• Refine Query
  • Source
  • Publication year
  • to
  • Language
  • 205
  • 48
  • 15
  • 15
  • 14
  • 6
  • 5
  • 3
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • Tagged with
  • 375
  • 85
  • 61
  • 60
  • 58
  • 56
  • 51
  • 49
  • 40
  • 37
  • 33
  • 32
  • 32
  • 25
  • 24
  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
361

Régulation mécano-transductionnelle des invaginations du mésoderme et de l’endoderme postérieur de l’embryon de Drosophile / Mechanotransductional regulation of mesoderm invagination and posterior endoderm invagination of the Drosophila embryo

Driquez, Benjamin 10 October 2013 (has links)
Au cours de gastrulation chez la Drosophile, deux vagues successives de constriction ont lieux au niveau des cellules ventrales menant à l'invagination du mésoderme. La première vague de constriction est stochastique et entraine la constriction de 40% des cellules mesodermales réparties aléatoirement et est contrôlée par le facteur de transcription Snail. La seconde vague de constriction arrive immédiatement après et implique également la constriction des 60% manquant de cellules mésodermales. Cette seconde vague est contrôlée par le facteur de transcription Twist et requière la présence de la protéine sécrétée Fog. L'invagination complète du mésoderme riquière la redistribution de la protéine moteur Myosine II au niveau de l'apex des cellules en cours de constriction. Il a été montré que la mutation de Snail mène à une perte des deux phases de constriction, mais qu'une indentation sur les cellules du mésoderme permet de rétablir la seconde phase de constriction Twist dépendante. Nous avons cherché à étudier les interaction entre les deux phases de constriction, la protéine sécrétée Fog et le moteur moléculaire Myosine II à l'aide d'une simulation numérique. Nous avons également chercher à étudier la corélation entre l'invagination globale du mésoderme et la phosphorylation de la Bêta-Cathenine qui est impliquée dans l'activation de Twist. Nous avons étudier l'invagination de l'endoderme postérieur qui présente de nombreuses similitude avec l'invagination de l'endoderme et leurs interactions. Enfin également à l'aide d'une simulation numérique, nous avons testé l'hypothèse de l'apparition d'une invagination dans un organisme primitif mécano-sensible ( la gastræ d'HAECKEL ) au contact avec le plancher océanique. / During Drosophila gastrulation, two waves of constriction occur in the apical ventral cells, leading to mesoderm invagination. The first constriction wave is a stochastic process mediated by the constriction of 40% of randomly positioned mesodermal cells and is controlled by the transcription factor Snail.The second constriction wave immediately follows and involves the other 60% of the mesodermal cells. The second wave is controlled by the transcription factor Twist and requires the secreted protein Fog. It is known that Snail mutation lead to the loss of the two constriction phases but a mechanical poking on the mesoderm cells can rescue de second phase of Twist dependent constriction. The interactions between the two constriction phases, la secreted protein Fog and the molecular motor Myosin II with a numerical simulation. The posterior endoderm invagination that presents similarities with mesoderm invagination have been study, as well as the interaction between them. Finally with an other numerical simulation, the hypothesis of an induced invagination on a primitive mechanosensible organism ( the HAECKEL grastrae ) on the contact with the oceanic floor has been tested.
362

Cell migration and antigen uptake are two antagonistic functions that are coupled by Myosin II in dendritic cells / La migration cellulaire et la capture d'antigènes sont des fonctions antagonistes couplées par la Myosine II dans les cellules dendritiques

