Mahmood, F., Mozere, M., Zdebik, A.A., Stanescu, H.C., Tobin, J., Beales, P.L., Kleta, R., Bockenhauer, D., and Russell, C. (2013) Generation and validation of a zebrafish model of EAST (Epilepsy, ataxia, sensorineural deafness and tubulopathy) syndrome. Disease models & mechanisms. 6(3):652-60.
Recessive mutations in KCNJ10, which encodes an inwardly rectifying potassium channel, were recently identified as the cause of EAST syndrome, a severe
and disabling multi-organ disorder consisting of epilepsy, ataxia, sensorineural deafness and tubulopathy that becomes clinically
apparent with seizures in infancy. A Kcnj10 knockout mouse shows postnatal mortality and is therefore not suitable for drug discovery. Because zebrafish are ideal for
in vivo screening for potential therapeutics, we tested whether kcnj10 knockdown in zebrafish would fill this need. We cloned zebrafish kcnj10 and demonstrated that its function is equivalent to that of human KCNJ10. We next injected splice- and translation-blocking kcnj10 antisense morpholino oligonucleotides and reproduced the cardinal symptoms of EAST syndrome – ataxia, epilepsy and renal
tubular defects. Several of these phenotypes could be assayed in an automated manner. We could rescue the morphant phenotype
with complementary RNA (cRNA) encoding human wild-type KCNJ10, but not with cRNA encoding a KCNJ10 mutation identified in
individuals with EAST syndrome. Our results suggest that zebrafish will be a valuable tool to screen for compounds that are
potentially therapeutic for EAST syndrome or its individual symptoms. Knockdown of kcnj10 represents the first zebrafish model of a salt-losing tubulopathy, which has relevance for blood pressure control.