Mutations linked to familial hypokalaemic periodic paralysis in the calcium channel α1 subunit gene (Ca_v1·1) are not associated with thyrotoxic hypokalaemic periodic paralysis

Abstract

Mutations linked to familial hypokalaemic periodic paralysis in the calcium channel alpha1 subunit gene (Cav1.1) are not associated with thyrotoxic hypokalaemic periodic paralysis. However, polymorphisms in nucleotides 1551 and 1564 in the exon 11 were found in patients with familial hypokalaemic periodic paralysis and thyrotoxic hypokalaemic periodic paralysis in higher frequency than in controls. The polymorphisms identified within the Cav1.1 gene are associated with thyrotoxic hypokalaemic periodic paralysis and represent a novel finding.

Autonomously Functioning Thyroid Nodule Associated with Thyrotoxic Periodic Paralysis

“…In view of the similarities between FHPP and TPP, such mutations have been examined in TPP patients. Most studies have demonstrated that none of the TPP patients carry the known mutations in CACNA1S, SCN4A, and KCNE3 genes [11,13,29,30]. In line with these studies, we did not detect the known defects in CACNA1S and KCNE3 genes, supporting the hypothesis that mutations in skeletal muscle ion channel genes associated with FHPP are not involved in the pathogenesis of TPP.…”

“…Furthermore, it remains unclear whether the mutations in ion channel genes, if any, can explain the important clinical difference between FHPP and TPP, that is, TPP resolves completely following normalization of thyroid function. Whereas we did not find the polymorphism GGC/GGT at nucleotide 1551 nor the polymorphism CCC/CCT at nucleotide 1564 in the CACNA1S gene [11] in the present case, the significance of these polymorphisms remains to be determined. Since Na/K-ATPase activity is significantly higher in TPP patients than in uncomplicated thyrotoxicosis [31], its gene was analyzed in Chinese patients with TPP and no mutations were identified [31].…”

“…The R1239H mutation creates an additional restriction site for NlaIII in the PCR products (81 bp); thus the wide-type allele presents two fragments of 48 and 33 bp, whereas the mutant allele does three fragments of 48, 28 and 5 bp [6,7]. Furthermore, to detect the CCC/CCT polymorphism at nucleotide 1564 and the GGC/GGT polymorphism at nucleotide 1551, we used BstOI and HhaI endonucleases (New England BioLabs) and digested the PCR products used in the screening for the R528H mutation at 60°C for 3 hr and at 37°C overnight, respectively [11]. The digestion products were run in 5% agarose gel electrophoresis and visualized with ethidium bromide.…”

“…Several mutations have been demonstrated in the human skeletal muscle genes encoding the voltage-gated calcium channel α1 subunit Cav1.1 (CACNA1S) [5][6][7], the MinK-related peptide 2 that coassembles with Kv3.4 (KCNE3) to form the voltage-gated potassium channel [8], and the voltagegated sodium channel Nav1.4 (SCN4A) [9,10]. In contrast, such defects in these ion channels have only rarely been reported in patients with TPP [11][12][13][14]. Thus, the pathogenic role of ion channel defects in TPP remains under debate.…”

Ion channelopathies in endocrinology: recent genetic findings and pathophysiological insights

“…Our group and others have demonstrated that mutations in the CACN1AS and SCN4A genes, present in familial forms of hypokalemic paralyses (FHypokPP), are not present in patients with TPP (11)(12)(13)(14). Kir2.x paralogues have constitutive thyroid hormone-responsive cis-elements (TREs) in their regulatory regions, therefore we screened the coding sequence of the KCNJ12 (Kir2.2), KCNJ4 (Kir2.3) and KCNJ14 (Kir2.4) genes.…”