Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10

Department of Genetics, The Howard Hughes Medical Institute, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 05/2009; 106(14):5842-5847. DOI: 10.1073/pnas.0901749106


We describe members of 4 kindreds with a previously unrecognized syndrome characterized by seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (hypokalemia, metabolic alkalosis, and hypomagnesemia). By analysis of linkage we localize the putative causative gene to a 2.5-Mb segment of chromosome 1q23.2-23.3. Direct DNA sequencing of KCNJ10, which encodes an inwardly rectifying K(+) channel, identifies previously unidentified missense or nonsense mutations on both alleles in all affected subjects. These mutations alter highly conserved amino acids and are absent among control chromosomes. Many of these mutations have been shown to cause loss of function in related K(+) channels. These findings demonstrate that loss-of-function mutations in KCNJ10 cause this syndrome, which we name SeSAME. KCNJ10 is expressed in glia in the brain and spinal cord, where it is believed to take up K(+) released by neuronal repolarization, in cochlea, where it is involved in the generation of endolymph, and on the basolateral membrane in the distal nephron. We propose that KCNJ10 is required in the kidney for normal salt reabsorption in the distal convoluted tubule because of the need for K(+) recycling across the basolateral membrane to enable normal activity of the Na(+)-K(+)-ATPase; loss of this function accounts for the observed electrolyte defects. Mice deficient for KCNJ10 show a related phenotype with seizures, ataxia, and hearing loss, further supporting KCNJ10's role in this syndrome. These findings define a unique human syndrome, and establish the essential role of basolateral K(+) channels in renal electrolyte homeostasis.

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Available from: Martin Häusler, Oct 05, 2015
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    • "For example, conditional knockout of Kir4.1 depolarizes astrocytic membranes, inhibits potassium uptake, and results in seizure (Djukic et al., 2007). Mutations in the human gene, KCNJ10 (coding Kir4.1) cause epilepsy (Bockenhauer et al., 2009; Scholl et al., 2009). In addition, both electrophysiological and molecular studies on the tissue specimens from some patients with epilepsy show reduced expression of the Kir4.1 channel (Schröder et al., 2000). "
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    ABSTRACT: Epilepsy is a neurological disorder that affects around 1% of the population worldwide. The two main therapies, pharmacology and the electrical stimulation, both have some shortcomings. For instance, pharmacological therapy is frequently accompanied by side effects, and current anticonvulsive drugs fail to be effective to around a third of patients. These patients could suffer astrocyte-related epilepsy, as increasing evidence indicates that dysfunctions of astrocytes can result in epilepsy. However, epilepsy drugs that affect astrocytes are not available currently. Although electrical stimulation has benefited many patients, the electrode stimulates unselective neurons or circuits. All these need to develop new strategies for improving the life of the patients. As channelrhodopsins (ChRs) were discovered, a novel method referred to as “optogenetics” was developed. It has advantages over electrical stimulation of being less-invasiveness and allowing spatiotemporally stimulation. Recently, a number of experiments have explored the treatments for epilepsy with optogenetic control of neurons. Here, we discuss the possibility that an optogenetic approach could be used to control the release of gliotransmitters and improve astrocyte function such as glutamate and K+ uptake, and thereby offer a potential strategy to investigate and treat astrocyte-related epilepsy.
    Brain Research Bulletin 11/2014; 110. DOI:10.1016/j.brainresbull.2014.10.013 · 2.72 Impact Factor
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    • "We will focus this review on the mechanism and structural details of polyamine block of the Kir2 subfamily channels (which are particularly sensitive to polyamines), as well as some of the details of their physiological roles and disruption in genetic channelopathies. It is noteworthy that “weak” inward rectifiers (with shallow voltage dependence, and weak polyamine sensitivity) play many important physiological roles, impacting diverse processes such as hormone secretion (Koster et al., 2000; Choi et al., 2011), ion transport in the nephron (Simon et al., 1996), and control of ionic gradients in the inner ear (Scholl et al., 2009). Thus, we also refer readers to a recent broad review that provides an overview of the structure, function, and physiology of the entire Kir channel family as an excellent starting point for further discussion of other Kir channel types (Hibino et al., 2010). "
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    ABSTRACT: Inwardly-rectifying potassium (Kir) channels contribute to maintenance of the resting membrane potential and regulation of electrical excitation in many cell types. Strongly rectifying Kir channels exhibit a very steep voltage dependence resulting in silencing of their activity at depolarized membrane voltages. The mechanism underlying this steep voltage dependence is blockade by endogenous polyamines. These small multifunctional, polyvalent metabolites enter the long Kir channel pore from the intracellular side, displacing multiple occupant ions as they migrate to a stable binding site in the transmembrane region of the channel. Numerous structure-function studies have revealed structural elements of Kir channels that determine their susceptibility to polyamine block, and enable the steep voltage dependence of this process. In addition, various channelopathies have been described that result from alteration of the polyamine sensitivity or activity of strongly rectifying channels. The primary focus of this article is to summarize current knowledge of the molecular mechanisms of polyamine block, and provide some perspective on lingering uncertainties related to this physiologically important mechanism of ion channel blockade. We also briefly review some of the important and well understood physiological roles of polyamine sensitive, strongly rectifying Kir channels, primarily of the Kir2 family.
    Frontiers in Physiology 08/2014; 5:325. DOI:10.3389/fphys.2014.00325 · 3.53 Impact Factor
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    • "In the Müller cells and astrocytes of humans and of most animals studied, inwardly rectifying K+ (Kir) channels, specifically Kir4.1 (Kcnj10), play a key role for glia-neuron interactions (for recent reviews, see [3], [25], [26], [27]), being fundamental for example for glutamate clearance [28], [29]. Genetic variations of Kir4.1 channels in humans and animals underlie severe disorders in the brain and in the retina, such as epilepsy, disruption of electroretinogram, glaucoma, stroke, ataxia, hypokalemia, hypomagnesemia, and metabolic alkalosis [27], [30], [31], [32], [33]. In addition, recently identified Kir4.1 mutations were found to result in autoimmune inhibition, contributing to pathogenesis of multiple sclerosis [34], hearing loss [35], autism [36] and seizures [30], [33]. "
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    PLoS ONE 05/2014; 9(5):e97155. DOI:10.1371/journal.pone.0097155 · 3.23 Impact Factor
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