Teses / dissertações sobre o tema "Syndrome métabolique – Génétique moléculaire"
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Didiot, Marie-Cécile. "Bases moléculaires du syndrome de l’X fragile : Etude de l'implication de la protéine FMRP dans le métabolisme des ARN messagers". Université Louis Pasteur (Strasbourg) (1971-2008), 2008. https://publication-theses.unistra.fr/public/theses_doctorat/2008/DIDIOT_Marie-Cecile_2008.pdf.
Texto completo da fonteMellaoui, Samia. "Rôle de la protéine FMRP dans la formation et le dynamisme des granules à ARN". Thesis, Université Laval, 2012. http://www.theses.ulaval.ca/2012/29529/29529.pdf.
Texto completo da fonteTurcot, Valérie. "Génétique et épigénétique du syndrome métabolique". Thesis, Université Laval, 2012. http://www.theses.ulaval.ca/2012/29169/29169.pdf.
Texto completo da fonteVigé, Alexandre. "Epigénomique nutritionnelle du syndrome métabolique". Paris 5, 2007. http://www.theses.fr/2007PA05P602.
Texto completo da fonteEpigenetic changes associated with DNA methylation and histone modifications leading to chromatin remodeling and regulation of gene expression underlie the developmental programming of obesity, type 2 diabetes, cardiovascular diseases and metabolic syndrome. This review focuses on converging data supporting the hypothesis that, in addition to "thrifty genotype" inheritance, individuals with obesity, type 2 diabetes, and metabolic syndrome (MetS) with an increased risk of cardiovascular diseases have suffered improper "epigenetic programming" during their fetal/postnatal development due to maternal inadequate nutrition and metabolic disturbances and also during their lifetime, that could even be transmitted to the next generation(s). We highlight the susceptibility of epigenetic mechanisms controlling gene expression to environmental influences due to their inherent malleability, emphasizing the participation of transposable elements and the potential role of imprinted genes during critical time windows in epigenetic programming, from the very beginning of development, throughout life. Increasing our understanding on epigenetic patterns significance and their role in development, evolution and adaptation and on small molecules (nutrients, drugs) that reverse epigenetic (in)activation should provide us with the means to "unlock" silenced (enhanced) genes, and to "convert" the obsolete human thrifty genotype into a "squandering" phenotype
Qu, Mengdi. "Molecular mechanism underlying CaMK1D-dependent function in AgRP neurons". Electronic Thesis or Diss., Strasbourg, 2024. http://www.theses.fr/2024STRAJ029.
Texto completo da fonteDisruption of stress response mechanisms in organisms can lead to cellular dysfunction and diseases like metabolic syndrome. Energy balance is mainly regulated by the central nervous system (CNS), which integrates hormonal, neuronal, and dietary signals from various tissues. Dysfunction in this system is linked to obesity and metabolic syndrome, both precursors to type 2 diabetes (T2D). Our laboratory discovered that calcium/calmodulin-dependent protein kinase ID (CaMK1D), a gene associated with T2D, promotes ghrelin-mediated food intake in mice. However, CaMK1D signaling in NPY/AgRP neurons still remains questions. In this work, we proformed RNA sequencing using the GT1-7 hypothalamic cell line. To this end, we found that CalHM6 is a downstream target of CaMK1D signaling. CalHM6 mRNA levels were significantly upregulated in CaMK1D-/- cells and downregulated when CaMK1D was re-expressed. This was confirmed in vivo in the hypothalamus of CaMK1D-/- mice. CalHM6, likely a voltage-gated calcium channel, showed increased intracellular Ca2+ levels in response to ghrelin in CaMK1D-/- cells compared to CaMK1D+/+ cells using jGCamps method. Altogether, our work showed CalHM6 is a novel target of CaMK1D. High CaMK1D, leading to low CalHM6 expression, may enhance food intake and obesity by modulating calcium-dependent signaling in NPY/AgRP neuron
Legry, Vanessa. "Recherche de déterminants génétiques des phénotypes associés au syndrome métabolique en population". Phd thesis, Université du Droit et de la Santé - Lille II, 2009. http://tel.archives-ouvertes.fr/tel-00426888.
Texto completo da fonteMaumus, Sandy. "Approche de la complexité du syndrome métabolique et de ses indicateurs de risuqe par la mise en œuvre de méthodes numériques et symboliques de fouille de données". Nancy 1, 2005. http://www.theses.fr/2005NAN12506.
Texto completo da fonteMaumus, Sandy. "Approche de la complexité du syndrome métabolique et de ses indicateurs de risuqe par la mise en œuvre de méthodes numériques et symboliques de fouille de données". Nancy 1, 2005. http://www.theses.fr/2005NAN10209.
Texto completo da fonteIssa, Sarah. "Améliorer la comprehension moléculaire du syndrome de Waardenburg". Thesis, Paris Est, 2017. http://www.theses.fr/2017PESC0012.
Texto completo da fonteWaardenburg Syndrome (WS) is a neurocristopathy that encompasses both auditory and pigmentary abnormalities and is usually due to an absence of melanocytes from the hair, skin, eyes and cochlea. Additional clinical findings such as musculoskeletal or craniofacial abnormalities, Hirschsprung disease or neurological deficiencies characterize the different subtypes of this syndrome (WS1-WS4).Starting with PAX3 in 1992, five major genes have been linked to WS. Nevertheless, a lot of cases remain unexplained, especially in WS2, which is the most difficult subtype to diagnose on the clinical point of view as it lacks any other feature. The five main genes; PAX3, MITF, SOX10, EDNRB and EDN3, seem to be part of a gene regulatory network.My PhD project was to enhance the molecular and genetic understanding of WS2. To do so, whole exome sequencing was performed on trios and families with WS2. After the identification of a mutation in EDNRB (previously involved in WS4) in a WS2 patient, screening of other cases revealed additional variations in this gene. Complementary clinical investigations, molecular studies and in vitro functional tests unraveled a dominant mode of inheritance with incomplete penetrance. We evaluated EDNRB mutations to be responsible for 5-6% of WS2 cases. This discovery helps in better understanding the molecular pathways of this syndrome and further confirms its genetic complexity
Bossé, Yohan. "Genetic Susceptibility to the Metabolic Syndrome". Thesis, Université Laval, 2004. http://www.theses.ulaval.ca/2004/22151/22151.pdf.
Texto completo da fonteThe metabolic syndrome is a cluster of interrelated cardiovascular risk factors co-occurring in the same individual. People with this syndrome are at increased risk for developing diabetes mellitus and cardiovascular diseases. Accordingly, it is important to elucidate the genetic aetiology governing this trait in order to better comprehend its pathogenesis. In the present thesis, heritability and complex segregation analyses as well as candidate gene and genome-wide scan approaches have been applied to shed some lights on the genetic architecture of the metabolic syndrome and its individual components. A total of three candidate genes have been investigated including peroxisome proliferator-activated receptor (PPAR) α and PPARγ as well as phospholipid transfer protein (PLTP). It has been shown that polymorphisms in both PPARα and PLTP genes are significantly associated with several indices of adiposity. In addition, significant gene-gene interactions have been observed between PPARα and PPARγ on glucose/insulin parameters. It has also been shown that the HDL2-cholesterol response to gemfibrozil therapy is modulated by the PPARα L162V polymorphism. Genome-wide linkage scans have been performed on lipid and lipoprotein concentrations. Many chromosome regions harbouring lipoprotein/lipid genes have been identified including 1q43, 11q13 q24, 15q26.1, and 19q13.32 for LDL-cholesterol, 12q14.1 for HDL-cholesterol, 2p14, 11p13, and 11q24.1 for triglycerides, 18q21.32 for LDL-apolipoprotein (apo) B, and 3p25.2 for apoAI. The genetic contribution of the variation in LDL peak particle diameter (LDL-PPD) has been also investigated. Overall, the results indicate: 1) that LDL-PPD strongly aggregates within families with heritability estimate above 50%; 2) the existence of a major gene effect affecting the phenotype; and 3) the presence of a major quantitative trait locus located on chromosome 17q. The apo H gene, a positional candidate gene, was then significantly associated with LDL-PPD, suggesting that this gene is responsible for the linkage signal observed on 17q. Finally, factor analyses have been used to construct a quantitative metabolic syndrome variable and a genome-wide linkage scan has been conducted to identify the genomic regions underlying this trait. A major quantitative trait locus has been observed on chromosome 15q suggesting a gene within this region contributing to the clustering of the metabolic syndrome-related phenotypes. Many of these findings must go through independent replication, while others produced new leads that deserve follow-up.
Inscrit au Tableau d'honneur de la Faculté des études supérieures
Haydar, Sara. "Rôle des aminoacides ramifiés dans le déterminisme génétique de la résistance à l’insuline". Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTT054.
Texto completo da fonteInsulin resistance (IR) is a fundamental biological process involved in majority of complex disorders with high impact on mortality of human populations and with a strong genetic component in interaction with nutritional factors. Branched chain amino acids (BCAA) are essential components of human diet and recognized as new actors in pathogenesis of obesity and diabetes mellitus either as biomarkers or regulators at the peripheral systemic and nervous system. This work was proposed in the frame of the European project MEDIGENE (FP7-279171) studying the metabolic syndrome in several Mediterranean populations. In this context, we have used a genetic approach combining SNP (single nucleotide polymorphism) and fine scale haplotype mapping. We identified new genes in the later steps of BCAA catabolism responsible for IR, albeit displaying a complex signal in relation with BCAA plasma levels and in vivo IR measured by minimal model. With a similar approach, we identified equally a new locus of Chromosome 4p14 for IR in cooperation with the cerebral rewarding system involving fibroblast growth factor (FGF) 21 regulation. These data roused particular interest in estimating BCAA intake leading to the development of a novel database of BCAA content in food. This database is embedded in a new computer program for collecting dietary records (24HDR) and can be used securely by practitioners around Mediterranean countries and opening new perspectives in the nutrigenomic field
Besnard, Thomas. "Syndrome de Usher : outils innovants pour une exploration moléculaire exhaustive". Thesis, Montpellier 1, 2012. http://www.theses.fr/2012MON13512/document.
Texto completo da fonteUsher syndrome is a genetic disorder combining sensorineural hearing loss (HL) and retinitis pigmentosa (RP). Some patients will also exhibit vestibular areflexia (VA). Clinical and genetic heterogeneity is recognized as the 3 clinical subgroups, defined mainly on the degree of HL and VA, can be caused by mutations in one of the 10 known genes. It is important to use all accessible genetic tools to identify and characterize molecular origin in order to improve the knowledge of the physiopathological mechanisms causing Usher Syndrome.In this context, we have developed an exhaustive approach. In a first step, we have implemented the analysis and established the mutational spectrum of the 2 minor USH2 genes (GPR98 and DFNB31). In addition, we have developed several tools, in particular to study variants susceptible to alter splicing or lying in the promoter regions of the USH2 genes.Thanks to this work, the USH2 mutation detection rate has now been raised to 90%, similar to that of USH1.We have then designed a targeted exome of the Usher genes to be sequenced using the GS Junior system (Roche 454). The aim of the study was to test the feasibility of this new technics for a possible transfer to diagnostic facilities. Quality criteria and variant priorization were set up on a control cohort (previously studied in one of the USH gene). The study has then been extended on a patient cohort. Our results indicate that NGS Usher-exome can be used in molecular diagnostics but improvement of the reliability of the sequencing technology, bioinformatics tools and dedicated databases is essential
Legendre, Marine. "Le syndrome CHARGE : étude clinique et moléculaire". Thesis, Poitiers, 2016. http://www.theses.fr/2016POIT1406/document.
Texto completo da fonteCHARGE syndrome is a rare disorder of multiple congenital anomalies ascribed to a CHD7 gene mutation in 60% to 90% of cases. The aim of this study was to improve the knowledge regarding molecular and clinical aspects of the syndrome in order to optimize the management of these patients with severe disability. Antenatal diagnosis remains challenging in many instances and a detailed clinicopathological survey in a series of 40 fetuses allowed us to refine the clinical description of CHARGE syndrome in fetuses, describe some novel features and set up diagnostic criteria. An endocrinologic study of 42 patients showed a hypogonadotrophic hypogonadism in 97% of cases. For this reason, it should be considered as a major symptom of the syndrome. An early screening should lead to a hormonal replacement therapy which dramatically impacts the condition.A study of a French cohort of 119 patients found that deafness and semi-circular canals hypoplasia were the most frequent symptoms (followed by hypogonadotrophic hypogonadism, arhinencephaly and external ears anomalies) and the only features statistically associated with a mutation in the CHD7 gene. A detailed study of the data is still going on.The syndrome is mainly due to de novo and private truncating mutations of the CHD7 gene but we report an intriguing hot spot of intronic mutations located in IVS25. Combining computational in silico analysis and ex vivo minigene assays, we explained this mutation hot spot by a particular genomic context, including a distant branch point, and confirmed the pathogenicity of these mutations
Touzot, Fabien. "Caractérisation phénotypique et moléculaire du syndrome de Hoyeraal-Hreidarsson". Paris 7, 2011. http://www.theses.fr/2011PA077057.
