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Novel susceptibility gene for nonfamilial hypokalemic periodic paralysis.

Publication ,  Journal Article
Song, I-W; Sung, C-C; Chen, C-H; Cheng, C-J; Yang, S-S; Chou, Y-C; Yang, J-H; Chen, Y-T; Wu, J-Y; Lin, S-H
Published in: Neurology
March 29, 2016

OBJECTIVE: To identify susceptibility genes to nonfamilial hypokalemic periodic paralysis (hypoKPP) consisting of thyrotoxic periodic paralysis (TPP) and sporadic periodic paralysis (SPP) and explore the potential pathogenic mechanisms. METHODS: We enrolled patients with nonfamilial hypoKPP not carrying mutations in CACNA1S, SCN4A, KCNJ18, or KCNJ2 and conducted genome-wide association analyses comparing 77 patients with TPP and 32 patients with SPP with 1,730 controls in a Han Chinese population in Taiwan. Replication was performed using an independent Han Chinese cohort of 50 patients with TPP, 22 patients with SPP, and 376 controls. RESULTS: We identified 4 single nucleotide polymorphisms (rs312692, rs312736, rs992072, rs393743) located about 100 Kb downstream of KCNJ2 on chromosome 17q24.3 associated with both TPP and SPP reaching genome-wide significance (p < 9 × 10(-8)). rs312736 was mapped to CTD-2378E21.1, a lincRNA, and direct sequencing revealed an exon variant rs312732 (risk allele A) highly associated with both TPP (p = 1.81 × 10(-12); odds ratio [OR] 3.22 [95% confidence interval (CI) 2.36-4.40]) and SPP (p = 8.6 × 10(-12); OR 5.4 [95% CI 3.17-9.18]). Overexpression of C (normal allele) CTD-2378E21.1 in C2C12 skeletal muscle cell, but not A (risk allele) CTD-2378E21.1, showed significantly decreased Kcnj2 expression, indicating A-type CTD-2378E21.1 has lost the ability to regulate Kcnj2. CONCLUSIONS: Our study reveals a shared genetic predisposition between TPP and SPP. CTD-2378E21.1 is a novel disease-associated gene for both TPP and SPP and may negatively regulate KCNJ2 expression. These findings provide new insights into the pathogenesis of nonfamilial hypoKPP.

Duke Scholars

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Published In

Neurology

DOI

EISSN

1526-632X

Publication Date

March 29, 2016

Volume

86

Issue

13

Start / End Page

1190 / 1198

Location

United States

Related Subject Headings

  • Taiwan
  • Polymorphism, Single Nucleotide
  • Neurology & Neurosurgery
  • Muscle, Skeletal
  • Molecular Sequence Data
  • Male
  • Hypokalemic Periodic Paralysis
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
 

Citation

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Song, I.-W., Sung, C.-C., Chen, C.-H., Cheng, C.-J., Yang, S.-S., Chou, Y.-C., … Lin, S.-H. (2016). Novel susceptibility gene for nonfamilial hypokalemic periodic paralysis. Neurology, 86(13), 1190–1198. https://doi.org/10.1212/WNL.0000000000002524
Song, I-Wen, Chih-Chien Sung, Chien-Hsiun Chen, Chih-Jen Cheng, Sung-Sen Yang, Yi-Chun Chou, Jenn-Hwai Yang, Yuan-Tsong Chen, Jer-Yuarn Wu, and Shih-Hua Lin. “Novel susceptibility gene for nonfamilial hypokalemic periodic paralysis.Neurology 86, no. 13 (March 29, 2016): 1190–98. https://doi.org/10.1212/WNL.0000000000002524.
Song I-W, Sung C-C, Chen C-H, Cheng C-J, Yang S-S, Chou Y-C, et al. Novel susceptibility gene for nonfamilial hypokalemic periodic paralysis. Neurology. 2016 Mar 29;86(13):1190–8.
Song, I. Wen, et al. “Novel susceptibility gene for nonfamilial hypokalemic periodic paralysis.Neurology, vol. 86, no. 13, Mar. 2016, pp. 1190–98. Pubmed, doi:10.1212/WNL.0000000000002524.
Song I-W, Sung C-C, Chen C-H, Cheng C-J, Yang S-S, Chou Y-C, Yang J-H, Chen Y-T, Wu J-Y, Lin S-H. Novel susceptibility gene for nonfamilial hypokalemic periodic paralysis. Neurology. 2016 Mar 29;86(13):1190–1198.

Published In

Neurology

DOI

EISSN

1526-632X

Publication Date

March 29, 2016

Volume

86

Issue

13

Start / End Page

1190 / 1198

Location

United States

Related Subject Headings

  • Taiwan
  • Polymorphism, Single Nucleotide
  • Neurology & Neurosurgery
  • Muscle, Skeletal
  • Molecular Sequence Data
  • Male
  • Hypokalemic Periodic Paralysis
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease