ArticleProceedings of the National Academy of Sciences of the United States of America2010
KCNJ10 gene mutations causing EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 129 papers.
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129 citing papers in PubMed, 213 citations in OpenAlex.
- Paroxysmal Kinesigenic Dyskinesia and Progressive Ataxia-Spasticity Syndrome Caused by a Biallelic Variant in KCNJ10.Movement disorders clinical practice · 2026Article
- Mechanistic target of rapamycin complex-1 plays a role in inhibiting kidney KAmerican journal of physiology. Renal physiology · 2026Article
- Review
- Optimizing anti-seizure medication selection for epilepsy in EAST/SeSAME syndrome: Insights from DrugBank and STRING databases.Genes & diseases · 2026Article
- Stimulation of basolateral calcium-sensing receptor inhibits Kir4.1/Kir5.1 in the mouse distal convoluted tubule.American journal of physiology. Renal physiology · 2026Article
- Novel Mutations in KCNJ10 Gene Associated With SeSAME Syndrome: Rare Disorder With Possible Common Mutation.Molecular genetics & genomic medicine · 2026Article
- Gender-Associated Differences in the Regulation of Potassium Channels in Astrocytes of Type 2 Diabetic Mice.Cells · 2026Article
- WONOEP XVII appraisal: Targeting network excitability beyond the synapse -Neurotransmitter, ionic, and electro -diffusions.Epilepsia · 2025Review
- Low level of expression of known deafness genes Kcne1, Kcnj10 or Col4a3 is sufficient to maintain hearing in mice.Hearing research · 2025Article
- Seizures in brain tumors: pathogenesis, risk factors and management (Review).International journal of molecular medicine · 2025Review
- Preclinical Insights into the Role of Kir4.1 in Chronic Pain and Depression: Mechanisms and Therapeutic Potential.Biomolecules · 2025Review
- Role of KThe American journal of pathology · 2025Article
- Article
- KCNJ16-depleted kidney organoids recapitulate tubulopathy and lipid recovery upon statins treatment.Stem cell research & therapy · 2024Article
- Kinase Scaffold Cab39 Is Necessary for Phospho-Activation of the Thiazide-Sensitive NCC.Hypertension (Dallas, Tex. : 1979) · 2024Article
- Repeated seizures lead to progressive ventilatory dysfunction in SSJournal of applied physiology (Bethesda, Md. : 1985) · 2023Article
- Article
- Glioma epileptiform activity and progression are driven by IGSF3-mediated potassium dysregulation.Neuron · 2023Article
- Clocking Epilepsies: A Chronomodulated Strategy-Based Therapy for Rhythmic Seizures.International journal of molecular sciences · 2023Review
- Diverse functions of the inward-rectifying potassium channel Kir5.1 and its relationship with human diseases.Frontiers in physiology · 2023Review
69 more citing papers are in PubMed but not listed here.
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17 authors at 5 institutions in 3 countries.
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No grant is acknowledged in the PubMed record.
Abstract
Mutations of the KCNJ10 (Kir4.1) K(+) channel underlie autosomal recessive epilepsy, ataxia, sensorineural deafness, and (a salt-wasting) renal tubulopathy (EAST) syndrome. 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. Kcnj10 and Kcnj16 were found in the basolateral membrane of mouse distal convoluted tubules, connecting tubules, and cortical collecting ducts. In the human kidney, KCNJ10 staining was additionally observed in the basolateral membrane of the cortical thick ascending limb of Henle's loop. EM of distal tubular cells of a patient with EAST syndrome showed reduced basal infoldings in this nephron segment, which likely reflects the morphological consequences of the impaired salt reabsorption capacity. When expressed in CHO and HEK293 cells, the KCNJ10 mutations R65P, G77R, and R175Q caused a marked impairment of channel function. R199X showed complete loss of function. Single-channel analysis revealed a strongly reduced mean open time. Qualitatively similar results were obtained with coexpression of KCNJ10/KCNJ16, suggesting a dominance of KCNJ10 function in native renal KCNJ10/KCNJ16 heteromers. The decrease in the current of R65P and R175Q was mainly caused by a remarkable shift of pH sensitivity to the alkaline range. In summary, EAST mutations of KCNJ10 lead to impaired channel function and structural changes in distal convoluted tubules. Intriguingly, the metabolic alkalosis present in patients carrying the R65P mutation possibly improves residual function of KCNJ10, which shows higher activity at alkaline pH.
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