Association of Novel Single Nucleotide Polymorphisms in the Calcium Channel α1 Subunit Gene (Cav1.1) and Thyrotoxic Periodic Paralysis
Abstract
Thyrotoxic (hypokalemic) periodic paralysis (TPP) is a frequent complication of thyrotoxicosis among Chinese men. To determine the genetic association of TPP, we studied 97 male TPP patients, 77 Graves' disease patients without TPP, and 100 normal male subjects. Mutations of the voltage-dependent calcium channel (Ca(v)1.1), sodium channel (Na(v)1.4), and potassium channel (K(v)3.4), and association of the microsatellite markers on chromosome 1 in the region of the Na/K-ATPase subunits alpha1, alpha2, and beta1 were studied. None of the TPP patients carried the known mutations in Ca(v)1.1, Na(v)1.4, and K(v)3.4 genes. There was no association of TPP with the microsatellite markers that mapped to 1p13, 1q21-23, and 1q22-25. We detected 12 single nucleotide polymorphisms (SNPs) in Ca(v)1.1 in our population, of which three were novel. Significant differences in the SNP genotype distribution between TPP compared with Graves' disease controls and normal controls were seen at the 5' flanking region nucleotide (nt) -476 (P = 0.02), intron 2 nt 57 (P < 0.01), and intron 26 nt 67 (P < 0.001). Because these SNPs lie at or near the thyroid hormone responsive element, it is possible that they may affect the binding affinity of the thyroid hormone responsive element and modulate the stimulation of thyroid hormone on the Ca(v)1.1 gene.
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CACNA1S mutations promote an excessive intracellular shift of potassium during hyperthyroidism, leading to hypokalemia, which reduces muscle membrane excitability and produces muscle weakness and paralysis.
“CACNA1S mutations have been linked to ion channel dysfunction that promotes an excessive intracellular shift of potassium during periods of hyperthyroidism, eventually leading to hypokalemia. This hypokalemia reduces muscle membrane excitability, similarly producing muscle weakness and paralysis.”
From Thyrotoxic Hypokalemic Periodic Paralysis: Pathophysiological Mechanisms (2025) · cites this paper as [21]
A mutation in the CACNA1S gene has been identified in patients with THPP from Brazil and southern China.
“A mutation in the Cav1.1 (CACNA1S) gene has also been identified in patients with THPP from Brazil [20] and southern China [21].”
From Thyrotoxic Hypokalemic Periodic Paralysis: Pathophysiological Mechanisms (2025) · cites this paper as [21]
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- Authors
- Kung, A. W. C., Lau, K. S., Fong, G. C. Y., & Chan, V.
- Affiliations
- Queen Mary Hospital (CN)
- Corresponding author
- Kung, Annie W. C.
- ORCID
- Kung, Annie W. C.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2004-03
- Volume
- 89
- Issue
- 3
- Pages
- 1340-1345
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2086553307
- Cited by
- 77
- References
- 34
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 4 · 2015: 2 · 2014: 2 · 2013: 3 · 2012: 4
- FWCI
- 2.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- 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 › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Keywords
- thyrotoxic periodic paralysis, hypokalemic periodic paralysis, CaV1.1, voltage-gated calcium channels, single nucleotide polymorphisms, genetic association, thyrotoxicosis, Graves' disease, chromosome 1, sodium channels, potassium channels, Chinese men
- MeSH terms
- Adult, Chromosomes, Human, Pair 1, Genotype, Humans, Male, Middle Aged, Muscle Proteins, Paralyses, Familial Periodic, Thyrotoxicosis, Calcium Channels, Potassium Channels, Sodium Channels, Microsatellite Repeats, Polymorphism, Single Nucleotide, 5' Flanking Region, Potassium Channels, Voltage-Gated, Shaw Potassium Channels, NAV1.4 Voltage-Gated Sodium Channel
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