Texto completo da fonteTelomeres represent the tips of linear chromosome. Their length, structure, and integrity are regulated by the telomerase complex, the shelterin telomeric factors, and components of the DNA damage response. In humans, telomere maintenance deficiency leads to dyskeratosis congenita (DC), a rare genetic disorder characterized by a progressive bonemarrow failure, accelerated ageing, and cancer predisposition. Hoyeraal-Hreidarsson syndrome (HH) is a severe variant of DC in which an early onset of BMF leading to combined immunodeficiency is associated with microcephaly, cerebellar hypoplasia, and growth retardation. We analyzed fibroblasts from five patients with HH, three of them with uncharacterized molecular origin. Although patients cells exhibit dysfunctional telomeres, sharp differences in the telomeric aberrations and telomere lengths where noted among these patients. In flbroblasts from three patients, we founc a dysfunctional telomere phenotype that associated normal telomere length with telomeric aberrations akin to fragile telomeres. Collectively, our observations provide the notions that: (i) différent telomere defects lead to similar clinical features, (ii) telomere dysfunction in cells from DC/HH is not always associated with short telomeres and, (iii) additional factors, likely involved in telomere protection rather than in length regulation, are responsible for these forms of DC/HH syndrome
Haquet, Emmanuelle. "Recombinaison entre chromosomes non-disjoints dans la Trisomie 21 et correlations génotypes/phénotypes dans le syndrome de Down". Montpellier 2, 2006. http://www.theses.fr/2006MON20070.
Texto completo da fonteDown syndrome (DS), which is mainly caused by trisomy 21, is characterized by many abnormalities affecting most organ systems. The majority of DS features are highly variable between patients in term of presence and severity. Nucleotidic variations (SNPs) within or around some triplicated genes could be partly responsible for this variability. On another hand, fine scale analysis of recombination in the sub-telomeric region should make it more precise the relationship previously reported between altered recombination and meiotic non-disjunction. We addressed these two questions by typing a hundred of SNPs along chromosome 21 in families with a trisomic child. Two set of 50 SNPs have been designed, one for each project. The first 50 SNPs set covers 2 megabases of the Down Syndrome Critical Region (21q22. 13-q22. 2). We have genotyped 81 patients and studied, for each SNP, the proportion of genotypes between patients with and without a DS trait (including mental retardation and cardiac malformation). We have observed two associations, one strong (p<0,001) and one weaker (p<0,05), between two intragenic SNPs and the presence of a septal cardiac defect. The concerned gene is KCNJ6 a potassium channel which potential implication in DS cardiopathy is a new way of investigations for understanding the variability of this DS trait. The second 50 SNPs set covers the 7. 9 sub-telomeric mégabases of chromosome 21. We could not observe significant differences between recombination distributions in context of normal and non-disjoined chromosomes. Nevertheless, the presence of a unique recombination event in a 2 Mb region, located at 2 Mb from the telomere, seems to be critical for the generation of non-disjoined chromosome 21
Murati, Anne. "Les protéines tyrosine kinases dans les syndromes myéloprolifératifs". Aix-Marseille 2, 2005. http://www.theses.fr/2005AIX20686.
Texto completo da fonteLugan, Raphaël. "Phénotypage métabolique des réponses aux stress abiotiques chez Arabidopsis thaliana : analyse fonctionnelle et intégrative du métabolome". Rennes 1, 2008. http://www.theses.fr/2008REN1S170.
Texto completo da fonteAbiotic stresses (extreme temperatures, salinity, drought) impair plant growth and development and are important agronomic challenges. Understanding stress responses developed by various species contributes to crop improvement and also constitutes an interesting approach of integrated mechanisms operating at different organisation levels in highly regulated ways. Availability of genotypes collections, molecular analysis tools and efficient bioinformatics pave the way to phenotyping of model plants at the genomic scale, in relation with their environment. Metabolmics, defined as unbiaised, nontargeted and exhaustive analysis of metabolites in biological samples, provide new insights into physiological processes like nutrition, biochemical and structural adaptation or cell signalling. Present work is an exploratory, diagnostic and correlative approach of primary metablome in the stress sensitive species Arabidopsis thaliana
Albertini, Marie-Vincente. "Caractérisation biochimique et moléculaire des fruits d'agrumes (Citrus sp. ) : modèle métabolique d'utilisation des acides organiques et des sucres". Corte, 2007. http://www.theses.fr/2007CORT4001.
Texto completo da fonteUnderstanding organic acid and sugar accumulation processes in citrus fruit (Citrus sp. ) plays an important role for improving their organoleptic quality. The aim of our work was to identify metabolic pathways and genes involved in these processes. Our strategy was to compare acidity (pH, titratable acidity and organic acid composition) and sugar composition between acid and acidless citrus varieties from three species (orange, lemon and lime). Two different methods based on molecular biology tools were undertaken to identify genes putatively involved in the variation of organic acid and sugar concentrations: (1) « candidate gene » aproch coupled with quantification of mRNA (Real Time PCR) and (2) construction of a cDNA bank involved in the acid character using subtractive and suppressive hybridization (SSH). Biochemical characterization of fruits showed that pH of acidic varieties decreases during the first stage of development concomitantly with titrable acidity increase. Citric acid is the major organic acid involved in the variation of acidity. By contrast, no variation of acidity was observed with acidless fruits (pH and titratable acidity were constant. Lacking of citric acid accumulation in acidless fruit was related to a more important fructose concentration. Among the eight selected « candidate genes », vacuolar acid invertase and NADP-isocitrate dehydrogenase mRNA were quantitatively higher in acidless fruits that suggest that citric acid, from acidless fruits, is metabolized via the GABA shunt pathway instead of being stored in acidic fruits. SSH results allowed selecting a partial cDNA which is sub-expressed in acidless fruit. Its identity was not yet determined. A metabolic model was proposed
Petit, Florence. "Génétique du développement des membres : contribution à son déterminisme moléculaire à partir de modèles d'étude en pathologie humaine". Thesis, Lille 2, 2014. http://www.theses.fr/2014LIL2S053/document.
