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.
Recently, we reported a previously unrecognized symptom constellation comprising epilepsy, ataxia, sensorineural deafness, and tubulopathy (EAST syndrome) associated with recessive mutations in the KCNJ10 gene.
Mutations in the K(+) channel KCNJ10 (Kir4.1) cause an autosomal recessive syndrome featuring seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME).
The functional importance of Kir4.1/Kir5.1 in renal ion transport has recently been highlighted by mutations in the human Kir4.1 gene (KCNJ10) that result in seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME)/epilepsy, ataxia, sensorineural deafness, and renal tubulopathy (EAST) syndrome, a complex disorder that includes salt wasting and hypokalemic alkalosis.
We investigated the localization of KCNJ10 and the homologous KCNJ16 in kidney and the functional consequences of KCNJ10 mutations found in our patients with EAST syndrome.
EAST (Epilepsy, Ataxia, Sensorineural deafness, Tubulopathy) or SeSAME (Seizures, Sensorineural deafness, Ataxia, Mental retardation, and Electrolyte imbalance) syndrome is a rare autosomal recessive syndrome first described in 2009 independently by Bockenhauer and Scholl.
The present cases harboring novel homozygous frameshift mutations in KCNJ10 expand the spectrum of brain abnormalities in EAST syndrome, including mild cerebellar atrophy and intramyelinic edema, resulting from abnormal function of the Kir4.1 inwardly rectifying potassium channel at the astrocyte endfeet, with disruption of water-ion homeostasis.
We investigated the localization of KCNJ10 and the homologous KCNJ16 in kidney and the functional consequences of KCNJ10 mutations found in our patients with EAST syndrome.
The molecular mechanism by which gamma-Na(+)/K(+)-ATPase is involved in DCT Mg(2+) handling remains unknown; (v) a high percentage of patients with mutations in the renal transcription factor HNF1B (hepatocyte nuclear factor 1 homeobox B) gene develop hypomagnesemia; and (vi) Gitelman and EAST/SeSAME syndrome patients suffer from a similar tubulopathy due to mutations in NCC (NaCl cotransporter) and Kir4.1, respectively.