2002 Global Researcher Conference Proceeding
April 26 - 28, 2002
|Conference:||2002 Global Researcher Conference|
|Title:||High proportion of ROMK processing defects underlying hyperprostaglandin E syndrome/antenatal Bartter syndrome|
|Authors:||Konrad, Martin; Peters, Melanie; Seyberth, M.D., Hannsjorg W.|
|Institutions:||Philipps University, University Children's Hospital, Philipps University Marburg|
Mutations in the renal inwardly rectifying K+ channel ROMK cause autosomal recessive hyperprostaglandin E syndrome/ antenatal Bartter syndrome (HPS/aBS), a severe salt-losing tubular disorder leading to extensive salt- and water wasting.
Numerous mutations distributed all over the protein have been identified in HPS/aBS patients. Until now, most of the missense mutations have been clustered in two regions: (i) the channel core region (amino acids 84-180), and (ii) the pH sensor built up from the amino acid residues Arg/Lys/Arg at positions 41, 80, and 311. Mutations in the channel core region are thought to lead to defective K+ conductance due to conformational changes, whereas mutations affecting the Arg/Lys/Arg triad shift the pH gating off the neutral range to more alkaline pH values. However, many ROMK mutations are not located in these two regions and thus other pathogenic mechanisms are conceivable, e.g. sorting or processing defects. In the present study, we evaluated the underlying pathogenic mechanisms of 18 naturally occurring ROMK mutations by heterologous expression in Xenopus oocytes and a human kidney cell line. ROMK mutations were functionally analyzed by electrophysiological methods in oocytes and immunofluorescence in oocytes and HEK-cells. We identified a high proportion of ROMK mutants (14/18) that did not reach the cell surface revealing defective processing. High expression levels rescued 6/14 ROMK mutants leading to significant potassium currents in the two electrode voltage clamp analysis.
In conclusion, this study revealed that defective ROMK processing might be the predominant pathogenic mechanism leading to HPS/aBS and this might enable the development of new therapeutic strategies directed at the restoration of channel function as already shown for other diseases caused by processing defects, such as cystic fibrosis or NDI.