Genetic Association of KCNJ10 rs1130183 with Seizure Susceptibility and Computational Analysis of Deleterious non-synonymous SNPs of KCNJ10 Gene

Phani, Nagaraja M and Acharya, Shreeshakala and Xavy, Seethu and Bhaskaranand, Nalini and Bhat, Manoj K and Jain, Aditya and Rai, Padmalatha S and Satyamoorthy, K (2013) Genetic Association of KCNJ10 rs1130183 with Seizure Susceptibility and Computational Analysis of Deleterious non-synonymous SNPs of KCNJ10 Gene. Gene, 536 (2). pp. 247-253.

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Abstract

Establishing genetic basis of Idiopathic generalized epilepsies (IGE) is challenging because of their complex in-heritance pattern and genetic heterogeneity. Kir4.1 inwardly rectifying channel (KCNJ10) is one of the independent genes reported to be associated with seizure susceptibility. In the current study we have performed a comprehensive in silico analysis of genetic variants in KCNJ10 gene at functional and structural level along with a case –control analysis for the association ofrs1130183 (R271C) polymorphism in Indian patients with IGE. Age and sex matched 108epileptic patients and normal healthy controls were examined. Genotyping of KCNJ10 rs1130183variation was performed using PCR-RFLP method. The risk association was determined by using odds ratio and 95% confidence interval. Functional effects of non-synonymous SNPs (nsSNPs) in KCNJ10 gene were analyzed using SIFT PolyPhen-2, I-Mutant 2.0, PANTHER and FASTSNP. Subsequently, homology modeling of protein three dimensional(3D)structureswasperformedusingModellertool(9.10v)andcompared the native protein with mutant for assessment of structure and stability. SIFT, PolyPhen-2, I-Mutant 2.0 and PANTHER collectively showed rs1130183, rs1130182 and rs137853073 SNPs in KCNJ10 gene affect protein structure and function. There was a considerable variation in the Root Mean Square Deviation (RMSD)value between the native and mutant structure (1.17 Ǻ). Association analysis indicate KCNJ10 rs1130183 did not contribute to risk of seizure susceptibility in Indian patients with IGE (OR- 0.38; 95%CI, 0.07 –2.05) and T allele frequency (0.02%) was in concordance with dbSNP reports. This study identifies potential SNPs that may contribute to seizure susceptibility and further studies with the selected SNPs in larger number of samples and their functional analysis is required for understanding the variants of KCNJ10 with seizure susceptibility.

Item Type: Article
Uncontrolled Keywords: Epilepsy; KCNJ10 rs1130183 (R271C) polymorphism; Seizure; Computational prediction tools
Subjects: Life Sciences > MLSC Manipal
Medicine > KMC Manipal > Paediatrics
Depositing User: KMC Manipal
Date Deposited: 13 Jan 2014 04:27
Last Modified: 13 Jan 2014 04:27
URI: http://eprints.manipal.edu/id/eprint/138332

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