Cell
Volume 140, Issue 1, 8 January 2010, Pages 88-98
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Article
Mutations in Potassium Channel Kir2.6 Cause Susceptibility to Thyrotoxic Hypokalemic Periodic Paralysis

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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.

Highlights

KCNJ18 mutations are associated with thyrotoxic hypokalemic periodic paralysis, TPP ► KCNJ18 encodes an inward rectifying potassium channel, Kir 2.6 ► Thyroid hormones regulate KCNJ18 both transcriptionally and posttranscriptionally

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14

These authors contributed equally to this work

15

Present address: Department of Biochemistry, Universidade Federal de São Paulo, São Paulo 04044-020, Brazil

16

Present address: Department of Dermatology, Texas Tech University, Lubbock, TX 79409, USA