Identification and Functional Characterization of Kir2.6 Mutations Associated with Non-familial Hypokalemic Periodic Paralysis
Open accessAbstract
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. 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.
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Mutations in KCNJ18 have been associated with THPP, particularly during thyrotoxic episodes.
“Mutations in potassium inwardly rectifying channel subfamily J member 18 (KCNJ18) have also been associated with THPP, particularly during thyrotoxic episodes [24].”
From Thyrotoxic Hypokalemic Periodic Paralysis: Pathophysiological Mechanisms (2025) · cites this paper as [24]
Loss-of-function mutations in the skeletal muscle-specific Kir channel Kir2.6 and loci on 17q involved in Kir2.1 gene expression confer susceptibility to TPP.
“Recent studies have shown that susceptibility to TPP can be conferred by loss-of-function mutations in the skeletal muscle-specific Kir channel, Kir2.6 (40, 41, 42), and loci on 17q involved in Kir2.1 gene expression (43, 44, 45).”
From A 10-year analysis of thyrotoxic periodic paralysis in 135 patients: focus on symptomatology and precipitants (2013) · cites this paper as [41]
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Self-citation
- Authors
- Cheng, C.-J., Lin, S.-H., Lo, Y.-F., Yang, S.-S., Hsu, Y.-J., Cannon, S. C., & Huang, C.-L.
- Affiliations
- Tri-Service General Hospital (TW)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Lin, Shih-Hua
- Huang, Chou-Long
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-08
- Volume
- 286
- Issue
- 31
- Pages
- 27425-27435
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3149336
- OpenAlex
- W2080643147
- Cited by
- 65
- References
- 35
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 5 · 2022: 2 · 2021: 7 · 2020: 1 · 2019: 3 · 2018: 5 · 2017: 3 · 2016: 6 · 2015: 7 · 2014: 6 · 2013: 7 · 2012: 5
- FWCI
- 2.59
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Texas Southwestern Medical Center (P30DK079328)
- National Science Council
- Ministry of Defense
- Tri-Service General Hospital
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK59530, R01DK059530, P30DK079328)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R37AR042703)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Potassium and Related Disorders
- Keywords
- thyrotoxic periodic paralysis, inwardly rectifying potassium channels, dominant negative inhibition, Kir2.1, skeletal muscle excitability, cell surface expression, single-channel conductance
- MeSH terms
- Adult, Amino Acid Sequence, Base Sequence, Female, Humans, Male, Molecular Sequence Data, Mutation, DNA Primers, Hypokalemic Periodic Paralysis, Potassium Channels, Inwardly Rectifying
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