Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis.
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.
Ryan
Devon P
DP
Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, 94158, USA.
da Silva
Magnus R Dias
MR
Soong
Tuck Wah
TW
Fontaine
Bertrand
B
Donaldson
Matt R
MR
Kung
Annie W C
AW
Jongjaroenprasert
Wallaya
W
Liang
Mui Cheng
MC
Khoo
Daphne H C
DH
Cheah
Jin Seng
JS
Ho
Su Chin
SC
Bernstein
Harold S
HS
Maciel
Rui M B
RM
Brown
Robert H
RH
Ptácek
Louis J
LJ
D000595:Amino Acid Sequence; D001483:Base Sequence; D004252:DNA Mutational Analysis; D055724:Electrophysiological Phenomena; D020022:Genetic Predisposition to Disease; D006801:Humans; D020514:Hypokalemic Periodic Paralysis / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014284:Triiodothyronine / Q000378:metabolism
C546860:KCNJ18 protein, human; C489463:Kir2.2 channel; D024661:Potassium Channels, Inwardly Rectifying; D014284:Triiodothyronine