Texto completo da fonteLimb development requires complex patterning along dorso-ventral, antero-posterior and proximo-distal axes. The molecular mechanisms underlying these stages are not fully delineated yet. Identification of the transcription factors involved is challenging because of their spatio-temporally restricted expression during limb bud development. Analysis of carefully selected series of patients affected with limb malformations is a clue to identify new mechanisms involved in this patterning. For this purpose, we studied several families presnsenting with Nail-Patella Syndrome corresponding to a disorder of dorso-ventral polarization; a large family affected with syndromic preaxial polydactyly and a series of Nager Syndrome cases as models of antero-posterior polarization; eventually, a cohort of patients affected with split hand/foot malformations corresponding to a defect in the signalisation center of proximo-distal growth and differenciation. This work has led us to emphasize the crucial role of gene expression regulation during limb bud patterning and more generally during embryological development
Tarnus, Évelyne. "L’adipocyte au cœur de la physiopathologie Obésité / Diabète. Petit voyage moléculaire et cellulaire dans le tissu adipeux". La Réunion, 2008. https://elgebar.univ-reunion.fr/login?url=http://thesesenligne.univ.run/08_22_Tarnus.pdf.
Texto completo da fonteGlobal incidence of obesity has increased dramatically during the last decades. The situation has become particularly alarming since obesity epidemic started to spread among children. Consequently, the impact of adipose tissue development on health, especially in excess fat accumulation conditions like obesity, has been highly studied. Adipose tissue function is critical for whole body homeostasis; this endocrine organ controls energy metabolism, modulates lipid flux, and secretes factors exhibiting endocrine, paracrine and autocrine activities. The dysregulation of adipocyte functions caused by chronic excess of energy has been directly involved in the etiology of metabolic disorders such as insulin resistance, type 2 diabetes and cardiovascular diseases. In view of the above considerations, this study was performed to detail the importance of fat mass in the body homeostasis. The study allowed the identification of new regulators of adipocyte functions and brings new evidence of adipocyte involvement in metabolic disorders
Castets, Marie. "Bases moléculaires du syndrome de l'X Fragile : de l'identification d'interacteurs de FMRP à l'établissement d'une connexion avec la voie de signalisation Rac1". Université Louis Pasteur (Strasbourg) (1971-2008), 2006. https://publication-theses.unistra.fr/public/theses_doctorat/2006/CASTETS_Marie_2006.pdf.
Texto completo da fonteFragile X syndrome results from the absence of a protein called FMRP. In order to precise FMRP function, a yeast two-hybrid screening has been carried out in our laboratory. This screening has allowed the identification of 82-FIP, a protein of unknown function. We have shown that 82-FIP is part of ribonucleoproteic complex associated to polyribosomes. Contrary to FMRP, 82-FIP subcellular localization changes through cell cycle. Thus, we propose that interaction between FMRP and 82-FIP could be transient. Characterization of CYFIP1, another protein identified in the yeast two-hybrid screening, had led to the establishment of a link between FMRP and the Rho GTPase Rac1 in Drosophila. We have shown that such a connexion is conserved in murine fibroblasts. We propose that FMRP could interfere with Rac1 signalling pathway by inhibiting the translation of PP2A, a phosphatase involved in dephosphorylation of Cofilin, a Rac1 effector that enhances actin depolymerization
Bégin, Stéphanie. "Étude de variations génétiques et épigénétiques de gènes candidats des complications métaboliques de l'obésité". Master's thesis, Université Laval, 2016. http://hdl.handle.net/20.500.11794/26948.
Texto completo da fonteObesity is now a major problem worldwide. Its associated morbidity is mostly related to the components of metabolic syndrome (MetS), a constellation of risk factors including hypertension, dyslipidemia (low HDL-C concentration and high concentration of TG), hyperglycemia and obesity. However, some obese subjects remain metabolically healthy. Genetic has thus been established as playing a major role in the development of obesity and its complications. Epigenetic factors may also be involved. The analysis of visceral adipose tissue (VAT) was thus done and led to the discovery of several differentially expressed and methylated genes between groups of obese affected and unaffected with MetS. The two candidate genes NMT1 and DGKZ were part of these and their associations with components of MetS were tested, as well as their methylation and expression levels.
Gorwa, Marie-Françoise. "Ingénierie métabolique des enzymes impliquées dans la distribution du flux d'électrons chez Clostridium acétobutylicum". Toulouse, INSA, 1996. http://www.theses.fr/1996ISAT0008.
Texto completo da fontePerron, Patrice. "Influence des polymorphismes de l'apolipoprotéine E et de la lipoprotéine lipase sur le phénotype de l'hypertriglycéridémie / hyperapobêtalipoprotéinémie". Thesis, Université Laval, 2006. http://www.theses.ulaval.ca/2006/23952/23952.pdf.
Texto completo da fonteGuo, Rongbing. "Biochemical and structural characterization of BLM Helicase". Paris 11, 2008. http://www.theses.fr/2008PA112168.
Texto completo da fonteBloom's syndrome (BS) is an autosomal recessive disorder, showing high frequency of sister chromatid exchange in lymphocyte of the patients. Since BS is preposition of a wide spectrum of cancer, the syndrome has been studied for understanding of the mechanism of cancer extensively. Ln the first part, we proved the existence of a zinc-binding domain in which a zinc ion is coordinated by four cysteines residues in RecQ-Ct domain of BLM. This conclusion is drawn from our biophysical and biochemical studies. We modeled the 3D structure of BLM protein based on that of E. Coli RecQ helicase, which revealed a similar structural domain in both helicases that coordinate zinc. The results from experiments with three mutants showed that their enzymatic activities were severely reduced or abrogated. The demetalization of zinc from BLM had no influence on the activities of BLM, but it would decrease the themostability of the protein. Ln conclusion, BLM contains a zinc binding domain with one zinc ion in each protein. The second part of our studies includes the work for understanding of causative molecular mechanism of missense mutations which happened in helicase domain of BLM found in BS patients. On the basis of the work inthe fist part, we further modeled the 3D structure of BLM in complex with A TPyS and DNA. With the model, we deduced the possible causative mechanism of mutants. We produced mutant proteins and purified them to homogeneity. The A TPase activity, A TP binding activity, DNA binding activity and helicase activity ofthe mutants were ail checked. Ln conclusion 1 showed that: 1. BLM642-129o possibly employ an "inchworm" model mechanism; 2. Amino acid residues from 861 to 901 are imprtant for DNA binding; 3. DNA binding ofBLM is mainly controlled by lobe2 and lobe3, lobel contribute to a transient ssDNA binding; 4. The annealing activity of RecQ helicase suggests a weak DNA binding activity
Laroche, Mélissa. "Lien entre la prééclampsie et les facteurs de risque cardiovasculaire : étude de gènes impliqués dans le processus inflammatoire et associés au syndrome métabolique". Thesis, Université Laval, 2009. http://www.theses.ulaval.ca/2009/26217/26217.pdf.
Texto completo da fontePreeclampsia (PE), a pregnancy complication characterized by increased blood pressure and proteinuria, is associated with significant maternal and neonatal mortality and morbidity worldwide. Recent studies suggest that women who suffered from PE are at increased risk of long term cardiovascular diseases (CVD) and that the link between these two entities could be explained by the metabolic syndrome (MS). As inflammation appears to be a major element involved as much in PE than in MS and CVD, our research aimed to investigate the potential association between genetic variations in candidate genes involved in the inflammatory process and PE risk in a study sample that included 307 women who suffered from PE and 603 matched controls. In this regard, we analysed known polymorphisms of interleukin-1α (IL-1α; 4845G>T), interleukin-6 (IL-6; -174C>G), interleukin-10 (IL-10; -1082A>G, -2849G>A), TNF-α (TNF-α; -308G>A, -857C>T) and TNF-α receptors (TNFRІ 36A>G, TNFRІІ 676T>G) genes. Our results suggest the presence of a dose-effect of the combination of genes involved in the inflammatory process on the risk of PE.
Malan, Valérie. "Apport des nouveaux outils de cytogénétique moléculaire à la définition clinique et moléculaire de nouveaux syndromes". Paris 5, 2010. http://www.theses.fr/2010PA05T025.
Texto completo da fonteChromosome abnormalities are the leading cause of mental retardation (MR) and congenital malformations. Today, because of its greater resolution (10 to 100), array CGH (Comparative Genomic Hybridization) supersedes karyotype analysis when a whole genome analysis is required. Using array CGH, 10-15% of chromosomal abnormalities are detected in patients presenting with mental retardation. The first objective of the present study was, using this novel molecular cytogenetic tool, to investigate chromosome abnormalities observed in patients presenting with a syndromic form of mental retardation. This study allowed to describe two novel clinically recognizable syndromes associated respectively with a 19q13. 11 microdeletion and Xq27. 3q28microduplication. In the second part of my thesis, a cohort of patients presenting with a syndromic overgrowth syndrome was explored using this novel approach. This cohort included patients with a clinically recognizable entity such as Sotos syndrome or Weaver syndrome as well as patients presenting with a nonspecific overgrowth conditions. Using a 1 Mb resolution BAC microarray, five pathogenic chromosome abnormalities were identified. This led us to investigate further the “negative branch” of the cohort (18 patients) using a high resolution array CGH (Agilent 244K). Interestingly, two 19p13. 3 non overlapping deletions disrupting the same gene NFIX were detected in two patients. Subsequently, the NFIX gene was studied at the molecular level in 76 patients presenting with an overgrowth syndrome. We identified by direct sequencing a heterozygous mutation of the NFIX gene in a patient with a “Sotos-like” phenotype. As the phenotype of these three patients were very similar, we hypothesized that haploinsufficiency of NFIX gene was causal. Interestingly, Nfix-/- mutant mice have a phenotype reminiscent of Marshall-Smith syndrome (MSS). This led us to screen MSS patients for NFIX mutations. We identified NFIX mutations in 9 MSS patients. The study of the consequences of these mutations on the stability of the mutated NFIX transcript led us to suggest that variation in efficiency of the process of “Nonsense-mediated mRNA decay” could explain the phenotypic differences between the Sotos-like syndrome and the Marshall-Smith syndrome. In conclusion, the present work illustrates the value of array CGH in identifying novel chromosomal disorders and in establishing the molecular basis of well described Mendelian diseases
Aury-Landas, Juliette. "Déterminisme génétique du syndrome de Li-Fraumeni : impact des mutations du gène TP53 et contribution des variations du nombre de copies d'ADN". Rouen, 2012. http://www.theses.fr/2012ROUES003.
Texto completo da fonteDumanchin-Njock, Cécile. "Les Formes autosomiques dominantes de la maladie d'Alzheimer et des démences frontotemporales associées à un syndrome parkinsonien : analyse moléculaire et fonctionnelle des gènes PS1 et tau". Rouen, 1999. http://www.theses.fr/1999ROUES063.
Texto completo da fonteChazelas, Pauline. "Syndrome de CANVAS – Analyse moléculaire des répétitions pentanucléotidiques du gène RFC1 et étude de leurs conséquences physiopathologiques". Electronic Thesis or Diss., Limoges, 2024. http://www.theses.fr/2024LIMO0006.
Texto completo da fonteThe CANVAS syndrome defines a group of clinical entities - cerebellar ataxia, sensory neuronopathy and vestibular areflexia - that together or separately are responsible for a variety of symptoms, the most common of which is a disturbance of balance. Interestingly, it has now been shown that the majority of patients present with a chronic refractory cough decades before the onset of neurological disorders. In 2019, the genetic cause of this syndrome was described. It involves the RFC1 gene, in which a biallelic expansion of AAGGG pentanucleotide repeats in intron 2 of the gene has been implicated in clinically affected patients. This large AAGGG motif replaces the AAAAG conformation, which is classically repeated 11 times in the general population. The pathophysiological cause of the disease is still unknown. Several studies have shown variability in the repeat zone, both in terms of motif conformation and number of repeats. The implications for pathology are not always clear.In this study, we focused on three aspects of this syndrome: (a) description of the variability of the repeated zone in a cohort of controls and in a cohort of patients referred for neuropathy, (b) histological study of peripheral nerve damage, particularly that of small nerve fibers, which has not been previously described, (c) study of the prevalence of biallelic expansion of the pentanucleotide AAGGG in a cohort of refractory chronic cough patients.Our results revealed novel complex repeats in both controls and patients with neuropathy. The involvement of small nerve fibers in CANVAS was objectified for the first time. Our cohort study of 68 patients with refractory chronic cough identified 16% of patients with a pathogenic AAGGG biallelic expansion, leading us to suggest that the cough of CANVAS patients is neurogenic.Taken together, the results of this thesis represent a breakthrough in the molecular and pathophysiological knowledge of CANVAS syndrome. Further work is required to understand the underlying pathophysiological mechanisms with a view to developing personalized therapies
Frappart, Pierre-Olivier. "Fonction biologique de la réponse aux lésions de l'ADN : étude génétique et moléculaire du gène responsable du Nijmegen Breakage Syndrome : NBS1". Montpellier, ENSA, 2005. http://www.theses.fr/2005ENSA0001.
