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Lysyl hydroxylases 1 and 2:characterization of their <em>in vivo</em> roles in mouse and the molecular level consequences of the lysyl hydroxylase 2 mutations found in Bruck syndromeHyry, M. (Marjo) 29 May 2012 (has links)
Abstract
The extracellular matrix is not just a scaffold for cells and tissues, but rather a dynamic part of the human body. Characteristics of collagens, the major protein components of the extracellular matrix, are determined already during synthesis and mutations in genes encoding collagens, unbalance of regulators or dysfunction of collagen modifying enzymes, for instance, can lead to severe clinical complications. Certain hydroxylysine residues formed by lysyl hydroxylases (LHs) function in collagens as precursors of collagen cross-links that stabilize collagenous structures and thereby tissues. In humans, a deficiency of LH1, which is known to hydroxylate lysines in the helical regions of collagen polypeptides, causes Ehlers-Danlos syndrome VIA (EDS VIA). It is characterized e.g. by progressive kyphoscoliosis and hypermobile joints. Mutations in LH2, which is known to hydroxylate lysines in the telopeptides of collagen polypeptides, cause Bruck syndrome type 2 (BS2). BS2 patients suffer from fragile bones and congenital joint contractures, for instance, but the syndrome is usually not lethal.
In this work we have generated and analyzed genetically modified LH1 and LH2 null mouse lines to study the in vivo functions and roles of these enzymes. Analyses concentrated also on collagen cross-links that were determined from several null or heterozygous mouse tissues. In the present work we also studied the effects of known BS2 mutations on recombinant human LH2 polypeptides to understand the molecular pathology of the syndrome.
As an animal model for human EDS VIA, LH1 null mice had certain characteristics typical for EDS VIA, such as muscular hypotonia, but generally the symptoms were milder. Like EDS VIA patients, the mice have an increased risk of arterial ruptures and ultrastructural changes can be seen in the wall of the aorta, explained by inadequate helical lysine hydroxylation accompanied by a changed cross-linking state of tissues. Similarly, analysis of the LH2 null mouse line demonstrated the importance of the enzyme in cross-link formation. We showed that even a reduced amount of LH2 in adult mice changes the cross-linking pattern in tissues and a total lack of the enzyme leads to embryonic lethality. Furthermore, we demonstrated that LH2 is particularly important in tissue structures supporting blood vessels in the developing mouse embryo or in extraembryonic tissues. Finally, our in vitro studies with recombinant human LH2 polypeptides revealed that the known BS2 mutations severely affect the activity of the enzyme thus explaining the clinical symptoms of the patients, but the mutations do not lead to a total inactivation of the enzyme, which may be critical for the survival of patients. / Tiivistelmä
Solunulkoinen matriksi ei ole ainoastaan soluja ja kudoksia tukeva rakenne, vaan se on dynaaminen osa ihmiskehoa. Kollageenien, solunulkoisen matriksin yleisimpien proteiinien ominaisuudet määräytyvät jo kollageenien synteesivaiheessa ja mutaatiot kollageeneja koodittavissa geeneissä, säätelytekijöiden epätasapaino tai esimerkiksi kollageeneja muokkaavien entsyymien toimintahäiriöt voivat johtaa vaikeisiin kliinisiin komplikaatioihin. Tietyt lysyylihydroksylaasien (LH) muodostamat hydroksilysiinitähteet toimivat kollageeneissa kollageeniristisidosten esiasteina. Ristisidokset vakauttavat kollageenirakenteita ja siten myös kudoksia. LH1 hydroksyloi lysiinejä kollageenipolypeptidien kolmoiskierteisellä alueella ja ihmisellä entsyymin puutos aiheuttaa tyypin VIA Ehlers-Danlosin syndrooman (EDS VIA), jossa potilailla on esimerkiksi etenevää kyfoskolioosia ja yliliikkuvat nivelet. Mutaatiot LH2-entsyymissä, joka hydroksyloi lysiinejä kollageenipolypeptidien telopeptidialueilla, aiheuttavat tyypin 2 Bruckin syndrooman (BS2). BS2-potilaat kärsivät mm. luiden hauraudesta ja niveljäykkyydestä, mutta syndrooma ei yleensä ole letaali.
Tässä työssä loimme ja analysoimme geneettisesti muunnellut LH1 ja LH2 hiirilinjat, joiden kyseinen LH-geeniaktiivisuus on hiljennetty. Linjojen avulla halusimme tutkia näiden entsyymien toimintaa ja merkitystä in vivo. Analyysit keskittyivät myös kollageeniristisidoksiin, joita tutkittiin useista poistogeenisten tai heterotsygoottisten hiirten kudoksista. Ymmärtääksemme BS2:n molekyylipatologiaa, tutkimme tässä työssä myös tunnettujen BS2-mutaatioiden vaikutuksia ihmisen LH2-rekombinanttiproteiinissa.
