Novel susceptibility gene for nonfamilial hypokalemic periodic paralysis

Neurology. 2016 Mar 29;86(13):1190-8. doi: 10.1212/WNL.0000000000002524. Epub 2016 Mar 2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Line
  • Cohort Studies
  • Female
  • Genetic Predisposition to Disease / epidemiology*
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study / methods*
  • Humans
  • Hypokalemic Periodic Paralysis / diagnosis
  • Hypokalemic Periodic Paralysis / epidemiology*
  • Hypokalemic Periodic Paralysis / genetics*
  • Male
  • Molecular Sequence Data
  • Muscle, Skeletal / pathology
  • Polymorphism, Single Nucleotide / genetics
  • Taiwan / epidemiology