Texto completo da fonteThe Nijmegen Breakage Syndrome (NBS) is an autosomal recessive disorder caused by mutations of the NBS 1 gene. Ln order to study the biological functions of the gene and its role in the tumorigenesis and in the central nervous system development, we generated NBS] mutant mouse models using conventional and conditional knock-out approaches. Homozygous disruption of the NBS] gene results in early embryonic letality associated with severe proliferation defects and increase apoptosis. Heterozygous NBS] mutant mice develop a large spectrum of epithelial tumours (liver, lung) in addition to lymphomas and exhibit a high susceptibility to ionising radiation. The inactivation of NBS] in neural stemlprogenitor cells leads to severe developmental defects of the central nervous system and particularly the cerebellum, including microcephaly, early postnatal ataxia. These anomalies are associated with impaired cellular proliferation of neuroprogenitor cells and increased cell death of post-mitotic differentiating neurones due to activation of the Atm/p53 DNA damage response pathway. Ln conclusion, these mouse models, as weIl as cells derived from mutant mice, which have been developed during my thesis represent powerful tools to study the function of the NBS 1 gene and the consequences of its inactivation
Akintayo, Ayodélé. "Caractérisation de mutations ponctuelles dans les domaines KH de la protéine FMRP". Thesis, Université Laval, 2010. http://www.theses.ulaval.ca/2010/27110/27110.pdf.
Texto completo da fontePoyau, Alain. "Etude moléculaire et génétique de la cytochrome c oxydase humaine et de la déficience de son assemblage dans le syndrome de Leigh". Lyon 1, 2000. http://www.theses.fr/2000LYO10110.
Texto completo da fonteCécille, Agnès. "Etude moléculaire des exons 8 et 9 du gène WT1 dans le syndrome de Denys-Drash et les scléroses mésangiales isolées". Paris 5, 1997. http://www.theses.fr/1997PA05P074.
Texto completo da fonteTeixeira, Luis. "Syndrome de Kallmann-de Morsier : caractérisation de deux nouveaux gènes responsables, PROK2 et PROKR2, et étude de la migration des cellules neuroendocrines à GnRH au cours de l'embryogénèse". Paris 5, 2010. http://www.theses.fr/2010PA05T032.
Texto completo da fonteKallmann syndrome (KS) combines hypogonadotropic hypogonadism and anosmia. Anosmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to gonadotropin-releasing hormone (GnRH) deficiency, which presumably results from a failure of the embryonic migration of neuroendocrine GnRH cells from the olfactory epithelium to the forebrain. In the first part, we foxind that mutations in PROKR2 and PROK2, encoding prokineticin receptor-2 and prokineticin-2, are présent in 9% of patients with KS. These mutations are mainly missense mutations resulting in loss of fonction. In addition, we discussed of the digenic or oligogenic mode of inheritance of PROKR2 and others genes involved in KS. Furthermore, we showed that PROKR2 and FGFR1 are co-expressed in same neurons, suggesting cross-talk between the FGF/FGFR1 and PROK2/PROKR2 signaling pathway. In the second part of the thesis, we observed that neuroendocrine cells synthetizing GnRHl migration defect is common in four arhinencephalie fetuses, including on fetus with KS. Based on these results we defined an olfacto-genital fetopathological sequence in human, that is to say different genetic developmental diseases resulting in abnormal olfactory development are responsible for a defect in migration of neuroendocrine cells synthetizing GnRHl
Labbé, Adam. "Profil d'expression des fibroblastes de souris embryonnaires avec une suppression dans le domaine hélicase de l'homologue du gène Werner traité avec du peroxyde d'hydrogène". Thesis, Université Laval, 2012. http://www.theses.ulaval.ca/2012/28800/28800.pdf.
Texto completo da fonteBlagosklonov, Oxana. "Pathologie moléculaire du locus AZF : recherche de corrélation génotype-phénotype gonadique". Besançon, 2002. http://www.theses.fr/2002BESA0010.
Texto completo da fonteBelhadj, Sahla. "Effet de Simmondsia chinensis sur le diabète et les maladies métaboliques : étude in vitro et in vivo". Electronic Thesis or Diss., Strasbourg, 2017. http://www.theses.fr/2017STRAJ061.
Texto completo da fonteHerbal medicine refers to medicine based on plant extracts and natural active ingredients. As the number of diabetic patient increase dramatically, many researchers have sought to evaluate the pharmacological action of several traditional plants. The jojoba (Simmondsia chinensis) is a shrub of the family Simmondsiaceae which has many properties linked to a very rich and diversified composition. The objectives pursued during this thesis were to validate the use of jojoba in the prevention of type 2 diabetes and its complications by evaluating in vitro the antioxidant effect of an aqueous extract of jojoba and compare this extract to a pure molecule, the simmondsin, on a pancreatic beta cell line, by demonstrating the efficacy of the various extracts of the jojoba seed on a hepatic cell line following chronic hyperglycemia and hyperinsulinemia and finally by validating in vivo the efficacy of jojoba on rat a model of glucose intolerance induced by high-fat high-fructose diet (HFHF). The results in vitro showed that the various extracts of the jojoba seed tested were not cytotoxic on the cell lines but provided protection against oxidative stress induced by hyperglycemia and hyperinsulinemia. This protection appears to be related to the inhibition of the expression of the p22phox pro-oxidant enzyme. In vivo, the study on the HFHF rat model confirmed the anorectic effect of jojoba combined with a curative effect on complications, in particular liver and kidney damage, which could be linked to its antioxidant properties. This study demonstrated the efficacy of jojoba seeds in the treatment of diabetes and its complications
Descargues, Pascal. "Développement et caractérisation d'un modèle murin du syndrome de Netherton : vers l'identification de cibles thérapeutiques". Toulouse 3, 2006. http://www.theses.fr/2006TOU30019.
Texto completo da fonteMaimaitiming-Madani, Suliya. "Contribution du système des peptides natriurétiques à la prédisposition génétique au syndrome d'insulino-résistance et au diabète de type 2 dans la population française : études prospectives D.E.S.I.R. et DIABHYCAR". Paris 7, 2010. http://www.theses.fr/2010PA077040.
