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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 3 1340-1345
Copyright © 2004 by The Endocrine Society

Association of Novel Single Nucleotide Polymorphisms in the Calcium Channel {alpha}1 Subunit Gene (Cav1.1) and Thyrotoxic Periodic Paralysis

Annie W. C. Kung, K. S. Lau, G. C. Y. Fong and Vivian Chan

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.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
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 (Cav1.1), sodium channel (Nav1.4), and potassium channel (Kv3.4), and association of the microsatellite markers on chromosome 1 in the region of the Na/K-ATPase subunits {alpha}1, {alpha}2, and ß1 were studied. None of the TPP patients carried the known mutations in Cav1.1, Nav1.4, and Kv3.4 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 Cav1.1 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 Cav1.1 gene.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THYROTOXIC PERIODIC PARALYSIS (TPP) is an alarming condition characterized by acute, reversible but recurrent episodes of severe muscle weakness that last from a few hours to 2–3 d. TPP is a complication of thyrotoxicosis, which affects predominantly Asians, in particular the Chinese and Japanese (1, 2). In Hong Kong, TPP affects 13% of male and 0.17% of female thyrotoxic patients (3, 4). Hypokalemia is the hallmark of TPP, and plasma potassium concentrations can range from 1.1 to 3.5 mmol/liter. Mortality due to cardiac arrhythmia associated with the hypokalemia has been reported (5). The pathogenesis of TPP remains unclear. It is observed that there is a massive shift of potassium from the extracellular into the intracellular compartment, leading to dramatic onset of muscle weakness and paralysis. Paralysis is precipitated by heavy carbohydrate intake and high sodium load (1). These clinical features of TPP are similar to that of an autosomal dominantly inherited syndrome, familial hypokalemic periodic paralysis (FHPP), which is not associated with thyrotoxicosis (6).

Defects in ionic channels have been identified as causes of FHPP. The majority of patients with FHPP have mutations identified in the voltage-gated calcium channel {alpha}1 subunit Cav1.1 (or the CACNA1S gene) (7, 8, 9, 10, 11). A few cases were reported to have mutations in the human skeletal muscle voltage-gated sodium channel Nav1.4 (or the SCN4A) (12, 13) and MinK-related peptide 2 (MiRP2) that coassembles with Kv3.4 (or the KCNE3) to form the human skeletal muscle voltage-gated potassium channel (14).

The Cav1.1 gene encodes for the dihydropyridine-sensitive [SCAP];l-type Ca2+ channel in the skeletal muscle (15, 16). It is an oligomeric protein consisting of two high molecular weight polypeptide subunits ({alpha}1 and {alpha}2) and three smaller units (ß, {gamma}, and {delta}). The {alpha}1 subunit confers the structural features needed for the Ca2+ channel function involved in coupling of excitation and contraction in muscle and also contains the binding sites for the Ca2+ channel blockers. The Cav1.1 gene maps to chromosome 1q31–1q32, spans about 73 kb, and consists of 44 exons (15).

At present, the genetic association of TPP has not been elucidated. So far, only one TPP patient of Portuguese descent was reported to be associated with a mutation in the Kv3.4 gene (17). It has been reported that in TPP patients, there is a massive shift of potassium from the extracellular into the intracellular compartments, associated with an increased sodium-potassium-ATPase (Na/K-ATPase) pump activity (18). It is thought that TPP subjects may have an underlying predisposition to activation of Na/K-ATPase activity and that thyroid hormone and hyperinsulinemia enhance the exaggerated response of the pump activity in these subjects (19). Na/K-ATPase is the enzyme responsible for the transport of sodium and potassium ions in most animal cells. The {alpha}- and ß-subunits of Na/K-ATPase are both encoded by multigene families located at different chromosomes, but the {alpha}1 (ATP1A1), {alpha}2 (ATP1A2), and ß1 (ATP1B1) subunits are all located on chromosome 1 at 1p13, 1q21–23, and 1q22–25, respectively.

