Mutations in Potassium Channel Kir2.6 Cause Susceptibility to Thyrotoxic Hypokalemic Periodic Paralysis

Abstract

SUMMARY Thyrotoxic hypokalemic periodic paralysis (TPP) is characterized by acute attacks of weakness, hypokalemia, and thyrotoxicosis of various etiologies. These transient attacks resemble those of patients with familial hypokalemic periodic paralysis (hypoKPP) and resolve with treatment of the underlying hyperthyroidism. Because of the phenotypic similarity of these conditions, we hypothesized that TPP might also be a channelopathy. While sequencing candidate genes, we identified a previously unreported gene (not present in human sequence databases) that encodes an inwardly rectifying potassium (Kir) channel, Kir2.6. This channel, nearly identical to Kir2.2, is expressed in skeletal muscle and is transcriptionally regulated by thyroid hormone. Expression of Kir2.6 in mammalian cells revealed normal Kir currents in whole-cell and single-channel recordings. Kir2.6 mutations were present in up to 33% of the unrelated TPP patients in our collection. Some of these mutations clearly alter a variety of Kir2.6 properties, all altering muscle membrane excitability leading to paralysis.

Identification and Functional Characterization of Kir2.6 Mutations Associated with Non-familial Hypokalemic Periodic Paralysis

“…Ryan et al (12) reported mutations of Kir2.6 ranging from 0 to 33% in TPP patients from several different populations. In our Taiwanese population, we found four mutations in 180 SPP and TPP patients.…”

“…These results strongly indicate that the Kir2.6 channel expresses functional currents at the cell surface of human cells, and decreased outward K ϩ currents through Kir2.6 and Kir2.1 (and perhaps other Kir channels as well) account for the pathogenesis of hypoKPP in patients with Kir2.6 mutations. Based on the observation that KCNJ18 contains a thyroid-responsive element and thyroid hormone upregulates the transcription of Kir2.6, Ryan et al (12) suggested that up-regulation of Kir2.6 expression is important for mutant channel subunits to contribute to the pathogenesis of TPP. Indeed, as disease Kir2.6 mutants cause dominant negative inhibition of wild type Kir2.6 and Kir2.1, an increase in the cell-surface abundance of mutant subunits by thyroid hormone would enhance the decrease of functional K ϩ currents in the sarcolemma.…”

“…Sequencing of KCNJ18 was performed as previously described (12). PCR primers were designed against the GenBank TM accession NM_021012 sequence with the forward primer containing two nucleotide mismatches to favor amplification of diverse products.…”

“…The phenotypic similarity between familial hypoKPP and TPP suggests defects in ion channels. Indeed, a recent study reported that mutations in KCNJ18 gene encoding a novel member of inward rectifier K ϩ channel, Kir2.6, occur in some TPP patients (12). Interestingly, the KCNJ18 gene contains a 5Ј-upstream thyroid hormone response element, which is important for the transcription of KCNJ18 enhanced by thyroid hormone.…”

Comparison of the effects of DC031050, a class III antiarrhythmic agent, on hERG channel and three neuronal potassium channels

“…Although there is no direct evidence linking these side effects to the dysfunction of noncardiac ion channels, the functional disorders of noncardiac ion channels are known to cause these syndromes. For example, mutations of brain-specific P/Q type calcium channels were linked to familial hemiplegic migraines [32] , whereas the functional down-regulation of Kir2.6, an inwardly rectifying potassium channel, was linked to thyrotoxic hypokalemic periodic paralysis [33] . Consistent with its adverse effects in the nervous system, a low concentration (100 μmol/L) of npg dofetilide acted on ion channels in hippocampal neurons (eg, the voltage-independent block of a calcium-dependent potassium channel (BK)) [34] .…”