Recently, we have identified mutations of the potassium channel KCNJ10 (Kir4.1) being causative for a novel autosomal recessive disease. This syndrome is characterized by epilepsy, ataxia, sensorineural deafness, and salt wasting tubulopathy (EAST (Bockenhauer D et al. 2009) or SeSAME (Scholl UI et al. 2009) syndrome). Here, we investigated the functional consequences of three published and one novel mutation of KCNJ10.

In whole cell patch clamp experiments, the mutation R199X leading to a truncated C-terminus resulted in a total loss of function. Cells transfected with the mutated forms of KCNJ10 R65P, G77R, and R175Q (novel mutation) showed a strongly reduced K⁺ conductance compared to cells transfected with wildtype KCNJ10. The reduction in whole cell K⁺ conductance was paralleled by a depolarized membrane voltage. Co-expression with KCNJ16 (a partner of KCNJ10 in native tissues) generally reduced the whole cell K⁺ conductance and did not improve function of mutated channels. Single channel analyses of homomeric KCNJ10 channels were performed in cell-attached mode. Wildtype KCNJ10 exhibited a high open probability and a single channel conductance of 26.8±1.4 pS (symmetric K⁺). R65P and R175Q showed strongly reduced open probabilities and channel flickering.

In conclusion, the four EAST-causing mutations of KCNJ10 led to complete or partial loss of function. Co-expression of mutated channels with KCNJ16 did not improve the residual function. In the future, pharmacological activation of residual channel function could help to improve clinical symptoms of EAST patients.

Bockenhauer D et al., 2009. N Engl J Med 360(19):1960-1970.

Scholl UI et al., 2009. Proc Natl Acad Sci U S A 106(14):5842-5847 begin_of_the_skype_highlighting