Increased KCNJ18 promoter activity as a mechanism in atypical normokalemic periodic paralysis

Abstract

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.

Thyrotoxic Periodic Paralysis: An Incidental Diagnosis!

“…The Kir channel family is encoded by KCNJ genes [9]. The KCNJ18 gene encodes Kir 2.6, which is one of the seven Kir subfamilies [1][2][9][10]. KCNJ18-related mutations have been found in up to 33% of the thyrotoxic patients with periodic paralysis [3,11].…”

Statistical methods to support diagnosing rare diseases

“…Interestingly enough, this channel was considered so far as a less likely candidate for paralysis and was no target candidate in well-established screening panels (see Kuhn and colleague [6]). The study and results were reported recently elsewhere in Soufi and colleagues [7]. Note that without the doctor's hint to consider ion channels, the patient would never have conducted these experiments.…”

Was das Unterhaltungsfernsehen zur Vermittlung von medizinischem Wissen an Studierende und Laien beitragen kann – Sensibilisierung für seltene Erkrankungen

“…Ihm wurde eine kaliumarme, eher natriumreiche Kost empfohlen sowie den Kaliumspiegel senkende Medikamente. Fortan waren die immer wiederkehrenden Lähmungsattacken verschwunden [ 41 ]. Im Nachgang zu der Sendung gab es zahlreiche Anfragen von Menschen mit ähnlichen Symptomen, die an heimatnahe Zentren für seltene Erkrankungen vermittelt werden konnten [ 42 ].…”