Because the clinical features of TPP are similar to that of FHPP, we analyzed the previously described FHPP mutations: R528H (arginine to histidine), R1239H, and R1239G (arginine to histidine/glycine) of the Cav1.1 gene; R669H, R672H, R672G of the Nav1.4 gene; and R83H of the Kv3.4 gene in a series of 97 Chinese TPP patients. Secondly, we sequenced the 5' promoter and the exonic regions of the Cav1.1 gene to determine whether new mutations or polymorphisms in these regions may be associated with TPP. Thirdly, to determine the association of Na/K-ATPase {alpha}1, {alpha}2, and ß1 subunits with TPP, we performed genotyping with the microsatellite markers on chromosome 1, which mapped closely to these three genes.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Southern Chinese patients who presented with TPP as acute muscle weakness and paralysis on admission to the Department of Medicine, The University of Hong Kong, Queen Mary Hospital, were recruited. All had biochemical hypokalemia, with serum potassium less than 3.5 mmol/liter (normal, 3.5–5.0 mmol/liter) as measured by an ion-specific electrode. The diagnosis of Graves’ disease (GD) was confirmed with symptoms and signs of thyrotoxicosis, clinically diffusely enlarged goiter, elevated serum free T4, suppressed TSH level, and positive antithyroid antibodies. Male patients who presented at the Thyroid Clinic of The University of Hong Kong, Queen Mary Hospital, with GD but no TPP were also recruited. Healthy male subjects without family history of GD and negative for antithyroid antibodies were recruited from the community. A total of 97 male TPP patients, 77 male GD patients without TPP, and 100 normal male controls were studied. All subjects gave informed consent, and the study was approved by the Ethics Committee of the University of Hong Kong.

Mutation detection

Genomic DNA was extracted from peripheral blood using standard protocol. Fifty nanograms of DNA were used for PCR. Briefly, genomic DNA samples were amplified in volumes of 20 µl, containing 10 mM Tris-HCl (pH 8.3), 2.5 mM MgCl2, 50 mM KCl, 2.5 mM deoxynucleoside triphosphate, and 0.5 U Taq polymerase (AmpliTaq Gold, Applied Biosystems, Foster City, CA). The PCR products were subjected to electrophoresis in a 6% polyacrylamide gel to verify the sizes. After standard procedures of purification and extraction with phenol chloroform and ethanol, the products were subjected to sequencing reaction. PCR was performed using primers flanking across the mutations R528H (arginine to histidine) and R1239H in the Cav1.1 gene (GenBank accession no. AL139159), mutation R672G (arginine to glycine) in the Nav1.4 gene (GenBank accession no. NM000334.1), and mutation R83H (arginine to histidine) in the Kv3.4 gene (GenBank accession no. AP001372). Primers were designed according to sequences of the GenBank accession numbers mentioned (Table 1Go).


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  		TABLE 1. Primer sequence for mutation detection of Cav1.1, Nav1.4, and Kv3.4

 
Single nucleotide polymorphism (SNP) detection

To define the SNPs of Cav1.1 in southern Chinese patients, we sequenced 1200 bp of the 5' region and all 44 exons and 500-bp immediate 5' and 3' splice junctions of the Cav1.1 gene in 50 normal male controls. DNA sequencing as well as product clean-up were performed according to the standard protocol of the DYEnamic ET terminator cycle sequencing kit (Amersham Bioscience, Piscataway, NJ) using dichlororhodamine dye terminator reagent as terminator. After postreaction clean-up, the sequencing products were electrophoresed on the automated sequencer (ABI Prism 3700, Applied Biosystems). The sequences were analyzed and read using the sequence analysis software (Sequencing Analysis version 3.7, Applied Biosystems). Polymorphisms were confirmed by sequencing with reverse primers. Primers were designed to perform PCR experiments based on the published CACNL1A3 sequence (GenBank accession nos. AL139159 and AL358473). After the position of the SNPs was defined, the genotype and allele frequency of the SNPs were determined in 100 normal controls by PCR. The specific primer sequence for each SNP and the specific PCR conditions are listed in Table 2Go.


