for the investigation of hormonal and metabolic pathways

2012 ◽  
Vol 302 (2) ◽  
pp. C327-C359 ◽  
Author(s):  
Max Lafontan
Keyword(s):  
Adipose Tissue ◽  
Hormonal Regulation ◽  
Cell Biology ◽  
Metabolic Regulation ◽  
Hormone Receptors ◽  
Fat Cells ◽  
Fat Cell ◽  
Cellular Mechanisms ◽  
Historical Perspectives ◽  
Stroma Vascular Fraction

For many years, there was little interest in the biochemistry or physiology of adipose tissue. It is now well recognized that adipocytes play an important dynamic role in metabolic regulation. They are able to sense metabolic states via their ability to perceive a large number of nervous and hormonal signals. They are also able to produce hormones, called adipokines, that affect nutrient intake, metabolism and energy expenditure. The report by Rodbell in 1964 that intact fat cells can be obtained by collagenase digestion of adipose tissue revolutionized studies on the hormonal regulation and metabolism of the fat cell. In the context of the advent of systems biology in the field of cell biology, the present seems an appropriate time to look back at the global contribution of the fat cell to cell biology knowledge. This review focuses on the very early approaches that used the fat cell as a tool to discover and understand various cellular mechanisms. Attention essentially focuses on the early investigations revealing the major contribution of mature fat cells and also fat cells originating from adipose cell lines to the discovery of major events related to hormone action (hormone receptors and transduction pathways involved in hormonal signaling) and mechanisms involved in metabolite processing (hexose uptake and uptake, storage, and efflux of fatty acids). Dormant preadipocytes exist in the stroma-vascular fraction of the adipose tissue of rodents and humans; cell culture systems have proven to be valuable models for the study of the processes involved in the formation of new fat cells. Finally, more recent insights into adipocyte secretion, a completely new role with major metabolic impact, are also briefly summarized.

scholarly journals Plasma cell maintenance and antibody secretion are under the control of Sec22b-mediated regulation of organelle dynamics

2022 ◽  
Author(s):  
Amelie Bonaud ◽  
Laetitia Gargowitsch ◽  
Simon Gilbert ◽  
Elanchezhian Rajan ◽  
Pablo Canales-Herrerias ◽  
...  
Keyword(s):  
Plasma Cell ◽  
Cell Biology ◽  
Plasma Cells ◽  
Critical Role ◽  
Serum Antibody ◽  
Cellular Mechanisms ◽  
Antibody Titres ◽  
And Function ◽  
Antibody Secretion ◽  
Cell Maintenance

Despite the essential role of plasma cells in health and disease, the cellular mechanisms controlling their survival and secretory capacity are still poorly understood. Here, we identified the SNARE Sec22b as a unique and critical regulator of plasma cell maintenance and function. In absence of Sec22b, plasma cells were barely detectable and serum antibody titres were dramatically reduced. Accordingly, Sec22b deficient mice fail to mount a protective immune response. At the mechanistic level, we demonstrated that Sec22b is indispensable for efficient antibody secretion but also for plasma cell fitness through the regulation of the morphology of the endoplasmic reticulum and mitochondria. Altogether, our results unveil a critical role for Sec22b-mediated regulation of plasma cell biology through the control of organelle dynamics.

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