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J Endocr Soc
2017 Feb 28;17:809-815. doi: 10.1210/js.2017-00015.
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Novel lincRNA Susceptibility Gene and Its Role in Etiopathogenesis of Thyrotoxic Periodic Paralysis.
Melo MCC
,
de Souza JS
,
Kizys MML
,
Vidi AC
,
Dorta HS
,
Kunii IS
,
Giannocco G
,
Carvalheira G
,
Dias-da-Silva MR
.
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Thyrotoxic periodic paralysis (TPP) is a life-threatening neuromuscular complication of thyrotoxicosis characterized by muscle weakness and hypokalemia and with an unclear etiopathogenesis. However, the 17q24.3 locus had been genetically linked to TPP, in which the genetic variant rs312691 (TC genotype) in long intergenic noncoding RNA (lincRNA) CTD-2378E21.1 is located downstream of inward-rectifier potassium (Kir) channel genes [KCNJ2 and its antisense KCNJ2 (AS-KCNJ2)]. A TPP patient with a suppressed thyroid-stimulating hormone level, a high free thyroxine level of (5.8 ng/dL), and low serum potassium level of (2 mEq/L) was evaluated for Kir channel expression during and after recovery from thyrotoxicosis. We observed that circulating lincRNA and Kir expression varied in accordance with thyroid status and TC genotype. To endorse this association of a lincRNA-rs312691 variant with a genetic risk of TPP, an additional series of 37 patients with TPP and 32 patients with thyrotoxic without paralysis (TWP) were assessed. We verified that the risk of minor allele C was greater in TPP than in TWP (odds ratio, 5.289; P = 0.0062), and protective major allele T was more frequent than observed in the 1000 genome controls (odds ratio, 11.90; P < 0.0001). AS-KCNJ2 was downregulated during thyrotoxicosis in the TWP controls carrying allele T and were upregulated in those with TPP with risk allele C. Moreover, KCNJ2 (Kir2.1) expression was reduced during thyrotoxicosis and restored in euthyroid status. We further excluded any other coding variant by performing targeted exome sequencing mutational screening in 17q24.3. Our data suggest that high lincRNA AS-KCNJ2 and CDT-2378E21.1 expression, possibly driven by the triiodothyronine regulatory mechanism, reduces the Kir2.1 expression observed during thyrotoxicosis. This finding could contribute to the understanding of the reduced inward-rectifying current observed during muscle weakness in genetically susceptible TPP patients.
Figure 1. Position and chromatogram representation of the risk allele C of rs312691 within lincRNA CTD-2378E21.1 found in association with TPP. The C risk is located ~150 kb downstream from the KCNJ2 gene (Kir2.1 channel), which might affect the transcription of the gene and result in periodic paralysis during thyrotoxicosis. The top two chromatograms demonstrate the heterozygous TC genotype and the bottom ones, the homozygous TT and CC genotype.
Figure 2. Expression analysis of Kir channel and lincRNAs in the novel TPP susceptibility locus 17q24.3. Gene expression of human KCNJ2 (Kir2.1) and lincRNAs (CTD-2378E21.1 and AS-KCNJ2) during and after resolved thyrotoxicosis related to rs312691 TT/TC genotype and thyrotoxic (Tox) status were analyzed by measuring peripheral blood circulating messenger RNA relative expression in arbitrary units (AU). In addition to the high triiodothyronine level in blood serum, RT-qPCR of ATP1A1 gene expression was used as a positive control gene for the thyrotoxic state. Allele C of rs312691 variant is the TPP risk one. Statistical significance comparing normal euthyroid condition (NL) with TPP in thyrotoxic (Tox; #) and euthyroid (Eut; *) status. Right box in light gray designates a TPP case-control patient and thyrotoxic patient compared with the recovered euthyroid status for KCNJ2, lincRNA CTD-2378E21.1, and antisense AS-KCNJ2 channel gene expression. F, female; M, male; NL, normal euthyroid control.
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