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Analyse fonctionnelle de nouvelles mutations pathogènes du canal chlorure CLC-KB impliquées dans le syndrome de Bartter

Abstract : Bartter's syndrome type III results from loss-of-function mutations in the CLCNKB gene that encodes the CLC-KB chloride channel. To date, few CLCNKB mutations have been fully functionally investigated. In this study, we have investigated the functional consequences of novel CLCNKB mutations (collected by the Department of Genetics of the European Georges Pompidou Hospital) in Xenopus laevis oocytes, HEK293T and MDCK cells, in terms of electrical activity and surface expression. We have demonstrated that all mutations decreased plasma membrane expression and conductance of CLC-KB in similar proportions, indicating that altered cell surface expression is the main functional defect caused by CLCNKB mutations. However, some mutations also alter external pH and calcium sensitivity. The physiological relevance of these regulations is open to question, but clearly, their alteration could have a pathological impact. In conclusion, this functional study highlights the essential role of CLC-KB in the preservation of sodium balance and provides new clues for finding specific therapeutic drugs that would be able to restore sufficient function of CLC-KB in patients with Bartter's syndrome type III. Moreover, functional analysis of mutations is an extremely powerful tool for structure-function studies. In association with the search of new partners, it should allow discovering the physiological regulations of this channel that are almost unknown.
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Submitted on : Friday, June 7, 2013 - 12:27:19 PM
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  • HAL Id : tel-00831597, version 1

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Mathilde Keck. Analyse fonctionnelle de nouvelles mutations pathogènes du canal chlorure CLC-KB impliquées dans le syndrome de Bartter. Physiologie [q-bio.TO]. Université Pierre et Marie Curie - Paris VI, 2012. Français. ⟨NNT : 2012PA066222⟩. ⟨tel-00831597⟩

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