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Maladies chromosomiques constitutionnelles : corrélations génotype-phénotype

Abstract : Classical theory saying that a balanced structural chromosome rearrangement is linked to a normal phenotype, and that an unbalanced one implies an alteration of the phenotype is not always true. Indeed, althrough new molecular techniques of cytogenetics, described in the first part of this manuscrit, allow too finely correlate genotype to phenotype, the occurence of genome polymorphism, complex regulation of gene expression and epigenetic effects can yield unexpected phenotypes. In the second part of this work, we discuss hypotheses that can explain such genotype-phenotype discrepancies through the study of published cases. These studies show the need for new molecular techniques in cytogenetics in order to better approach the cases where caryotypes and observed phenotypes are discordant. In the third part, we used the congenital diaphragmatic hernia disease, a malformation linked to many chromosomal abnormalities, and the retinoic pathway hypothesis as a model to study the correlation between genotype and phenotype. A literature search allowed us to identify many candidate genes, and to discuss their possible role in the CDH genesis. In parallel, expression of many genes from the retinoic signaling pathway was measured in fetal skin fibroblasts carrying or not CDH. The final aim of this work is to support the hypothesis that retinoids are implicated in the formation of diaphragmatic hernia and to identify new candidate genes.
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Submitted on : Wednesday, August 29, 2012 - 3:21:22 PM
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Carole Goumy. Maladies chromosomiques constitutionnelles : corrélations génotype-phénotype. Génétique. Université d'Auvergne - Clermont-Ferrand I, 2009. Français. ⟨NNT : 2009CLF1MM19⟩. ⟨tel-00726288⟩

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