Molekulargenetische Studien bei Patienten mit Gitelman-Syndrom

Das Gitelman-Syndrom wurde vor ungefähr 50 Jahren erstbeschrieben und ist eine laborchemisch durch hypokaliämische Alkalose, Hypokalziurie und Hypomagnesiämie charakterisierte renale Salzverlusterkrankung, die sich meist im Jugend- oder Erwachsenenalter mit Adynamie, Muskelkrämpfen und eher mild...

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Bibliographic Details
Main Author: Swoboda, Maximilian
Contributors: Klaus, Günter (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2017
Online Access:PDF Full Text
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Gitelman syndrome (GS) was first described about 50 years ago and is a renal salt-losing tubulopathy, biochemically characterized by hypokaleamic alkalosis, hypocalicuria and hypomagnesiemia which appears first in adolescence or adulthood with adynamia, muscle cramps and rather modest loss of salt. This autosomal recessive disease is caused by inactivating mutations in the SLC12A3-gene which encodes for the NaCl-Cotransporter NCCT in the distal convolut (DCT) of the renal tubule system. In this present paper a genetic characterization of a large cohort of 73 GS patients who are not related to each other was performed. Interestingly, at least one out of five pathologic mutations (G741R, G439S, C994Y, IVS24(+1)G>T, L859P) were detected in almost two-thirds of the patients. 11 patients (15%) were even carrying two of the five mentioned mutation either in a compound heterozygotic or homozygotic state. Furthermore, 43 additional mutations could be identified. Considering these facts, the majority of the european patients underlies only a few pathogenetic mutations which can be detected with the help of a simple algorithm. Despite new developments in the genetic diagnostics using high-throughput screening (next-generation-sequencing), a time- and costefficient initial screening of the SLC12A3-gene for patients with GS, which primary analyses those parts of the gene containing the five mutations, can be made possible. This screening method would have detected at least one disease relevant mutation in almost 80% within the scanned cohort. The use of this simplified screening algorithm was veryfied by a retrospective analysis of the mutational spectrum of a great american GS-cohort. To resolve the reason for the observed mutational accumulation, haplotypes researches using SNP- and microsatellite tests were executed in patients carrying at least one of the mentioned five mutations. For all of the five mutations a mutation-associated haplotype could be identified. Hereby it could be shown that the mutational accumulation do not underlie recurrent mutational events, but rather are a singular mutational event which occurred many years ago in a common ancestor („founder“).