Increased KCNJ18 promoter activity as a mechanism in atypical normokalemic periodic paralysis
| Autor: | Richard C Dodel, Guenter F. Pilz, Susanne Rinné, Bilgen Kurt, Andreas Maieron, Muhidien Soufi, Juergen R. Schaefer, Tobias Mueller, Niels Decher, Volker Ruppert |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Candidate gene Chemistry HEK 293 cells Periodic paralysis KCNE3 Transfection medicine.disease Molecular biology 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Extracellular medicine Luciferase Neurology (clinical) Gene 030217 neurology & neurosurgery Genetics (clinical) |
| Zdroj: | Neurology Genetics. 4:e274 |
| ISSN: | 2376-7839 |
| Popis: | ObjectiveTo identify the genetic basis of a patient with symptoms of normokalemic sporadic periodic paralysis (PP) and to study the effect of KCNJ18 mutations.MethodsA 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.ResultsAlthough 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.ConclusionsWe 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. |
| Databáze: | OpenAIRE |
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