Chabaud, Mélanie 27 June 2014 (has links)
Les cellules dendritiques (DCs) patrouillent les tissus périphériques à la recherche de dangers potentiels en se déplaçant à travers les tissus et en incorporant de grande quantité de matériel extracellulaire. Cet événement précoce de la réponse immunitaire adaptative est susceptible de déterminer l'amplitude et la qualité de l'activation des lymphocytes T et B. De ce fait, les DCs pourraient avoir besoin d'orchestrer leur motilité et leur fonction de capture des antigènes afin d'initier un réponse immunitaire efficace et adaptée. Afin d'étudier les mécanismes responsables de l'optimisation de l'échantillonnage des tissus par les DCs, nous avons suivi leur migration et leur capacité à capturer des antigènes dans des chambres micro-fluidiques contenant des canaux étroits qui permettent de reproduire l'espace confiné des tissus périphériques. De manière surprenante, nous avons découvert que la migration des DCs et leur aptitude à accumuler des antigènes sont des fonctions antagonistes et dépendent de l'activité du moteur moléculaire Myosine II. Nous avons observé que les DCs se déplacent en alternant des phases rapides au cours desquelles la Myosine II est distribuée de manière asymétrique à l'arrière des cellules, et des phases plus lentes pendant lesquelles la Myosine II est enrichie à l'avant. Les enrichissements transitoires de Myosine II à l'avant des DCs dépendent de l'association de la Myosine II avec la chaîne invariante associée au CMH-II (Ii). Ces évenements favorisent l'absorption d'antigènes et leur transport dans les compartiments endolysosomaux. Des expériences menées avec une pince optique nous ont permis de montrer que l'activité de la Myosine II à l'avant des cellules génère des forces mécaniques qui induisent le transport des vésicules vers l'intérieur de la cellule, probablement en modulant le flux rétrograde d'actine. Ainsi, au cours de cette thèse, nous avons montré que la Myosine II était nécessaire à la fois pour la migration cellulaire et la capture d'antigènes, établissant un mécanisme moléculaire qui permet de coordonner ces deux processus dans le temps et l'espace. Nous proposons que l'alternance de phases de haute mobilité et de phases d'arrêt associées à la capture d'antigènes confère aux DCs une stratégie de recherche intermittente qui leur permettrait d'optimiser la surveillance des tissus périphériques. / Dendritic cells (DCs) patrol peripheral tissues in search for potential dangers by actively crawling and internalizing extracellular materiel. This initial event of an adaptive immune response is likely to determine the magnitude and quality of T cell and B cell immunity. Therefore, DCs might need to tightly orchestrate their migration and their antigen uptake function in order to mount an efficient and adapted immune response. To investigate the mechanisms responsible for the optimization of tissues sampling by DCs, we monitored their migration and their ability to capture antigens in micro-fluidic chambers containing narrow channels that mimic the confined space of peripheral tissues. Surprisingly, we found that cell migration and antigen accumulation in endolysosomes are antagonistic, both relying on the activity of the motor protein Myosin II. We observed that DCs alternate between phases of fast motility during which Myosin II is asymmetrically distributed at the cell rear, and phases of slow motility during which Myosin is enriched at the cell front. Transient Myosin II enrichments at the leading edge depends on its association with the MHC-II associated Invariant Chain (Ii). These events promote antigen uptake and arrival in endolysosomal compartments. Using optical tweezers, we further showed that Myosin II activity at the leading edge generates mechanical forces that drive vesicles transport toward the cell body probably through the modulation of F-actin retrograde flow. Thus, during my PhD, we have shown that Myosin II is required for both migration and antigen capture, providing a molecular mechanism to couple these two processes and allow their coordination in time and space. We propose that alternation between phases of fast motility and phases of low motility associated with efficient antigen capture imposes an intermittent search behavior on DCs, which might be optimal for environment patrolling.
363

Role of Supervillin, a Membrane Raft Protein, in Cytoskeletal Organization and Invadopodia Function