EDS VIA:n eläinmallina LH1 poistogeenisillä hiirillä on joitakin ominaisuuksia, kuten lihashypotonia, jotka ovat tyypillisiä EDS VIA:lle, mutta yleisesti oireet ovat lievempiä. Kuten EDS VIA-potilailla, hiirillä on kohonnut valtimoiden repeytymisriski ja aortan seinämän ultrarakenteessa voidaankin havaita muutoksia. Oireita voidaan selittää riittämättömällä kollageenien kolmoiskierteisen alueen lysiinien hydroksylaatiolla, joka muuttaa kollageenien ristisidostilaa kudoksissa. Myös LH2-hiirilinjan analysointi osoitti kyseisen entsyymin tärkeyden ristisidosten muodostamisessa. Jo alentunut LH2:n määrä aikuisissa hiirissä muuttaa kudosten kollageeniristisidoksia ja täydellinen entsyymin puuttuminen johtaa sikiön kuolemaan. Lisäksi osoitimme, että LH2 on erityisen tärkeä kudosrakenteissa, jotka tukevat kehittyvän hiiren sikiön tai sikiön ulkopuolisten kudosten verisuonia. In vitro-tutkimukset ihmisen LH2-rekombinanttiproteiinilla paljastivat, että tunnetut BS2-mutaatiot vaikuttavat erittäin haitallisesti entsyymin toimintaan, mikä selittää potilaiden kliiniset oireet, mutta mutaatiot eivät kuitenkaan aiheuta entsyymin täydellistä inaktivaatiota, mikä voi olla kriittistä potilaiden selviytymisen kannalta.
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Rôle de la Ténascine-X dans l’activation du TGF bêta latent / Role of Tenascin-X in latent TGF beta activationAlcaraz, Lindsay 09 September 2015 (has links)
La Ténascine-X (TNX) est une glycoprotéine architecturale de la matrice extracellulaire. Outre ce rôle, la TNX est également considérée comme une protéine matricellulaire qui est capable de réguler le comportement de cellules normales et tumorales. Toutefois, aucun mécanisme moléculaire et cellulaire ne permettait d'expliquer les effets cellulaires de la TNX, avant notre étude. Au laboratoire, nous avons démontré que le domaine C-terminal de type fibrinogène (FBG) de la TNX était capable d'induire l'activation du Transforming Growth Factor (TGF) bêta latent. En effet, les trois isoformes du TGF bêta sont sécrétées sous la forme de complexes inactifs formés à partir de liaisons non covalentes entre le TGF bêta mature et son propeptide N-terminal LAP (Latency Associated Peptide). Nous avons montré que le domaine FBG de la TNX interagissait physiquement avec le TGF bêta latent, in vitro et in vivo, et induisait un changement de conformation du complexe latent, afin de permettre son activation en une molécule bioactive. De plus, nous avons identifié l'intégrine alpha11 bêta1 comme un récepteur membranaire pour la TNX et nous avons montré que cette intégrine était cruciale pour le processus d'activation du TGF bêta latent par le domaine FBG. Nous avons également démontré que les Méprines alpha et bêta deux protéases de la famille des astacines, pouvaient cliver la TNX, permettant ainsi de libérer des fragments contenant le domaine FBG, capables d'activer le TGF bêta latent. Enfin, nous avons entamé une étude de la pertinence biologique de l'activation du TGF bêta latent par la TNX in vivo en analysant la voie de signalisation du TGF bêta dans des souris déficientes ou non en TNX / Tenascin-X (TNX) is an architectural glycoprotein of the extracellular matrix. Beyond this role, TNX is also considered as a matricellular protein that is able to regulate the behavior of normal and tumor cells. However, no molecular and cellular mechanism has been described to explain TNX cellular effects before our study. In the laboratory, we showed that the C-terminal fibrinogen-like domain (FBG) of TNX was able to induce the latent transforming growth factor (TGF beta activation. Indeed, the three TGF beta isoforms are secreted as inactive complexes formed from non-covalent bonds between the mature TGF beta and its N-terminal propeptide, called LAP (Latency Associated Peptide). We showed that the FBG domain of TNX physically interacted with the latent TGF beta, in vitro and in vivo, and induced a conformational change of the latent complex to allow its activation into a bioactive molecule. Furthermore, we identified alpha1 beta1 integrin as a cell-surface receptor for TNX and showed that this integrin was crucial for the FBG-induced latent TGF beta activation. We also demonstrated that Meprins alpha and beta, two proteases belonging to the astacin family, could cleave the TNX, thereby releasing fragments containing the FBG domain capable of activating latent TGF beta. Finally, we have initiated a study regarding the biological relevance of latent TGF beta activation by TNX in vivo by analyzing the TGF beta signaling pathway in wild type or TNX-deficient mice
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En kvalitativ undersøgelse af silversplints som behandling af hypermobilitet i fingrene hos personer, der lever med Ehlers-Danlos syndrom / A qualitative exploration of silversplints as an orthotic management of finger hypermobility for people living with Ehlers-Danlos syndromeWejse, Daniel Langborg, Christensen, Linea Hua Bjerre January 2020 (has links)
