Association of novel single-nucleotide polymorphisms in the dihydropyridine sensitive L-type Alpha-3 Calcium Channel (CACNL1 α 3) and Thyrotoxic Periodic Paralysis (TPP)

Abstract

TPP is a frequent complication of thyrotoxicosis occurring sporadically among southern Chinese men. Intracellular shift of potassium results in hypokalaemia and acute muscle paralysis. The clinical presentation of TPP is very similar to an autosomal dominantly inherited disease familial hypokalaemic periodic paralysis (FHPP), which is not associated with thyrotoxicosis. FHPP is associated predominantly with mutations in the dihydropyridine receptor gene, which encodes a subunit of calcium channel in muscle (CACNL1a3), and in a few cases mutations involving the sodium channel (SCN4A) or potassium channel (KCNE3). To study whether there are similar mutations occurring among the TPP subjects, we directly sequenced the 44 exons of the candidate gene for mutations in 97 male TPP patients, 77 patients with Graves’ disease (GD) but no TPP and 100 normal male subjects. We also studied the microsatellite markers in chromosome 1 in the region of the Na/K-ATPase subunit a1, a2, and b1. Results showed that none of the TPP patients carried the known mutations in the CACNL1a3, SCN4A and KCNE3 gene. There was no association of TPP with the microsatellite markers that mapped to 1p13, 1q21-23, 1q22-25 and 1q31-32. We detected 12 single nucleotide polymorphisms (SNPs) in the CACNL1a3 in our population, of which 4 were novel. An A/G polymorphism in intron 26 was significantly associated with TPP as compared to GD and normal controls (p , 0.001). The identification of the associated SNPs may enable detection of carriers who may be predisposed to TPP.