Crowley, Jessica Lynn 12 February 2009 (has links)
Crucial to a cell’s ability to migrate is the organization of its plasma membrane and associated proteins in a polarized manner to interact with and respond to its surrounding environment. Cells interact with the extracellular matrix (ECM) through specialized contact sites, including podosomes and invadopodia. Tumor cells use F-actin-rich invadopodia to degrade ECM and invade tissues; related structures, termed podosomes, are sites of dynamic ECM interaction and degradation. We show here that supervillin (SV), a peripheral membrane protein that binds F-actin and myosin II,reorganizes the actin cytoskeleton and potentiates invadopodial function. Overexpressed SV increases the number of F-actin punctae, which are highly dynamic and co-localize with markers of podosomes and invadopodia. Endogenous SV localizes to the cores of Src-generated podosomes in COS-7 cells and with invadopodia in MDA-MB-231 cells. EGFP-SV overexpression increases the average amount of matrix degradation; RNAi-mediated downregulation of SV decreases degradation. Cortactin, an essential component of both podosomes and invadopodia, binds SV sequences in vitro and contributes to the formation of EGFP-SV induced punctae. Additionally, SV affects cortactin localization,which could provide a mechanism for SV action at invadopodia. The formation of cholesterol-rich membrane rafts is one method of plasma membrane organization. A property of membrane rafts is resistance to extraction with cold Triton X-100 and subsequent flotation to low buoyant densities. The actin cytoskeleton has been implicated in many signaling events localized to membrane rafts, but interactions between actin and raft components are not well characterized. Our laboratory isolated a heavy detergent resistant membrane fraction from neutrophils, called DRM-H, that contains at least 23 plasma membrane proteins. DRM-H is rich in cytoskeletal proteins, including fodrin, actin, myosin II, as well as supervillin. DRM-H also contains proteins implicated in both raft organization and membrane-mediated signaling. DRM-H complexes exhibit a higher buoyant density than do most DRMs (referred to as DRM-L), which are deficient in cytoskeletal proteins. By using similar purification methods, I find that COS-7 cells also contain cytoskeleton-associated DRMs. In addition, when transfected into COS-7 cells, estrogen receptor (ER)α associates with DRM-H, while ERβ is seen in both DRM-L and DRM-H populations, suggesting a role for DRM-H in nongenomic estrogen signaling. Thus, the cytoskeleton-associated DRM-H not limited to hematopoietic cells and could constitute a scaffold for membrane raftcytoskeleton signaling events in many cells. Taken together, our results show that SV is a component of cytoskeleton-associated membrane rafts as well as podosomes and invadopodia, and that SV plays a role in invadopodial function. SV, with its connections to both membrane rafts and the cytoskeleton, is well situated to mediate cortactin localization, activation state, and/or dynamics of matrix metalloproteases at the ventral cell surface for proper matrix degradation through invadopodia. The molecular dissection of invadopodia formation and function may contribute to a greater understanding of in vivo invasion, and thus, tumor cell metastasis.
364

Development of a Substrate with Photo-Modulatable Rigidity for Probing Spatial and Temporal Responses of Cells to Mechanical Signals: A Dissertation

Frey, Margo Tilley 01 July 2008 (has links)
Topographical and mechanical properties of adhesive substrates provide important biological cues that affect cell spreading, migration, growth, and differentiation. The phenomenon has led to the increased use of topographically patterned and flexible substrates in studying cultured cells. However, these studies may be complicated by various limitations. For example, the effects of ligand distribution and porosity are affected by topographical features of 3D biological constructs. Similarly, many studies of mechanical cues are compounded with cellular deformation from external forces, or limited by comparative studies of separate cells on different substrates. Furthermore, understanding cell responses to mechanical input is dependent upon reliable measurements of mechanical properties. This work addresses each of these issues. To determine how substrate topography and focal adhesion kinase (FAK) affect cell shape and movement, I studied FAK-null (FAK -/-) and wild type mouse 3T3 fibroblasts on chemically identical polystyrene substrates with either flat surfaces or micron-sized pillars, I found that, compared to cells on flat surfaces, those on pillar substrates showed a more branched shape, an increased linear speed, and a decreased directional stability, which were dependent on both myosin-II and FAK. To study the dynamic responses to changes in substrate stiffness without other confounding effects, I developed a UV-modulatable substrate that softens upon UV irradiation. As atomic force microscopy (AFM) proved inadequate to detect microscale changes in stiffness, I first developed and validated a microsphere indentation method that is compatible with fluorescence microscopy. The results obtained with this method were comparable to those obtained with AFM. The UV-modulatable substrates softened by ~20-30% with an intensity of irradiation that has no detectable effect on 3T3 cells on control surfaces. Cells responded to global softening of the substrate with an initial retraction followed by a gradual reduction in spread area. Precise spatial control of softening is also possible - while there was little response to posterior softening, anterior softening elicited a pronounced retraction and either a reversal of cell polarity or a significant decrease in spread area if the cells move into the softened region. In conclusion, these techniques provide advances in gaining mechanistic insight into cellular responses to topographical and mechanical cues. Additionally, there are various other potential applications of the novel UV-softening substrate, particularly in regenerative medicine and tissue engineering.
365

Remodelling of the F-actin Cytoskeleton of Polarized Epithelial Cells by the Type 3 Secretion System-1 Effector Proteins of Salmonella enterica sv. Typhimurium

