Klassifikation und Reparatur von Mutanten des nierenspezifischen Kalium- Kanals ROMK, ursächlich beteiligt am Krankheitsbild des Hyperprostaglandin- E-/ antenatalen Bartter- Syndroms

Das Hyperprostaglandin E Syndrom / antenatale Bartter Syndrom (HPS/ aBS) ist ein autosomal rezessiv vererbtes Krankheitsbild, das durch die typische Trias pränatale Manifestation, Hypo-/ Isosthenurie und Nephrokalzinose gekennzeichnet ist. Das Polyhydramion führt zu Frühgeburtlichkeit und ohne adäqu...

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Bibliographische Detailangaben
1. Verfasser: Ermert, Saskia Christine
Beteiligte: Waldegger, Siegfried (Prof. Dr.) (BetreuerIn (Doktorarbeit))
Format: Dissertation
Sprache:Deutsch
Veröffentlicht: Philipps-Universität Marburg 2008
Zentrum für Kinder- und Jugendmedizin
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Inhaltsangabe: Hyperprostaglandin E Syndrome (HPS), also called antenatal Bartter Syndrome (aBS), is an autosomal recessive disease. It shows three typical symptoms, namely prenatal manifestation, Hypo-/Isosthenuria and Nephrocalcinosis. The accompanying polyhydramion leads to premature birth and the children die of renal failure if not supplied with enough liquid and electrolytes. Molecular characteristics of this clinical picture are NKCC2- mutations and a defect in the potassium channel ROMK. ROMK is a member of the potassium-selective inwardly directed Kir- channel family and is located apically in the ascending tubule of the Henle loop. Currently there is no causal therapy available. Children are treated with Indometacin, a cyclooxigenase- inhibitor that alleviates the symptoms through an unknown mechanism. The aim of this work was to classify ROMK-mutations based on a five-class-model and to show that it is possible to repair ROMK-mutations. We could show through Western Blot and immunofluorescence analyses that the aminoglycosides gentamycin and G-418 can in part repair the ROMK 1 stop- mutants W77X and Y79X: After in-vitro treatment with aminoglycosides, 5- 20 % of the analyzed HEK 293 cells expressed wild-type ROMK near the plasma membrane. The butyratanalogon 4-Phenylbutyrate led to a change in the cytoplasmatic localization of ROMK in all of the eight available trafficking- mutants (T71M, V72E, Y79H, A198T, L220F, A306T, R324L, F325C). Additionally, after this treatment we observed the channel protein near the plasma membrane in 15- 45 % of the A198T, L220F, A306T und R324L mutants and we were able to investigate the general effect of 4-PBA on transfected and untransfected cells with growth curves. In conclusion we showed that different ROMK- mutation-classes can be manipulated. This finding could be the first step to develop a causable treatment for HPS/ aBS.