Association of Novel Single Nucleotide Polymorphisms in the Calcium Channel α1 Subunit Gene (Ca_v1.1) 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.

Thyrotoxic periodic paralysis as the first manifestation of a thyrotropin-secreting pituitary adenoma

“…[26][27][28] Moreover, an association between certain single-nucleotide polymorphisms (SNPs) of the L-type calcium channels a1-subunit Cav1.1 has been reported in Southern Chinese TPP patients. 29 However, no specific association of HLA haplotypes or SNPs polymorphisms and predisposition to TPP has been documented.…”

Toxic Thyroid Adenoma Presenting as Hypokalemic Periodic Paralysis

“…Although no mutations were found in the hot spots of FHPP in the Ca v 1.1 gene [12,[39][40][41][42][43], single-nucleotide polymorphisms (SNPs) of Ca v 1.1 were associated in patients with TTP [12,13] and a positional implication with the TRE has been discussed because these SNPs lie at or near the TRE half site sequence. Similarly, although most of studies failed to detect mutations of the Na v 1.4 and K v 3.4 genes [13,14,41,43], one pediatric Caucasian patient with TTP had an R672G mutation of the Na v 1.4 and one TPP patient of Portuguese descent had an R83H mutation in the K v 3.4 gene. However, the R672G mutation of the Na v 1.4 was also carried by the family members who had hypokalemic paralysis without thyrotoxicosis and the patient with R83H mutation in the K v 3.4 seems to have been also reported as FHPP [14,44].…”

Manifestation, Management and Molecular Analysis of Candidate Genes in Two Rare Cases of Thyrotoxic Hypokalemic Periodic Paralysis

“…No mutations in these candidate genes were detected, however. In line with this, Kung et al [22] found no disease causing mutations in CACNA1S, SCN4A or KCNE3 genes in 97 male Chinese THypoKPP patients, but reported an association of single nucleotide polymorphisms (SNPs) in the CACNA1S gene with THypoKPP. These SNPs were located in the 5′flanking region and in introns 2 and 26, close to the thyroid hormone responsive element [22].…”

“…In line with this, Kung et al [22] found no disease causing mutations in CACNA1S, SCN4A or KCNE3 genes in 97 male Chinese THypoKPP patients, but reported an association of single nucleotide polymorphisms (SNPs) in the CACNA1S gene with THypoKPP. These SNPs were located in the 5′flanking region and in introns 2 and 26, close to the thyroid hormone responsive element [22]. It was speculated that they may affect binding affinity of the thyroid responsive element and modulate the stimulation of the CACNA1S gene by thyroid hormones [22].…”