Felipe-López, Alfonso 30 November 2015 (has links)
Darmepithelzellen entwickeln eine spezielle apikale Oberfläche zur Aufnahme von Nährstoffen aus dem Darminhalt. Diese Oberfläche besteht aus F-Aktin Protrusionen und werden als Mikrovilli (MV) bezeichnet. MV regulieren die kommensalen Bakterien und schützen die inneren Gewebe gegen den Angriff pathogener Mikroorganismen. Dennoch kann das Enteropathogen Salmonella enterica (Salmonella) die MV auslöschen und zerstört durch sein Typ-3-Sekretionssystem und dessen sekretierte Virulenzsproteine die Epithelschicht. Diese Virulenzproteine werden in das Zytoplasma der Wirtzellen injiziert und führen während des Eindringens von Salmonella zur F-Aktin Umlagerung. Durch Untersuchungen des Einflusses einiger T3SS-1 Effektorproteine auf die Zerstörung der MV konnte nachgewiesen werden, dass allein die Translokation von SopE die MV-Auslöschung verursachte und ausreichend für die Wiederherstellung der Invasion war. Echtzeitlebend-zellmikroskopie zeigte, dass MV ausgelöscht werden während Membranausstülpungen (Ruffles) gebildet werden. Diese Ruffle-Bildung vereinfachte ein paralleles Eindringen nicht-invadierender Stämme von Salmonella. Es konnte beobachtet werden, dass die Ausschaltung von Villin und Myosin 1a durch shRNA in C2BBe1 Zellen die Invasionsrate von Salmonella ermäßigte. Darüber hinaus wurde Ezrin zu den intrazellulären Bakterien aber nicht zur apikalen Seite rekrutiert. Außerdem verhinderte die durch das SopE verursachte Umlagerung des F-Aktins, welche die MV-Auflösung zur Folge hatte, die Makropinozytose der infizierten Zellen. Es lässt sich daraus schließen, dass die Zerstörung der MV für eine effiziente Invasion von Salmonella nötig ist. Die F-Aktin Umlagerung begünstigt zudem das Eindringen von nicht-invadierenden Bakterien. Des Weiteren benötigt Salmonella MV-Proteine zur F-Aktin Polymerisierung und Invasion in polarisierten Epithelzellen, was die Makropinozytose der Zellen beeinträchtigt. Möglicherweise tragen diese Phänotypen zur Infektion in vivo bei und verursachen das klinische Bild des Durchfalls.
366

Differentiation and contractility of colon smooth muscle under normal and diabetic conditions

Touw, Ketrija 07 October 2013 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Intestinal smooth muscle development involves complex transcriptional regulation leading to cell differentiation of the circular, longitudinal and muscularis mucosae layers. Differentiated intestinal smooth muscle cells express high levels of smooth muscle-specific contractile and regulatory proteins, including telokin. Telokin is regulatory protein that is highly expressed in visceral smooth muscle. Analysis of cis-elements required for transcriptional regulation of the telokin promoter by using hypoxanthine-guanine phosphoribosyltransferase (Hprt)-targeted reporter transgenes revealed that a 10 base pair large CC(AT)₆GG ciselement, called CArG box is required for promoter activity in all tissues. We also determined that an additional 100 base pair region is necessary for transgene activity in intestinal smooth muscle cells. To examine how transcriptional regulation of intestinal smooth muscle may be altered under pathological conditions we examined the effects of diabetes on colonic smooth muscle. Approximately 76% of diabetic patients develop gastrointestinal (GI) symptoms such as constipation due to intestinal dysmotility. Mice were treated with low-dose streptozotocin to induce a type 1 diabetes-like hyperglycemia. CT scans revealed decreased overall GI tract motility after 7 weeks of hyperglycemia. Acute (1 week) and chronic (7 weeks) diabetic mice also had decreased potassium chloride (KCl)-induced colon smooth muscle contractility. We hypothesized that decreased smooth muscle contractility at least in part, was due to alteration of contractile protein gene expression. However, diabetic mice showed no changes in mRNA or protein levels of smooth muscle contractile proteins. We determined that the decreased colonic contractility was associated with an attenuated intracellular calcium increase, as measured by ratio-metric imaging of Fura-2 fluorescence in isolated colonic smooth muscle strips. This attenuated calcium increase resulted in decreased myosin light chain phosphorylation, thus explaining the decreased contractility of the colon. Chronic diabetes was also associated with increased basal calcium levels. Western blotting and quantitative real time polymerase chain reaction (qRT-PCR) analysis revealed significant changes in calcium handling proteins in chronic diabetes that were not seen in the acute state.These changes most likely reflect compensatory mechanisms activated by the initial impaired calcium response. Overall my results suggest that type 1 diabetes in mice leads to decreased colon motility in part due to altered calcium handling without altering contractile protein expression.
367