Sammenfatning Baggrund: Silversplints som behandling af hypermobilitet i fingrene hos personer med Ehlers-Danlos syndrom (EDS), er blevet mere udbredt i Danmark igennem de sidste 10 år, men der findes endnu ingen publicerede artikler om denne ortosebehandling og målgruppe. EDS er en gruppe sjældne heterogene bindevævssygdomme der kendetegnes ved generel hypermobilitet og smerte. Silversplints er håndlavede finger- og håndledsskinner af sølv, der er opbygget som et 3-punkts kraftsystem, der kan støtte og korrigere hypermobile led, modvirke fejlstillinger, samt begrænse bevægeligheden af fingrene. Formål: Bacheloropgaven har til formål at undersøge hvordan personer med EDS oplever at have silversplints på og hvilke vanskeligheder de oplever at have i hverdagen ud fra ICF. Metode: Bacheloropgaven anvender semi-structured interviews for at undersøge hvordan 3 deltagere med EDS oplever silversplints som behandling af hypermobilitet i fingrene. Den teoretiske referenceramme er Interpretative Phenomenological Analysis, som er en induktiv tilgang og iterativ proces. Resultat: Ud fra analysen opstod følgende 4 temaer: jeg er ikke min sygdom, energiforbrug, smertens mange ansigter, et farverigt liv. Gennem disse temaer gives et indblik i den positive effekt silversplints kan have for nogle personer med EDS. Anvendelsen af ICF viste at især funktionsevnen blev påvirket. Dette indebærer at kroppens funktioner og anatomi opleves vanskeligt, hvilket fører til begrænsninger i deltagernes mulighed for aktivitet og deltagelse. Konklusion: De identificerede temaer demonstrerer silversplints effekt på deltagernes mentale og fysiske helbred, samt giver et detaljeret billede af deltagernes oplevede problemer og funktionsevne, med og uden silversplints. Bacheloropgaven identificerer hvilke dele, kategorier og domæner indenfor ICF, personer med EDS oplever som problematiske, hvilket kan anvendes til at skabe et core set i videre forskning. / Abstract Background: Silversplints as orthotic management of finger hypermobility for people with Ehlers-Danlos Syndrome (EDS) has become more widespread in Denmark during the last 10 years, but no articles has yet been published about this orthotic management and population. EDS is a group of rare heterogeneous connective tissue disorders which is characterized by general hypermobility and pain. Silversplints are handmade finger and wrist splints made of silver, which are structured as 3-point force systems, which supports, corrects hypermobile joints, and corrects deformities as well as limits the movement of the fingers. Purpose: The aim of the thesis is to explore how people with EDS experience the use of silversplints and which difficulties they experience in their daily life based on ICF. Methods: The thesis uses semi-structured interviews to explore how 3 participants with EDS experience silversplints as orthotic management of hypermobility in the fingers. The theoretical framework is Interpretative Phenomenological Analysis, which is an inductive approach and iterative process. Results: From the analysis 4 themes emerged: I am not my disorder, energy consumption, the many faces of pain, a colorful life. Through these themes an insight is gained into the positive effects silversplints may display for some people with EDS. The use of ICF showed that especially functioning and disability was affected. This involves that the body functions and structures are experienced as difficult, which leads to limitations in the participants possibility of activities and participation. Conclusion: The identified themes demonstrates silversplints’ effect on the participants mental and physical health, as well as provides a detailed picture of the participants’ experienced problems and functional capability, with and without silversplints. The thesis identifies which parts, categories, and domains within ICF, people with EDS experience as problematic, which can be used to generate a core set for further research.
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Multifocal periapical cemental dysplasia in periodontal Ehlers–Danlos syndrome combined with leukoencephalopathy in the mutation of c.890G > a, G297D [pEDS]Nilius, Manfred, Nilius, Minou Helene, Müller, Charlotte, Lauer, Guenter, Koch, Berit, Kohlhaas, Marcus 04 June 2024 (has links)
Periodontal Ehlers-Danlos syndrome (pEDS) is a rare disorder caused by heterozygous mutations in complement 1 subunit genes C1R and C1S. To date, 148 cases have been described in the literature.We describe a case of a suspected de novo-mutation of pEDS with generalized Periapical cemental dysplasia (PCD) and cerebral leukoencephalopathy.
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