Variable loss of Kir4.1 channel function in SeSAME syndrome mutations

Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455,USA.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 09/2010; 399(4):537-41. DOI: 10.1016/j.bbrc.2010.07.105
Source: PubMed


SeSAME syndrome is a complex disease characterized by seizures, sensorineural deafness, ataxia, mental retardation and electrolyte imbalance. Mutations in the inwardly rectifying potassium channel Kir4.1 (KCNJ10 gene) have been linked to this condition. Kir4.1 channels are weakly rectifying channels expressed in glia, kidney, cochlea and possibly other tissues. We determined the electrophysiological properties of SeSAME mutant channels after expression in transfected mammalian cells. We found that a majority of mutations (R297C, C140R, R199X, T164I) resulted in complete loss of Kir4.1 channel function while two mutations (R65P and A167V) produced partial loss of function. All mutant channels were rescued upon co-transfection of wild-type Kir4.1 but not Kir5.1 channels. Cell-surface biotinylation assays indicate significant plasma membrane expression of all mutant channels with exception of the non-sense mutant R199X. These results indicate the differential loss of Kir channel function among SeSAME syndrome mutations.

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Available from: Paulo Kofuji, Aug 29, 2015
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    • "Seizure susceptibility has been linked to mutations in four selected candidate genes; Pex19 [81], Kcnj10 [82], Pigm [83], and Cabc1 [84]. There is a reduction in LS area as well as the number of GABAergic neurons in rats with pilocarpine-induced status epilepticus [85]. "
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    • "Heterologous expression demonstrated that the mutations indeed affected Kir4.1 function and produced depolarization and reduced transmembrane currents (Bockenhauer et al., 2009; Reichold et al., 2010; Williams et al., 2010). The EAST/SeSAME syndrome-related decrease in K 1 conductance could not be rescued by co-expression with Kir5.1, and mutated Kir4.1 had no dominant-negative effect when co-expressing wildtype Kir4.1 (Tang et al., 2010). The mutations increased pH i -sensitivity of the channel and impeded its surface expression (Sala-Rabanal et al., 2010; Williams et al., 2010). "
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    • "Thus, the functional expression of Kir4.1 channels in glial membranes is important for voltage-dependent transport processes, such as glutamate uptake [12], [13]. The important role of the Kir4.1 channels is demonstrated by a number of studies identifying mutations in the Kir4.1 gene (KCNJ10) as a reason for symptoms found in the EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) [14]–[18]. Moreover, possible associations between polymorphisms of the gene for aquaporin-4 and epilepsy have been described [19]. "
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