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• W2894888227 abstract "Objective To identify the genetic basis of a patient with symptoms of normokalemic sporadic periodic paralysis (PP) and to study the effect of KCNJ18 mutations. Methods A candidate gene approach was used to identify causative gene mutations, using Sanger sequencing. KCNJ18 promoter activity was analyzed in transfected HEK293 cells with a luciferase assay, and functional analysis of Kir2.6 channels was performed with the two-electrode voltage-clamp technique. Results Although we did not identify harmful mutations in SCN4A, CACNA1S, KCNJ2 and KCNE3, we detected a monoallelic four-fold variant in KCNJ18 (R39Q/R40H/A56E/I249V), together with a variant in the respective promoter of this channel (c.-542T/A). The exonic variants in Kir2.6 did not alter the channel function; however, luciferase assays revealed a 10-fold higher promoter activity of the c.-542A promoter construct, which is likely to cause a gain-of-function by increased expression of Kir2.6. We found that reducing extracellular K + levels causes a paradoxical reduction in outward currents, similar to that described for other inward rectifying K + channels. Thus, reducing the extracellular K + levels might be a therapeutic strategy to antagonize the transcriptionally increased KCNJ18 currents. Consistently, treatment of the patient with K + reducing drugs dramatically improved the health situation and prevented PP attacks. Conclusions We show that a promoter defect in the KCNJ18 gene is likely to cause periodic paralysis, as the observed transcriptional upregulation will be linked to increased Kir2.6 function. This concept is further supported by our observation that most of the PP attacks in our patient disappeared on medical treatment with K + reducing drugs." @default.
• W2894888227 created "2018-10-12" @default.
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• W2894888227 date "2018-10-01" @default.
• W2894888227 modified "2023-09-26" @default.
• W2894888227 title "Increased KCNJ18 promoter activity as a mechanism in atypical normokalemic periodic paralysis" @default.
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• W2894888227 doi "https://doi.org/10.1212/nxg.0000000000000274" @default.
• W2894888227 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6186026" @default.
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