Recently, several families were reported having seizures, sensorineural deafness, ataxia and renal wasting of Na+, K+ and Mg++ (SeSAME/EAST syndrome) linked to loss of function mutations of the Kir4.1 K+ channel. We have used two-electrode voltage clamp, immunoblotting, immunofluorescence and molecular modeling to show that impaired pH gating of the channel underlies the decreased function seen in many of the mutants. We are currently studying the renal phenotype of a Kir4.1 knockout mouse which appears to recapitulate the human disease. Future work will be directed toward understanding how loss of function of this basolaterally localized channel is coupled to the decreased reabsorption of Na+, K+ and Mg++ on the apical surface of the tubules through use of distal nephron derived cell lines.
A family in my outpatient nephrology clinic suffers with this rare genetic disease which is linked to mutations in fibronectin and which results in fibronectin deposition within glomeruli and end stage renal disease by median age of ~50. We are developing a transgenic mouse model overexpressing mutant fibronectin in order to gain insight into the pathogenesis of this disease and potential therapeutic targets.