From GWAS to function: Genetic variation in sodium channel gene enhancer influences electrical patterning

Boogaard, Malou van den; Barnett, Phil; Christoffels, Vincent M.

doi:10.1016/j.tcm.2013.09.001

Cited by 9 publications

(4 citation statements)

References 42 publications

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“… 22 , 23 The impact of SNVs in promoters and enhancer elements on voltage-gated channel expression has been already shown for the SCN5A/SCN10A locus in arrhythmia susceptibility and Brugada syndrome. 24 – 26 Therefore, our findings support that in PP, promoter mutations can be disease causative by altering the current densities of ion channels.…”

Section: Discussionsupporting

confidence: 78%

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

Soufi¹,

Ruppert

Rinné

et al. 2018

Neurol Genet

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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.

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Section: Discussionsupporting

confidence: 78%

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

Soufi¹,

Ruppert

Rinné

et al. 2018

Neurol Genet

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show abstract

“…Loss‐of‐function mutation in Tbx5 (G145R) has been shown to cause BrS in humans . Tbx5 and Tbx3 have been also shown to regulate the BrS susceptibility genes “SCN5A‐SCN10A” locus and effect the expression of SCN5A . Hey2 has been recently shown to be a BrS susceptibility gene by modulating cardiac transmural ion channel patterning and electrical heterogeneity .…”

Section: Discussionmentioning

confidence: 99%

Coexistence of atrioventricular accessory pathways and drug‐induced type 1 Brugada pattern

Hasdemir

Juang

Köse

et al. 2018

Pacing Clinical Electrophis

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“…The presence of an enhancerbinding domain of SCN5A within the SCN10A gene, encompassing exons 17 and 18, supports this concept. [43][44][45] Lastly, SCN10A, which has robust expression in the cholinergic vagal neurons and dorsal root ganglia, has been associated with modulation of cardio-vagal input from the peripheral nervous system. 27,46,47 No prior studies attributed QT prolongation to mutations in SCN10A.…”

Section: Introductionmentioning

confidence: 99%

Deleterious protein‐altering mutations in the SCN10A voltage‐gated sodium channel gene are associated with prolonged QT

et al. 2017

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From GWAS to function: Genetic variation in sodium channel gene enhancer influences electrical patterning

Cited by 9 publications

References 42 publications

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

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

Coexistence of atrioventricular accessory pathways and drug‐induced type 1 Brugada pattern

Deleterious protein‐altering mutations in the SCN10A voltage‐gated sodium channel gene are associated with prolonged QT

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