Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis
Open accessAbstract
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.
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For MAP2K3 and KCNJ18, GATK discovered 487 more variants than DRAGEN, which are likely false positives.
“For MAP2K3, which is related to skin and liver diseases67, and KCNJ18, which is related to other rare diseases68, GATK discovered 487 more variants than DRAGEN, which are likely false positives23 (Supplementary Table 11).”
From Comprehensive genome analysis and variant detection at scale using DRAGEN (2025) · cites this paper as [68]
Individuals susceptible to TPP may have a channelopathy involving a loss-of-function mutation of the Kir2.6 channel, an inwardly rectifying K+ channel usually stimulated by thyroid hormones.
“Individuals susceptible to TPP may have a channelopathy involving a loss-of-function mutation of the Kir2.6 channel, an inwardly rectifying K+ channel, which is usually stimulated by thyroid hormones.”
From Thyrotoxic Periodic Paralysis With Hypokalemia: A Case Study (2023) · cites this paper as [11]
This loss of function may predispose someone to periodic paralysis by disrupting K+ regulation, resulting in inactivation of muscle sarcolemmal sodium channels and subsequent paralysis.
“This loss of function may predispose someone to periodic paralysis by disrupting K+ regulation, resulting in the inactivation of muscle sarcolemmal sodium channels and subsequent paralysis [11].”
From Thyrotoxic Periodic Paralysis With Hypokalemia: A Case Study (2023) · cites this paper as [11]
Mutations in the gene encoding Kir2.6 are associated with TPP and predispose these patients to acute paralytic attacks.
“Recent studies have shown that mutations in the gene encoding Kir2.6, a skeletal muscle-specific Kir channel, are associated with TPP and predispose these patients to acute paralytic attacks.”
From Thyrotoxic Periodic Paralysis: Clinical Challenges (2014) · cites this paper as [18]
The prevalence of Kir2.6 mutation was up to 33% in Caucasians and Brazilians with TPP.
“A study by Ryan et al. [18] showed that the prevalence of Kir2.6 mutation was up to 33% in Caucasians and Brazilians with TPP.”
From Thyrotoxic Periodic Paralysis: Clinical Challenges (2014) · cites this paper as [18]
Genetic mutations in the Kir2.6 channel play a role in the pathogenesis of TPP.
“Evidence is building up showing role of genetic mutations in Kir2.6 channel in the pathogenesis of TPP.”
From Thyrotoxic Periodic Paralysis: Clinical Challenges (2014) · cites this paper as [18]
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“This loss of function may predispose someone to periodic paralysis by disrupting K+ regulation, resulting in the inactivation of muscle sarcolemmal sodium channels and subsequent paralysis [11].”
Background
- Authors
- Ryan, D. P., Dias da Silva, M. R., Soong, T. W., Fontaine, B., Donaldson, M. R., Kung, A. W. C., Jongjaroenprasert, W., Liang, M. C., Khoo, D. H. C., Cheah, J. S., Ho, S. C., Bernstein, H. S., Maciel, R. M. B., Brown, R. H., & Ptáček, L. J.
- Affiliations
- University of California, San Francisco (US)
- National University of Singapore (SG)
- Inserm (FR)
- Queen Mary Hospital (CN)
- Mahidol University (TH)
- Singapore General Hospital (SG)
- Universidade Federal de São Paulo (BR)
- Massachusetts General Hospital (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Ptáček, Louis J.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2010-01
- Volume
- 140
- Issue
- 1
- Pages
- 88-98
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2885139
- OpenAlex
- W2150382251
- Cited by
- 311
- References
- 43
- Citations by year
- 2026: 5 · 2025: 16 · 2024: 19 · 2023: 20 · 2022: 21 · 2021: 17 · 2020: 21 · 2019: 12 · 2018: 16 · 2017: 16 · 2016: 10 · 2015: 18 · 2014: 30 · 2013: 30 · 2012: 25
- FWCI
- 11.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1293 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- National University of Singapore (submittedVersion)
- Americanae (AECID Library) (submittedVersion, other-oa)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- Funders
- Howard Hughes Medical Institute
- Singapore General Hospital
- Universidade de São Paulo
- National Center for Research Resources (U54 RR19481)
- 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 hypokalemic periodic paralysis, inwardly rectifying potassium channels, Kir2.2, channelopathies, hypokalemia, thyrotoxicosis, hyperthyroidism, skeletal muscle excitability, potassium channel mutations, thyroid hormone regulation
- MeSH terms
- Amino Acid Sequence, Base Sequence, DNA Mutational Analysis, Humans, Molecular Sequence Data, Mutation, Transcription, Genetic, Triiodothyronine, Genetic Predisposition to Disease, Hypokalemic Periodic Paralysis, Potassium Channels, Inwardly Rectifying, Electrophysiological Phenomena
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