Étude du remodelage du muscle lisse bronchique chez les chevaux asthmatiques légers à modérés

Dupuis-Dowd, Florence 08 1900 (has links)
L’asthme équin est une condition inflammatoire fréquente affectant les voies respiratoires inférieures. Cette maladie est caractérisée par une bronchoconstriction, une hyperréactivité bronchique, ainsi que des changements des différentes couches tissulaires des voies respiratoires que l’on regroupe sous le terme de remodelage pulmonaire. Le remodelage du muscle lisse bronchique dans l’asthme comprend une hyperplasie, une hypertrophie, ainsi qu’une altération des propriétés contractiles des myocytes. Bien que ces changements aient été décrits dans la forme sévère de l’asthme équin, la présence de telles altérations chez les chevaux atteints des formes légères à modérées de l’asthme demeure incertaine. L’objectif de notre étude est donc de déterminer si le muscle lisse bronchique présente un remodelage chez les chevaux asthmatiques légers à modérés. Des biopsies endobronchiques provenant de 18 chevaux asthmatiques et de 7 chevaux contrôles ont été étudiées. Le diagnostic était basé sur les signes cliniques et confirmé par cytologie du lavage bronchoalvéolaire. La prolifération des cellules du muscle lisse bronchique était évaluée par l’expression du proliferating cell nuclear antigen marqué par immunohistochimie, et l’expression génique de l’isoforme rapide de la myosine, une protéine hypercontractile, a été mesurée par RT-qPCR. Cette étude a permis de mettre en évidence une surexpression de l’isoforme rapide de la myosine chez les chevaux asthmatiques légers à modérés. Malgré l’absence de différence dans le taux de prolifération cellulaire du muscle lisse bronchique entre les groupes, le pourcentage de myocytes en prolifération était corrélé à l’inflammation pulmonaire neutrophilique ainsi qu’à l’expression de l’isoforme rapide de la myosine chez les chevaux asthmatiques. Cette première étude évaluant le remodelage du muscle lisse bronchique chez les chevaux asthmatiques légers à modérés a démontré une altération fonctionnelle du muscle lisse bronchique dans les formes légères de l’asthme équin, une possible influence de la neutrophilie pulmonaire sur la prolifération du muscle lisse, ainsi qu’une association entre les phénotypes prolifératifs et contractiles. Les altérations identifiées pourraient servir de biomarqueurs potentiels dans l’évolution de la maladie et de la réponse aux traitements. / Equine asthma is a common inflammatory condition affecting the lower airways. This disease is characterised by bronchoconstriction, airway hyperreactivity, and changes in the different tissue layers of the airways, which are referred to as airway remodelling. Remodelling of the smooth muscle in asthma includes hyperplasia, hypertrophy, and altered contractile properties of the myocytes. Although these changes have been described in severe equine asthma, their presence in horses with milder forms of asthma remains unclear. The aim of our study was therefore to determine whether airway smooth muscle remodelling occurs in horses with mild to moderate asthma. Endobronchial biopsies from 18 asthmatic horses and 7 control horses were studied. The diagnosis was based on clinical signs and confirmed by bronchoalveolar lavage cytology results. Airway smooth muscle cell proliferation was assessed by the expression of immunohistochemically labelled proliferating cell nuclear antigen, and the gene expression of the fast contracting myosin isoform, a hypercontractile protein, was measured by RT-qPCR. This study showed overexpression of the fast contracting myosin isoform in horses with mild to moderate asthma. Although there was no difference in the proliferation rate of airway smooth muscle myocyte between groups, it was correlated with neutrophilic lung inflammation as well as with the expression of the fast myosin isoform in asthmatic horses. This first study evaluating airway smooth muscle remodelling in mild to moderate asthmatic horses has demonstrated a functional alteration of airway smooth muscle in mild equine asthma, as well as a possible influence of pulmonary neutrophilia on smooth muscle proliferation, and an association between proliferative and contractile phenotypes. The identified alterations could eventually serve as biomarkers in the evolution of the disease and the response to treatments.
368

The Development and Regeneration of the Serotonergic System

Hawthorne, Alicia Lynn 06 July 2010 (has links)
No description available.
369

Functional investigation of arabidopsis long coiled-coil proteins and subcellular localization of plant rangap1