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  		TABLE 2. Primer sequence for SNP detection in Cav1.1 gene

 
Genotyping analysis

Genotyping of chromosome 1 with six microsatellite markers (D1S2726, D1S252, D1S484, D1S2878, D1S196, and D1S218) was done. These markers are mapped to chromosome 1 at 1p13, 1q21–23, and 1q22–25, where the Na/K-ATPase {alpha}1, {alpha}2, and ß1, respectively, are located. These microsatellite markers are part of the Linkage Mapping Set version 2 (Applied Biosystems).

PCR was performed using different colored fluorescent-labeled primers (FAM, HEX, and NED giving blue, green, and yellow PCR products, respectively) to cover microsatellites of varying allele size distributed throughout this particular chromosome. There was no overlap between products of the same color. Products from different markers were pooled and analyzed in a single gel lane by urea-denaturing gel electrophoresis on the automated sequencer (ABI 377, Applied Biosystems), with an internal ROX-labeled (red color) DNA size standard. The results were analyzed using the Genescan version 3.7 software (Applied Biosystems).

Statistics

Distribution of genotype and allele frequencies among the three different study groups was calculated with data analysis software (Stata Corporation, College Station, TX) to determine the {chi}2 statistics for significance levels. The significance level was set at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
There was no difference in the age of all three groups (TPP, 35 ± 10 yr; GD, 38 ± 10 yr; normal, 34 ± 11 yr). There was also no difference in the serum free T4 levels between GD patients with or without TPP (TPP, 48 ± 29 pmol/liter; GD, 45 ± 32 pmol/liter; normal, 12 ± 6 pmol/liter). The mean serum potassium level on admission among the TPP patients was 2.4 ± 1.1 mmol/liter. No difference was detected in the antithyroglobulin, antithyroid peroxidase, and anti-TSH- receptor antibody titers between GD patients with or without TPP (data not shown).

None of the subjects harbored any of the studied mutations in the Cav1.1, Nav1.4, or Kv3.4 genes. By sequencing at 1200 bp upstream from the start site, at the 5' flanking region, and at all of the 44 exons including flanking intronic sequences of the Cav1.1 gene, 13 SNPs were found, with four in the 5' flanking region, six in the flanking intronic sequences, and the remaining three in the exons (Table 3Go). Among these 13 SNPs, 10 were previously reported, but three were novel, namely an A/G polymorphism in the 5' flanking region at position -878 (SNP I), a silent SNP AAC/AAT in the coding sequences of exon 11 at position 1491, coding for asparagine (SNP VIII), and an A/G polymorphism in intron 15 nucleotide (nt) 59 (SNP XI) (Table 4Go).


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  		TABLE 3. SNP information including location and their encoding proteins

 

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  		TABLE 4. Distribution of SNP genotype frequencies in TPP patients, GD without TPP, and normal controls

 
After determination of the SNPs of Cav1.1 in our population, the SNP genotype and allele frequencies in the 97 TPP subjects were compared with 77 GD controls and 100 healthy controls. Among the 13 SNPs, only three SNPs showed statistical difference in the genotype distribution frequencies among the three groups of subjects (Table 4Go). For SNP II at the 5' region at nt position -476, the variant genotype AA was more commonly found in the TPP patients (80.0%) than in the normal controls (57.8%) or GD controls (58.9%) ({chi}2 = 11.974; P = 0.023). The t test analysis showed significant difference between TPP patients and GD controls vs. normal controls (P = 0.05), but not between TPP patients and GD controls.

For SNP VI at intron 2 nt 57, a significant difference was observed in the distribution of the variant AA genotype between the three groups (TPP, 57.3%; GD controls, 73.3%; normal controls, 46.7%; {chi}2 = 13.472; P < 0.01; Table 4Go). The t test analysis showed a difference in the distribution between TPP and GD controls (P < 0.05) but no difference between TPP and normal controls.

