Dokument

Zusammenfassung:
Das Gitelman Syndrom ist eine autosomal rezessiv vererbte renale Tubulopathie, die durch eine hypokalämische Alkalose, eine Hypomagnesiämie und eine Hypocalciurie charakterisiert ist. Die Erkrankung basiert auf Mutationen im SCL12A3 Gen, das für den Natrium-Chlorid-Transporter (NCCT) im distalen Abschnitt des Tubulussystems der Niere kodiert. Funktionelle Untersuchungen mittel Cl-Uptakes sowie Untersuchungen zur Proteinbiochemie mittels Western Blot und Immunfluoreszenz wurden durchgeführt, um den Effekt von acht neuen Mutationen auf die NCCT-Funktion zu analysieren. Nach heterologer Expression des Wildtyps in Eizellen des südafrikanischen Krallenfrosches zeigten die Mutationen keine signifikant gesteigerte Chloridaufnahme. Bei keiner der Mutationen konnte eine Restaktivität nachgewiesen werden. In den Western Blot Untersuchungen konnte kein Unterschied zwischen dem Wildtyp und den Mutationen gesehen werden: alle, bis auf die Mutation T180R, wiesen eine spezifische Bande bei 110kD auf. Die Oberflächenexpression wurde mit Hilfe von Immunfluoreszenzanfärbungen untersucht. Die Mutation T180R konnte passend zum Ergebnis der Western Blot Analyse nicht mit Hilfe der Immunfluoreszenz angefärbt werden. Die Mutation R83W konnte nur im Cytoplasma der Zelle nachgewiesen werden. Die Mutationen G731R, R887Q und V1015M zeigten sowohl Signale im Cytoplasma als auch in der Plasmamembran. Nicht zu unterscheiden vom WT und fast ausschließlich in der Plasmamembran anzufärben, waren die Mutationen R135C, D486N und S614P. Weitere funktionelle Untersuchungen mit Hilfe der WNK1 zeigten, dass im Gegensatz zum Wildtyp die mutierten NCCT Proteine nicht aktiviert wurden. Zusammenfassend stellt diese Studie dar, dass der Grund für den Funktionsverlust der mutierten NCCT Transporter in unterschiedlichen Mechanismen zu suchen ist: in der gestörten Proteinsynthese, in der gestörten Proteinweiterverarbeitung, in dem gestörten Einbau in die Plasmamembran oder in der intrinsischen Aktivität des Transporters. Eine Korrelation zwischen dem Genotyp und der Krankheitsausprägung bei den Gitelman Patienten kann mit dieser Studie nicht gezeigt werden.

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