Texto completo da fonteThe natriuretic peptides System plays an important role in lipid metabolism and in blood pressure regulation. We evaluated the effect of polymorphisms at NPPA-NPPB locus in the metabolic syndrome, the intermediate phenotypes of this syndrome, the blood pressure, the risk of the hyperglycemia and the BNP plasma concentrations in a nine-year follow-up study in a general population in France, the cohort: DESIR. We also studied the associations of these polymorphisms with the blood pressure and the vascular complications of the type 2 diabetes in DIABHYC AR study. A replication study with 7 international populations was also carried out. Our results shown that the polymorphisms at NPPA-NPPB locus were associated with the metabolic syndrome, with several metabolic syndrome related traits, with the risk of hyperglycemia, with BNP plasma concentrations and the blood pressure in the DESIR study, and were associated with the blood pressure in DIABHYCAR study. There was no significant association with the vascular complications. In conclusion, the genetic variations at NPPA-NPPB locus were able to modify the BNP plasma levels and they were associated with the metabolic syndrome, the intermediate phenotypes of this syndrome, the hyperglycemia risk and the blood pressure. We suggest that even replicated and biologically plausible genetic association ?studies based or surrogate markers do not easily translate into clinically meaningful prognosis
Dina, Christian. "Analyse d'association génome entier de 3 pathologies : le diabète de type 2, le syndrome de Brugada et le prolapsus valvulaire mitral : observations sur l'architecture génétique de traits complexes". Nantes, 2012. http://archive.bu.univ-nantes.fr/pollux/show.action?id=d029660f-aac0-4e98-ad6a-35894eef4403.
Texto completo da fonteThe escalating prevalence of cardio-vascular and metabolic disorders, and the limitations of currently available preventive and therapeutic options are increasingly important factors reducing the quality and life expectancy resulting in a dramatic increase in public spending in the health field. This emergency highlights the need for a more complete understanding of the pathogenesis of these diseases as well as the need for bio-markers to increase their predictability is a priority. The genetic approach, in this context, is among the most promising strategies. This approach has many variants. One of the most popular in the last decade is the approach of genome-wide association studies. The strategy is based on the assumption of an important role played by common genetic variants for common diseases. This paradigm has been called the assumption of "common variant, common disease". As part of my thesis, I explored the effect of common variants in three diseases, Diabetes Type 2, Mitral Valvular Prolapse, both being common pathologies and the Brugada syndrome, which is rare in the population. These three diseases strongly contribute to the explosion of population health needs, either by the severity of complications for Type 2 Diabetes, through the need of major surgery for Mitral Valvular Prolapse and through the increased risk of Sudden Death for Brugada Syndrome. I applied various techniques such as genetic imputation, meta-analysis and correction of stratification to help highlight their genetic bases. In Type 2 diabetes, highlighting of the genetic architecture was already well advanced and I participated in the deepening of knowledge. This work helped identify up to 40 genes. We have also shown that there is a substantial polygenic component underlying the genetic architecture of this disease and that most of the identified genes point to a dysfunction of beta cells. Studies on Mitral Valvular Prolapse are less advanced. I selected genetic variants showing a possible association and these variants are being replicated. Preliminary results on the Framingham study showed the possible involvement of genes of the extracellular matrix. Finally, for Brugada Syndrome, I clearly identified three loci that show a highly significant association with the disease. These loci were replicated as well in a European population in Japanese population. If the involvement of genes coding for ion channel proteins (SCN5A and SCN10A) seems to be confirmed, strengthening the definition of Brugada Syndrome as a channelopathy, another pathway possibly related to cardiac development was also identified (through the gene HEY2). Finally, during my PhD, I also contributed to create the concept of common variant for rare disease (CV/CR)
Belhadj, Sahla. "Effet de Simmondsia chinensis sur le diabète et les maladies métaboliques : étude in vitro et in vivo". Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAJ061.
Texto completo da fonteHerbal medicine refers to medicine based on plant extracts and natural active ingredients. As the number of diabetic patient increase dramatically, many researchers have sought to evaluate the pharmacological action of several traditional plants. The jojoba (Simmondsia chinensis) is a shrub of the family Simmondsiaceae which has many properties linked to a very rich and diversified composition. The objectives pursued during this thesis were to validate the use of jojoba in the prevention of type 2 diabetes and its complications by evaluating in vitro the antioxidant effect of an aqueous extract of jojoba and compare this extract to a pure molecule, the simmondsin, on a pancreatic beta cell line, by demonstrating the efficacy of the various extracts of the jojoba seed on a hepatic cell line following chronic hyperglycemia and hyperinsulinemia and finally by validating in vivo the efficacy of jojoba on rat a model of glucose intolerance induced by high-fat high-fructose diet (HFHF). The results in vitro showed that the various extracts of the jojoba seed tested were not cytotoxic on the cell lines but provided protection against oxidative stress induced by hyperglycemia and hyperinsulinemia. This protection appears to be related to the inhibition of the expression of the p22phox pro-oxidant enzyme. In vivo, the study on the HFHF rat model confirmed the anorectic effect of jojoba combined with a curative effect on complications, in particular liver and kidney damage, which could be linked to its antioxidant properties. This study demonstrated the efficacy of jojoba seeds in the treatment of diabetes and its complications
Le, Hellard Stéphanie. "Cartographie génétique de facteurs de susceptibilité à l'épilepsie myoclonique juvénile et étude de l'implication du récepteur nicotinique neuronal à l'acétylcholine dans les épilepsies idiopathiques". Montpellier 2, 1998. http://www.theses.fr/1998MON20272.
Texto completo da fonteTournier, Isabelle. "Mécanismes d'inactivation des gènes impliqués dans les deux formes majeures de prédisposition héréditaire aux cancers : la prédisposition aux cancers du sein et de l'ovaire et le cancer colorectal héréditaire non polyposique (HNPCC) ou syndrome de Lynch". Rouen, 2007. http://www.theses.fr/2007ROUE04NR.
Texto completo da fonteKobiita, Ahmad. "Un décalage de l'alimentation déclenche une asynchronie entre l'horloge circadienne centrale et les horloges périphériques et engendre un syndrome métabolique". Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAJ003/document.
Texto completo da fonteThe sequence of molecular events through which alterations in externals cues may impinge on circadian clocks, and generate pathologies, was mostly unknown. During my thesis work, I have molecularly deciphered, how switching feeding in mice, from the “active” to the "rest" phase [Restricted Feeding (RF)] , alters the metabolism through hypoinsulinemia during the “active” phase, leading to increased PPARα activity, thereby reprograming both metabolism and RevErbα expression and leads to a 12h circadian clock-shift in peripheral tissues.Most notably, the lack of PPARα expression in the suprachiasmatic nuclei (SCN) prevents a shift of the central clock. Therefore, the “active” and “rest” phases controlled by the SCN clock and gene expression controlled by the peripheral circadian clocks are misaligned. Most interestingly, this misalignment generates a metabolic syndrome-like pathology, similar to that associated with shiftwork schedules
Lachapelle, Sophie. "Identification de nouveaux partenaires protéiques de la protéine WERNER". Thesis, Université Laval, 2011. http://www.theses.ulaval.ca/2011/28276/28276.pdf.