For SNP XIII at intron 26 nt 67, the genotype GG was seen more commonly in TPP patients (41.1%) than in GD controls (15.6%) or normal controls (34.7%). The distribution of this genotype was significantly different among these three groups ({chi}2 = 18.567; P < 0.001). The t test analysis showed significant difference in the distribution between TPP patients and GD controls (P < 0.001) and between TPP patients and normal controls (P < 0.05).

For SNP IX at exon 11 nt 1551 and SNP X at exon 11 nt 1564, the frequency of the respective variant allele C and T was very low, and the distribution of the SNP genotype frequency was similar between the three groups.

The association of the microsatellite markers on chromosome 1 was analyzed (Table 4Go). There was no association of TPP with any of the microsatellite markers in the region of Na/K-ATPase {alpha}1, {alpha}2, or ß1 subunits.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our study, which consisted of a large population of southern Chinese TPP patients, demonstrated the association of SNPs of Cav1.1 gene with TPP. Many similarities in the clinical presentations are seen between TPP and FHPP. These include recurrent episodes of acute muscle paralysis that are precipitated by exercise or carbohydrate load (1, 2, 3, 19). The most prominent feature is hypokalemia due to intracellular shift. For FHPP, the affected patients are generally well between attacks. Similarly, in the patients with TPP, attacks only occur when the patient is hyperthyroid, but not during euthyroidism. However, FHPP is an autosomal dominant condition affecting mostly Caucasians (20, 21), whereas TPP is a sporadic disease found mainly in Asian males, and the familial trait is rare (1, 2, 3).

Due to similarities between the two conditions, we tested the hypothesis that TPP patients may have similar genetic predispositions as FHPP patients, with the presentation of paralysis being unmasked by thyrotoxicosis. Our genetic analysis revealed that none of the known mutations in the cationic (calcium, sodium, and potassium) voltage-gated channels described in FHPP patients are present in any of our Chinese TPP subjects. Previous publications also failed to detect mutations in the Cav 1.1 gene (11, 22).

Our data showed that three SNPs of Cav1.1 were found to be more common among the TPP subjects. These polymorphisms are the AA genotype at nt -476 of the 5' region, the AA genotype of SNP VI at intron 2 nt 57, and the GG genotype of SNPXIII at intron 26 nt 67. Association of SNPs of Cav1.1 has recently been reported in Brazilian TPP patients (22). Among the 13 sporadic subjects studied, Dias da Silva et al. (22) reported that 77% were heterozygous GGC/GGT at nt 1551 (equivalent to SNP IX of the present study), and 31% were heterozygous CCC/CCT at nt 1564 (equivalent to SNP X). These figures were significantly higher than those of normal controls (18% were heterozygous GGC/GGT, and 8.6% were heterozygous CCC/CCT), who were mainly of Japanese rather than Brazilian descent. However, in our Chinese patients, there was no difference in the genotype distribution at these two sites between TPP subjects and GD or normal controls.

The possible mechanism for the association of TPP to SNPs of the Cav1.1 gene is unclear. This L-type {alpha}1 calcium channel subunit has four domains connected by intracellular loops (6, 7). Each domain is subdivided into six transmembrane hydrophobic segments. Segment 4 contains a positively charged amino acid at each third position, these positions all acting as voltage sensors. Thus, segment 4 is responsible for the voltage-gated function of this protein, which plays an important role in the excitation-contraction coupling of skeletal muscle. In patients with FHPP, three-point mutations had been found in segment 4, involving a single amino acid substitution of the highly conserved arginine to histidine or glycine. Functional analysis revealed decreased current density and slower activation, but faster deactivation of the skeletal muscles in subjects carrying these mutations. There is also reduced sarcolemmal KATP current in FHPP patients with these mutations (23). However, we failed to detect any association with TPP at SNPs located near the voltage sensors of the protein, namely SNP IX, X, and XII.

