Novel susceptibility gene for nonfamilial hypokalemic periodic paralysis

I-Wen Song; Chih-Chien Sung; Chien-Hsiun Chen; Chih-Jen Cheng; Sung-Sen Yang; Yi-Chun Chou; Jenn-Hwai Yang; Yuan-Tsong Chen; Jer-Yuarn Wu; Shih-Hua Lin

doi:10.1212/WNL.0000000000002524

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Novel susceptibility gene for nonfamilial hypokalemic periodic paralysis

Journal article

Peer reviewed

Novel susceptibility gene for nonfamilial hypokalemic periodic paralysis

I-Wen Song, 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

Neurology, Vol.86(13), pp.1190-1198

03/29/2016

DOI: 10.1212/WNL.0000000000002524

PMID: 26935888

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Abstract

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. 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. 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. 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.

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

Details

Title: Subtitle: Novel susceptibility gene for nonfamilial hypokalemic periodic paralysis
Creators: I-Wen Song - Academia Sinica
Chih-Chien Sung - National Defense Medical Center
Chien-Hsiun Chen - Duke University
Chih-Jen Cheng - China Medical University
Sung-Sen Yang
Yi-Chun Chou
Jenn-Hwai Yang
Yuan-Tsong Chen
Jer-Yuarn Wu
Shih-Hua Lin
Resource Type: Journal article
Publication Details: Neurology, Vol.86(13), pp.1190-1198
DOI: 10.1212/WNL.0000000000002524
PMID: 26935888
ISSN: 0028-3878
eISSN: 1526-632X
Language: English
Date published: 03/29/2016
Academic Unit: Nephrology; Internal Medicine
Record Identifier: 9984383923302771

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