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Contribution à l’amélioration des connaissances sur la relation génotype-phénotype dans la mucoviscidose et caractérisation phénotypique de l’inflammation pulmonaire

Abstract : Cystic fibrosis (CF) is the most common severe autosomal recessive disorder in the Caucasian population. Apart from classical CF, there is a broad range of phenotypes associated with a huge genotypic variability concerning the mutations in the CFTR gene. In order to develop a mutation specific therapeutic approach, a better understanding of the phenotype]genotype correlation and its underlying mechanism is primordial. In the first part of our work, we focused on genotype‐phenotype correlation. With a retrospective study on 694 cases of prenatal diagnosis of CF for fetal bowel anomalies, we report on the most evocative digestive abnormal patterns and propose to revise current strategies for the CFTR gene analysis. The second part concerns the CFTR promoter functional analysis. Mutations which conserve a residual CFTR channel function, such as mutations affecting the gene regulation, can be involved in atypical phenotypes. However, knowledge about the CFTR promoter reminds poor and the clinical significance of new variants identified in this region is difficult to evaluate. Our implementation of functional analysis tools will improve the appreciation of such new variants in the CFTR promoter and open new insights for the gene regulation study. In the third part, we contributed to study the inappropriate pulmonary inflammation which characterizes CF, the respiratory affection being the major factor of morbidity and mortality in the disease. COMMD1 is a pleiotropic protein involved in CFTR trafficking, ionic exchanges in the airways surface liquid and inflammation inhibition. In our study, we show the anti]inflammatory role of COMMD1 in the context of cystic fibrosis. Modulation of the exaggerated inflammation belongs to currently therapeutic challenges, and we show the ability of COMMD1, a protein partner of CFTR, to buffer the NF-kB pathway activation
Keywords : Cftr Promoter
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https://tel.archives-ouvertes.fr/tel-00733488
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Submitted on : Tuesday, September 18, 2012 - 5:12:14 PM
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Alix De Becdelièvre. Contribution à l’amélioration des connaissances sur la relation génotype-phénotype dans la mucoviscidose et caractérisation phénotypique de l’inflammation pulmonaire. Médecine humaine et pathologie. Université Paris-Est, 2011. Français. ⟨NNT : 2011PEST0084⟩. ⟨tel-00733488⟩

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