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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“).