Texto completo da fonteV, de Medeiros Paula F. G. "Syndromes liés à la délétion 22q11 : 1) Contribution à l'étude phénotypique : 2) Analyse cytomoléculaire de la taille de la délétion : 3) Recherche d'une corrélation clinique et moléculaire (Doctorat: Génétique Médicale)". Strasbourg 1, 1996. http://www.theses.fr/1996STR1M425.
Texto completo da fonteHuot, Marc-Étienne. "Études de l'expression des protéines fragile X related 1 (FXR1P) durant le développement des vertébrés". Thesis, Université Laval, 2005. http://www.theses.ulaval.ca/2005/22666/22666.pdf.
Texto completo da fonteFragile X Mental Retardation Protein (FMRP) is part of a mRNA-binding proteins family that includes the Fragile X Related 1 and 2 proteins (FXR1P and FXR2P). These proteins share multiple functional domains typical of mRNA-binding domain (two KH domains and 1 RGG box) as well as a nuclear and a cytoplasmic localization domain. Whereas absence of FMRP is the cause of Fragile X Mental Retardation in human, it is not known whether FXR1P and FXR2P are associated to any pathology and whether these homologous proteins can compensate for the absence of FMRP in the case of the Fragile X syndrome. Knockout mice for FXR proteins are powerful tools that are commonly used in research to shed light on the functions of these proteins and point out their embryonic involvement. However, the Fxr1 knockout mouse didn’t proved to be a good model as the two mentioned above. In mammals, we have shown that FXR1 play a key role in muscle differentiation, since two of the six isoforms are muscle specific and are believed to be essential for the normal development of the cardiac and skeletal muscle. Although essential for embryonic development, it is nearly impossible to study the developmental implication of the differential expression of these tissues specific proteins in mammals due to the large number of FXR1P isoform. Simpler model such as drosophila melanogaster are being used, but this model have only one proteins (dFMRP) which is expressed ubiquitously in this organism and do not represent the tissue specific expression of some of the family member. We choose an intermediate model such as Xenopus laevis, which is an extensively used model for developmental studies, and proceeded with the inactivation of xFxr1. In Xenopus laevis, we found two different xFxr1 proteins isoform; one short isoform (84 KDa) is ubiquitously expressed in every tissues except in muscle, whereas the long isoform (88 KDa) is expressed only in cardiac and skeletal muscle. Specific inactivation of xFxr1 messengers during the early development gave us new insight on the specific functions of these proteins during the embryogenesis and primary myogenesis.
Le, Guen Tangui. "Caractérisation phénotypique et moléculaire de déficiences humaines liées à des dysfonctions des télomères et / ou de la réparation de l’ADN". Thesis, Paris 5, 2013. http://www.theses.fr/2013PA05T092/document.
Texto completo da fonteMaintaining genome integrity is essential for cell survival and propagation of the genetic information. Improper management of DNA damages and / or aberrations in maintenance of telomere - the ends of linear chromosomes - causes humans disorders associated with genetic instability. Thus, in humans, telomere dysfunction causes Dyskeratosis Congenita (DC), and its rare and severe form, Hoyeraal-Hreidarsson Syndrome (HHS). DC and HHS are mainly characterized by progressive bone marrow failure, developmental defects and predisposition to cancer. In addition, many syndromes involving immunodeficiency and developmental abnormalities are caused by defects in DNA repair (e.g. severe immune deficiencies, Fanconi Anemia (FA), Ataxia Telangiectasia (AT),…). In this work, we performed a phenotypic and genetic study of patients with two syndromes presenting distinct clinical features. This work permitted : 1) on one hand, to identify RTEL1 mutations in patients with HHS and describe a new molecular cause of this disease. The analysis of patients’ cells revealed the crucial role for RTEL1 in genome stability and telomere maintenance in human cells. 2) on the other hand, to identify mutations in MYSM1, a histone deubiquitinase, in a new immuno-hematological syndrome associated with defects in DNA repair and sharing some similarities with Fanconi anemia. This study demonstrates for the first time that, in addition to its role in transcriptional regulation, MYSM1 is required to cope with DNA damages
Mechakra, Asma. "Étude cellulaire et moléculaire de quelques aspects de la fibrillation atriale et du syndrome du QT long : rôle des connexines 40 et 43, du facteur de transcription PITX2c et du canal potassique codé par KCNH2". Thesis, Lyon 1, 2014. http://www.theses.fr/2014LYO10005.
Texto completo da fonteAtrial fibrillation (AF) is the most common sustained arrhythmia in adults. It is associated with an increased risk of stroke, heart failure and mortality. A mechanism of atrial torsades has been described in patients with congenital long QT syndrome (LQTS). Despite the already existing body of literature, the mechanisms involved in the genesis and maintenance of these arrhythmias remain poorly understood and constitute an obstacle in diagnosis and management of these diseases. In the first part of this work, we discussed the histology of connexins (Cxs) and their distribution in two groups of patients (with and without FA), by confocal microscopy approach. We have described a network of fibroblasts and myocytes communicating across Cx 40 and 43 and the presence of myofibroblasts, of a strong fibrosis and of a remodeling of Cx 40 and 43 distribution in the tissue of AF patients. In addition, to identify new mutations involved in these arrhythmias, we studied a cohort of 60 patients with AF. Genetic investigations and functional study enabled us to associate five novel mutations with AF: M207V and P41S (PITX2), G277E (Cx 40) A253V (Cx 43) and P1034H (KCNH2). These mutations likely play a key role in the formation of the arrhythmogenic substrate. Finally, we explored the electrophysiological impact of a KCNH2 variant, R148W, initially found in a child who died suddenly during sleep and subsequently disclosed in several family members, some with a long QT interval. When expressed in Xenopus oocytes and studied in voltage-clamp, this variant reduces the current by 29%, which might predispose to torsades de pointes and partly explain the QTc prolongation. In addition to these newly discovered gene variants, this work is the first to report a gain-of-function mutation of the transcription factor PITX2c in AF. Histological remodeling of Cxs and the nucleotide variants affecting GJA1, GJA5, PITX2 and KCNH2 might thus participate in the etiology of AF and LQTS