Abstract
SUMMARYRecessive 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.
Highlights
We and others elucidated the pathophysiological basis of a multisystem disorder characterised by infantile-onset epilepsy, debilitating ataxia, sensorineural deafness and a salt-wasting tubulopathy, i.e. EAST syndrome (Bockenhauer et al, 2009; Scholl et al, 2009)
The authors identified and cloned kcnj10, the zebrafish homologue of human KCNJ10, and used antisense technology to knock down its expression in zebrafish during embryonic and larval stages
A BLAST search using the human protein KCNJ10 on ZF reference sequence (RefSeq) produced XP_001342993 as the best hit
Summary
We and others elucidated the pathophysiological basis of a multisystem disorder characterised by infantile-onset epilepsy, debilitating ataxia, sensorineural deafness and a salt-wasting tubulopathy, i.e. EAST syndrome (Bockenhauer et al, 2009; Scholl et al, 2009). Current treatment for this disorder caused by malfunction of the potassium channel KCNJ10 in affected organs is non-specific and unsatisfactory. The specific cause(s) of deafness in individuals with EAST syndrome are still unclear (Rozengurt et al, 2003). KCNJ10 is expressed in the retina, and patients show specific electroretinographic changes (Thompson et al, 2011)
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