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Identification and Functional Characterization of Kir2.6 Mutations Associated with Non-familial Hypokalemic Periodic Paralysis
Journal article   Open access   Peer reviewed

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

Chih-Jen Cheng, Shih-Hua Lin, Yi-Fen Lo, Sung-Sen Yang, Yu-Juei Hsu, Stephen C. Cannon and Chou-Long Huang
The Journal of biological chemistry, Vol.286(31), pp.27425-27435
08/05/2011
DOI: 10.1074/jbc.M111.249656
PMCID: PMC3149336
PMID: 21665951
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https://doi.org/10.1074/jbc.M111.249656View
Published (Version of record) Open Access

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Abstract

Hypokalemic periodic paralysis (hypoKPP) is characterized by episodic flaccid paralysis of muscle and acute hypokalemia during attacks. Familial forms of hypoKPP are predominantly caused by mutations of either voltage-gated Ca2+ or Na+ channels. The pathogenic gene mutation in non-familial hypoKPP, consisting mainly of thyrotoxic periodic paralysis (TPP) and sporadic periodic paralysis (SPP), is largely unknown. Recently, mutations in KCNJ18, which encodes a skeletal muscle-specific inwardly rectifying K+ channel Kir2.6, were reported in some TPP patients. Whether mutations of Kir2.6 occur in other patients with non-familial hypoKPP and how mutations of the channel predispose patients to paralysis are unknown. Here, we report one conserved heterozygous mutation in KCNJ18 in two TPP patients and two separate heterozygous mutations in two SPP patients. These mutations result in V168M, R43C, and A200P amino acid substitution of Kir2.6, respectively. Compared with the wild type channel, whole-cell currents of R43C and V168M mutants were reduced by ∼78 and 43%, respectively. No current was detected for the A200P mutant. Single channel conductance and open probability were reduced for R43C and V168M, respectively. Biotinylation assays showed reduced cell surface abundance for R43C and A200P. All three mutants exerted dominant negative inhibition on wild type Kir2.6 as well as wild type Kir2.1, another Kir channel expressed in the skeletal muscle. Thus, mutations of Kir2.6 are associated with SPP as well as TPP. We suggest that decreased outward K+ current from hypofunction of Kir2.6 predisposes the sarcolemma to hypokalemia-induced paradoxical depolarization during attacks, which in turn leads to Na+ channel inactivation and inexcitability of muscles.
 Ion Channels Hypokalemic Periodic Paralysis Inward Rectifier K+ Channel Membrane Biophysics Potassium Channels Skeletal Muscle Thyroid Thyrotoxic Periodic Paralysis

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