Mutationsanalysen bei hereditären Salzverlusttubulopathien

Inherited salt-losing tubulopathies with hypokaliemic alkalosis involve an overlapping set of renal tubular disorders that can be subdivided into at least 4 phenotypes: 1) classic Bartter syndrome (cBS), 2) Gitelman syndrome (GS), 3 ) hyperprostaglandin E syndrome/antenatal Bartter syndrome (HPS/aBS), and 4) antenatal Bartter syndrome with sensorineuronal deafness (BSND). We looked for mutations in 71 kindreds. 34 of them view the phenotype of the HPS, 22 of the cBS and 15 kindred could not assign to the HPS or cBS, but did not show symptoms of GS or BSND. First we examined the KCNJ1 gene, encoding for the apical inwardly rectifying potassium channel ROMK in the thick ascending limb of Henles loop (mTAL) in the nephron. Mutations in this gene causes the antenatal form of Bartter syndrome (HPS). We could show 19 mutations, 5 of them appeared homocygot and the other 14 heterocygot. We found point mutations (14), deletions (4) an one insertion. In the second part the basolateral chloride channel ClC-Kb was examined. It is also located in the thick ascending limb of Henles loop in the distal nephron. Mutations in this gene causes the classic variant of Bartter syndrome We showed 9 mutations, eight heterocygot and one homocygot. They were presented as point mutations (5), three deletions and one complex mutation be made of a combination of a point mutation, a 12 bp deletion and 9 bp insertion. The great number of mutations found in these children underline the main role of ROMK and ClC-Kb in causing HPS and cBS. It was difficult to show a correlation between the kind of mutation and the severe of the phenotype because of antenatal treatment of the children with indometacin and the less data from children treatd in other hospitals. We did not found mutations in every case of our cohort. That ist why there must be at least one more gene which causes Bartters syndrome.