We analyzed the location of the SNPs of the Cav1.1 gene to determine the possible mechanism for the association with TPP. Thyroid hormone and its receptor bind to imperfect repeats of two or more thyroid hormone responsive element (TRE) half-sites consisting of a six-nucleotide core binding motif 5'-(A/G)GG(TCA/AGG)-3' (24). It is known that the repeats may be separated at a distance, and the nucleotides flanking the binding motif may influence the affinity of thyroid hormone receptor for its response element. We searched 1200 bp of the 5' flanking region, all 44 exons, including the entire 500 bp immediately 5' and 3' of the exon/intron splice site intervening sequence of the published Cav1.1 gene sequence, for the presence of putative TRE and noted that the A/G polymorphism at nt -476 of the 5'region (SNP II) is present right at the TRE 5'-AGGAA/GG-3' of nt -479 to-474, with the other TRE 3'-AGGTCA-5' being found at nt -647 to -652. Also, SNP VI at intron 2 nt 57 is found right at the putative TRE 5'-GGGAG/AG-3' at intron 2 nt 53 to 58, and the other TRE core binding motif 5'-AGGTCA-3' is present at intron 1 nt 1725 to 1730. Similarly, close to SNP XIII at intron 26 nt 67, putative TRE are identified at intron 26 nt 35 to 40 (ACTGGG) and intron 26 nt 192 to 197 (AGGAGG). No other TRE core binding motif is found elsewhere in the sequence that we searched. Although TRE is usually present in the 5' flanking region of the responsive gene, it also has been reported to occur in the intervening sequence and the 3' untranslated region (25, 26). It is likely that the SNPs may influence the binding activity of the TRE of these thyrotoxic patients and modulate the influence of thyroid hormone on the expression of Cav1.1 gene. This, of course, must be confirmed by transcriptional studies to document the functional status of these TRE motifs and the difference in activity between TPP patients and controls.

In addition, thyroid hormone may exert indirect action by activating other transcription factors that exert cis- or trans-activation or inactivation of the Cav1.1 gene. Searching the transcription factors that are being modulated by thyroid hormone and matching the nucleotide sequence failed to detect such interaction. Similarly, none of the cis-acting transcription factors of Cav1.1 within the nucleotide sequence that we searched are known to be affected by thyroid hormone. Of course, there remains a possibility that the association of SNPs of Cav1.1 with TPP is due to linkage of these SNPs with another yet unidentified relevant gene.

Increased Na/K-ATPase pump activity in TPP patients was also thought to be one of the mechanisms for the intracellular shift of serum potassium and hypokalcemia in TPP patients (27). Various groups have shown that the number of Na/K-ATPase pumps as well as Na/K-ATPase-mediated cation influx were increased in leukocytes and platelets of TPP patients compared with GD and normal controls (28, 29, 30). Apart from direct action, thyroid hormone also increased the ß-adrenergic stimulation of Na/K-ATPase (18, 31) and enhanced insulin response of the Na/K-pump (32, 33). In this study, we examined the association of Na/K-ATPase {alpha}1, {alpha}2, and ß1 subunits with TPP by studying the microsatellite markers that mapped to these three genes. Our results failed to find any associations with the markers that mapped to 1p13, 1q21–23, and 1q22–25. Whether there could be other polymorphic sites in these genes to account for an underlying predisposition for the activation of Na/K-ATPase remains to be confirmed.

In conclusion, we observed an association of SNPs of Cav1.1 gene with TPP in southern Chinese men. Because these sites lie at or near the TRE binding motif, presence of the polymorphism may alter thyroid hormone action on the Cav1.1 gene and predispose such patients to TPP.


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  		TABLE 5. Analysis of chromosome 1p13-25 region in TPP patients, GD without TPP, and normal controls

 

   Footnotes
 
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.

Received May 28, 2003.

Accepted November 18, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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A. W. C. Kung
Thyrotoxic Periodic Paralysis: A Diagnostic Challenge
J. Clin. Endocrinol. Metab., July 1, 2006; 91(7): 2490 - 2495.
[Abstract] [Full Text] [PDF]

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 Mayo Clin Proc.Home page
S.-H. Lin
Thyrotoxic Periodic Paralysis
Mayo Clin. Proc., January 1, 2005; 80(1): 99 - 105.
[Abstract] [PDF]

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