ArticleThe Journal of biological chemistry2011
Identification and functional characterization of Kir2.6 mutations associated with non-familial hypokalemic periodic paralysis.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 63 citations in OpenAlex.
- Thyrotoxicosis presenting with periodic paralysis in a young male: a case report.Annals of medicine and surgery (2012) · 2026Article
- Thyrotoxic Hypokalemic Periodic Paralysis: Pathophysiological Mechanisms.Endocrinology and metabolism (Seoul, Korea) · 2025Review
- Insulin-induced severe thyrotoxic periodic paralysis: A case report.World journal of clinical cases · 2025Article
- Article
- Periodic paralysis.Handbook of clinical neurology · 2024Review
- Thyrotoxic periodic paralysis in a Caucasian man without identifiable genetic predisposition: a case report.Thyroid research · 2023Article
- Absence of 2899C<T Mutation in the WNK4 Gene in a Free-Ranging Lion (Animals : an open access journal from MDPI · 2022Article
- Case report: SCN4A p.R1135H gene variant in combination with thyrotoxicosis causing hypokalemic periodic paralysis.Frontiers in neurology · 2022Article
- Probing ion channel functional architecture and domain recombination compatibility by massively parallel domain insertion profiling.Nature communications · 2021Article
- Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy.Cells · 2021Review
- Hypokalemic paralysis in hyperthyroidism: Not all that glitter are gold.Clinical case reports · 2021Article
- Inwardly Rectifying Potassium Channel Kir2.1 and its "Kir-ious" Regulation by Protein Trafficking and Roles in Development and Disease.Frontiers in cell and developmental biology · 2021Review
- Thyrotoxic Periodic Paralysis with Thyroid Storm as the First Presentation of Graves' disease; a Case Report.Archives of academic emergency medicine · 2021Article
- Disease Associated Mutations in KBiomolecules · 2019Review
- Assessment of Molecular Subtypes in Thyrotoxic Periodic Paralysis and Graves Disease Among Chinese Han Adults: A Population-Based Genome-Wide Association Study.JAMA network open · 2019Observational
- IncreasedNeurology. Genetics · 2018Article
- Kir2.2 p.Thr140Met: a genetic susceptibility to sporadic periodic paralysis.Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology · 2018Article
- Thyrotoxic periodic paralysis: case report and review of the literature.Electronic physician · 2018Article
- Whole genome and exome sequencing realignment supports the assignment of KCNJ12, KCNJ17, and KCNJ18 paralogous genes in thyrotoxic periodic paralysis locus: functional characterization of two polymorphic Kir2.6 isoforms.Molecular genetics and genomics : MGG · 2016Article
- Rare KCNJ18 variants do not explain hypokalaemic periodic paralysis in 263 unrelated patients.Journal of neurology, neurosurgery, and psychiatry · 2016Article
Corrections and comments
- Erratum issued
Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
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 Ca(2+) 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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