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Association of Novel Single Nucleotide Polymorphisms in the Calcium Channel 1 Subunit Gene (Ca_v1.1) and Thyrotoxic Periodic Paralysis

Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, People’s Republic of China

Address all correspondence and requests for reprints to: Annie Kung, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, People’s Republic of China. E-mail: awckung{at}hkucc.hku.hk.

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_v1.1), sodium channel (Na_v1.4), and potassium channel (K_v3.4), and association of the microsatellite markers on chromosome 1 in the region of the Na/K-ATPase subunits 1, 2, and ß1 were studied. None of the TPP patients carried the known mutations in Ca_v1.1, Na_v1.4, and K_v3.4 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_v1.1 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_v1.1 gene.

This work was supported by the Endocrine and Osteoporosis Research Fund and the CRCG grant of the University of Hong Kong.

Abbreviations: FHPP, Familial hypokalemic periodic paralysis; GD, Graves’ disease; Na/K-ATPase, sodium-potassium-ATPase; nt, nucleotide; SNP, single nucleotide polymorphism; TPP, thyrotoxic periodic paralysis; TRE, thyroid hormone responsive element.

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