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Mutations in the ROMK gene in antenatal Bartter syndrome are associated with impaired K+ channel function
C Derst1, M Konrad, A Köckerling
1Institute of Physiology, Philipps University, Marburg, Germany.
Insights
Mutations in the renal potassium channel ROMK cause salt wasting in antenatal Bartter syndrome. These genetic defects impair kidney function, leading to significant salt loss in affected children.
Area of Science:
- Nephrology
- Molecular Biology
- Genetics
Background:
- Antenatal Bartter syndrome involves impaired salt reabsorption in the thick ascending limb of Henle's loop (TALH).
- Mutations in the renal potassium channel ROMK (KCNJ1) are identified in some patients with this condition.
Purpose of the Study:
- To analyze the electrophysiological function of five novel ROMK channel mutations.
- To understand the molecular basis of renal salt wasting in Bartter syndrome.
Main Methods:
- Whole-cell patch-clamp recordings were performed on COS-7 kidney cells transfected with wild-type and mutant ROMK1.
- Electrophysiological properties of ROMK channel mutations (V72E, D108H, P110L, A198T, V315G) were assessed.
Main Results:
- Wild-type rat ROMK1 exhibited significant K+ currents, characteristic of inwardly rectifying KIR channels.
- Mutated ROMK1 channels showed either no current or significantly reduced currents (<200 pA).
Conclusions:
- ROMK channel mutations lead to loss of tubular K+ channel function.
- This dysfunction likely inhibits apical membrane potassium recycling and Na-K-2Cl-cotransport in the TALH.
- Mutations in the ROMK potassium channel are primary causes of renal salt wasting in a subset of antenatal Bartter syndrome patients.
Abstract:
Children with the antenatal variant of Bartter syndrome present the typical pattern of impaired salt reabsorption in the thick ascending limb of Henle's loop (TALH) resulting in marked ante- and postnatal salt wasting. In some of these patients mutations in the renal potassium channel ROMK (KCNJ1) have been found. We analyzed the electrophysiological function of five recently described ROMK channel mutations (V72E, D108H, P110L, A198T and V315G). In whole cell patch clamp recordings wildtype rat ROMK1 exhibited K+ currents of >1 nA at a membrane potential of 100 mV when transfected into COS-7 kidney cells. These currents were sensitive to external Ba2+ and internal Mg2+, which are typical features of the inwardly rectifying KIR channel. In contrast mutated ROMK1 cDNAs expressed either no or only infrequently small currents (<200 pA). Loss of tubular K+ channel function probably prevents apical membrane potassium recycling with secondary inhibition of Na-K-2Cl-cotransport in the TALH. We conclude that mutations in the potassium channel ROMK are the primary events causing renal salt wasting in a subset of patients with the antenatal variant of Bartter syndrome.