Jeong, Sun Yong 20 July 2004 (has links)
No description available.
370

Mutationen und Polymorphismen im Beta-MHC- und Troponin T-Gen bei Patienten mit dilatativer Kardiomyopathie

Dähmlow, Steffen 19 April 2006 (has links)
Die ersten identifizierten Krankheitsgene der dilatativen Kardiomyopathie (DCM) kodierten alle für Proteine des Zytoskeletts. Deshalb wurde DCM als Erkrankung des Zytoskeletts bezeichnet. Bei der hypertrophen Kardiomyopathie (HCM) wurden bisher mehr als 250 Mutationen in neun Sarkomerprotein-Genen beschrieben. Deshalb wurde HCM als Erkrankung des Sarkomers bezeichnet. In den letzten Jahren wurde dieses Konzept durch Entdeckung von Mutationen in Sarkomerprotein-Genen bei DCM jedoch in Frage gestellt. Vor diesem Hintergrund haben wir die Sarkomerprotein-Gene beta-MHC und Troponin T bei 46 nicht verwandten DCM-Patienten untersucht. Das systematische Mutationsscreening wurde mit Hilfe von SSCP-Analyse und DNA-Sequenzierung durchgeführt. Im beta-MHC-Gen konnten wir die zwei Missense-Mutationen Ala223Thr und Ser642Leu bei zwei jungen Patienten identifizieren. Beide Mutationen wurden weder bei 136 HCM-Patienten noch bei 88 Kontrollen gefunden. Mit dem Editor for Structural Alignment of Proteins (STRAP) wurden die Mutationen auf die Proteinstruktur des Myosins projiziert. Hier ist erkennbar, dass Ala223Thr in der oberen 50 kDa Domäne und Ser642Leu in der Aktin-Myosin-Bindungsregion liegt. Der Austausch von Alanin zu Threonin könnte die Raumstruktur des Proteins verändern, Thermostabilität verringern und die Proteinfaltung und somit die Proteinmotilität beeinträchtigen. In der Aktin-Myosin-Bindungsregion liegt neben Ser642Leu die bereits bekannte DCM-assoziierte Mutation Ser532Pro. Durch eine Verminderung der Krafterzeugung könnten die beiden Mutationen zu DCM führen. Ferner wurden die zwei stummen Mutationen IVS11+23A>T und Asp376Asp und sechs Polymorphismen identifiziert. Im Troponin T-Gen wurden keine Mutationen, jedoch sechs Polymorphismen beobachtet. Es ergab sich kein Anhaltspunkt auf eine funktionelle Relevanz der stummen Mutationen oder Polymorphismen. Wir konnten also bestätigen, dass Mutationen in Sarkomerprotein-Genen sowohl zu HCM als auch zu DCM führen können. / All of the initially identified disease-causing genes in dilated cardiomyopathy (DCM) encoded proteins of the cytoskeleton. Therefore DCM has been termed a disease of the cytoskeleton. In hypertrophic cardiomyopathy (HCM) more than 250 mutations in nine sarcomeric protein genes have been identified so far. Therefore HCM has been termed a disease of the sarcomere. However, in the last few years this concept has been queried by findings of mutations in sarcomeric protein genes in DCM. According to this consideration we screened the sarcomeric protein genes beta-MHC and troponin T in 46 patients with DCM. Systematic mutation screening was done using SSCP analysis and DNA sequencing. In the beta-MHC gene we identified the two missense mutations Ala223Thr and Ser642Leu in two young patients. Both mutations were neither found in 136 HCM patients nor in 88 controls. Using the Editor for Structural Alignment of Proteins (STRAP) the mutations were projected onto the protein structure of myosin. Ala223Thr turned out to be localized in the upper 50 kDa domain and Ser642Leu in the actin-myosin-interface region. The exchange from alanine to threonine might alter the spatial structure of the protein, decrease its thermostability and affect the protein folding and thus the protein motility. Closely to Ser642Leu the DCM-associated mutation Ser532Pro is located in the actin-myosin-interface region. By a decrease in force production both mutations might cause DCM. Furthermore we identified the two silent mutations IVS11+23A>T and Asp376Asp and six polymorphisms. In the troponin T gene no mutations but six polymorphisms were detected. No evidence was found for functional relevance of the silent variants or polymorphisms. Thus, we could confirm that mutations in sarcomeric protein genes can lead to both HCM and DCM.

Page generated in 0.0353 seconds