Epilepsy, Ataxia, Sensorineural Deafness, Tubulopathy, and KCNJ10 Mutations

Great Ormond Street Hospital-University College London, London, United Kingdom.
New England Journal of Medicine (Impact Factor: 55.87). 06/2009; 360(19):1960-70. DOI: 10.1056/NEJMoa0810276
Source: PubMed


Five children from two consanguineous families presented with epilepsy beginning in infancy and severe ataxia, moderate sensorineural deafness, and a renal salt-losing tubulopathy with normotensive hypokalemic metabolic alkalosis. We investigated the genetic basis of this autosomal recessive disease, which we call the EAST syndrome (the presence of epilepsy, ataxia, sensorineural deafness, and tubulopathy).
Whole-genome linkage analysis was performed in the four affected children in one of the families. Newly identified mutations in a potassium-channel gene were evaluated with the use of a heterologous expression system. Protein expression and function were further investigated in genetically modified mice.
Linkage analysis identified a single significant locus on chromosome 1q23.2 with a lod score of 4.98. This region contained the KCNJ10 gene, which encodes a potassium channel expressed in the brain, inner ear, and kidney. Sequencing of this candidate gene revealed homozygous missense mutations in affected persons in both families. These mutations, when expressed heterologously in xenopus oocytes, caused significant and specific decreases in potassium currents. Mice with Kcnj10 deletions became dehydrated, with definitive evidence of renal salt wasting.
Mutations in KCNJ10 cause a specific disorder, consisting of epilepsy, ataxia, sensorineural deafness, and tubulopathy. Our findings indicate that KCNJ10 plays a major role in renal salt handling and, hence, possibly also in blood-pressure maintenance and its regulation.

Download full-text


Available from: Kjell Tullus, Sep 30, 2015
1 Follower
56 Reads
    • "Importantly , humans with loss of function mutations in Kir4 . 1 exhibit ataxia , and extreme lower motor extremity weakness resulting in a loss of ambulation ( Bockenhauer et al . , 2009 ; Scholl et al . , 2009 ) . Other CNS abnormalities include early onset seizures ( 3 months of age ) , sensorineural deafness , ataxia , and mental retardation , all of which indicate a critical role for Kir4 . 1 in brain development . Humans dis - playing mutations in GLT - 1 have not been identified ; how - ever , GLT - 1 knockout mic"
    [Show abstract] [Hide abstract]
    ABSTRACT: Alexander Disease (AxD) is a "gliopathy" caused by toxic, dominant gain-of-function mutations in the glial fibrillary acidic protein (GFAP) gene. Two distinct types of AxD exist. Type I AxD affected individuals develop cerebral symptoms by 4 years of age and suffer from macrocephaly, seizures, and physical and mental delays. As detection and diagnosis have improved, approximately half of all AxD patients diagnosed have onset >4 years and brainstem/spinal cord involvement. Type II AxD patients experience ataxia, palatal myoclonus, dysphagia, and dysphonia. No study has examined a mechanistic link between the GFAP mutations and caudal symptoms present in type II AxD patients. We demonstrate that two key astrocytic functions, the ability to regulate extracellular glutamate and to take up K(+) via K+ channels, are compromised in hindbrain regions and spinal cord in AxD mice. Spinal cord astrocytes in AxD transgenic mice are depolarized relative to WT littermates, and have a three-fold reduction in Ba(2+) -sensitive Kir4.1 mediated currents and six-fold reduction in glutamate uptake currents. The loss of these two functions is due to significant decreases in Kir4.1 (>70%) and GLT-1 (>60%) protein expression. mRNA expression for KCNJ10 and SLC1A2, the genes that code for Kir4.1 and GLT-1, are significantly reduced by postnatal Day 7. Protein and mRNA reductions for Kir4.1 and GLT-1 are exacerbated in AxD models that demonstrate earlier accumulation of GFAP and increased Rosenthal fiber formation. These findings provide a mechanistic link between the GFAP mutations/overexpression and the symptoms in those affected with Type II AxD. GLIA 2015. © 2015 Wiley Periodicals, Inc.
    Glia 07/2015; DOI:10.1002/glia.22893 · 6.03 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Müller cells, the principal glial cells of the vertebrate retina, are fundamental for the maintenance and function of neuronal cells. In most vertebrates, including humans, Müller cells abundantly express Kir4.1 inwardly rectifying potassium channels responsible for hyperpolarized membrane potential and for various vital functions such as potassium buffering and glutamate clearance; inter-species differences in Kir4.1 expression were, however, observed. Localization and function of potassium channels in Müller cells from the retina of crocodiles remain, hitherto, unknown. We studied retinae of the Spectacled caiman (Caiman crocodilus fuscus), endowed with both diurnal and nocturnal vision, by (i) immunohistochemistry, (ii) whole-cell voltage-clamp, and (iii) fluorescent dye tracing to investigate K+ channel distribution and glia-to-neuron communications. Immunohistochemistry revealed that caiman Müller cells, similarly to other vertebrates, express vimentin, GFAP, S100β, and glutamine synthetase. In contrast, Kir4.1 channel protein was not found in Müller cells but was localized in photoreceptor cells. Instead, 2P-domain TASK-1 channels were expressed in Müller cells. Electrophysiological properties of enzymatically dissociated Müller cells without photoreceptors and isolated Müller cells with adhering photoreceptors were significantly different. This suggests ion coupling between Müller cells and photoreceptors in the caiman retina. Sulforhodamine-B injected into cones permeated to adhering Müller cells thus revealing a uni-directional dye coupling. Our data indicate that caiman Müller glial cells are unique among vertebrates studied so far by predominantly expressing TASK-1 rather than Kir4.1 K+ channels and by bi-directional ion and uni-directional dye coupling to photoreceptor cells. This coupling may play an important role in specific glia-neuron signaling pathways and in a new type of K+ buffering.
    PLoS ONE 05/2014; 9(5):e97155. DOI:10.1371/journal.pone.0097155 · 3.23 Impact Factor
  • Source
    • "Missense variations in KCNJ10, the gene encoding Kir4.1, have been linked to seizure susceptibility in man (Buono and others 2004). Loss-of-function mutations in KCNJ10 underlie an autosomal recessive disorder characterized by seizures, ataxia, sensorineural deafness, mental retardation, and tubulopathy (EAST/SeSAME syndrome) (Bockenhauer and others 2009; Scholl and others 2009). Patients suffering from this disorder display at Fraunhofer-Gesellschaft -FhG on March 13, 2014 "
    [Show abstract] [Hide abstract]
    ABSTRACT: During the last 20 years, it has been well established that a finely tuned, continuous crosstalk between neurons and astrocytes not only critically modulates physiological brain functions but also underlies many neurological diseases. In particular, this novel way of interpreting brain activity is markedly influencing our current knowledge of epilepsy, prompting a re-evaluation of old findings and guiding novel experimentation. Here, we review recent studies that have unraveled novel and unique contributions of astrocytes to the generation and spread of convulsive and nonconvulsive seizures and epileptiform activity. The emerging scenario advocates an overall framework in which a dynamic and reciprocal interplay among astrocytic and neuronal ensembles is fundamental for a fuller understanding of epilepsy. In turn, this offers novel astrocytic targets for the development of those really novel chemical entities for the control of convulsive and nonconvulsive seizures that have been acknowledged as a key priority in the management of epilepsy.
    The Neuroscientist 03/2014; 21(1). DOI:10.1177/1073858414523320 · 6.84 Impact Factor
Show more