Computational screening of disease associated mutations on NPC1 gene and its structural consequence in Niemann-Pick type-C1

Abstract

Niemann-Pick disease type C1 (NPC1), caused by mutations of NPC1 gene, is an inherited lysosomal lipid storage disorder. Loss of functional NPC1 causes the accumulation of free cholesterol (FC) in endocytic organelles that comprised the characteristics of late endosomes and/or lysosomes. In this study we analyzed the pathogenic effect of 103 nsSNPs reported in NPC1 using computational methods. R1186C, S940L, R958Q and I1061T mutations were predicted as most deleterious and disease associated with NPC1 using SIFT, Polyphen 2.0, PANTHER, PhD-SNP, Pmut and MUTPred tools which were also endorsed with previous in vivo experimental studies. To understand the atomic arrangement in 3D space, the native and disease associated mutant (R1186C, S940L, R958Q and I1061T) structures were modeled. Quantitative structural and flexibility analysis was conceded to observe the structural consequence of prioritized disease associated mutations (R1186C, S940L, R958Q and I1061T). Accessible surface area (ASA), free folding energy (FFE) and hydrogen bond (NH bond) showed more flexibility in 3D space in mutant structures. Based on the quantitative assessment and flexibility analysis of NPC1 variants, I1061T showed the most deleterious effect. Our analysis provides a clear clue to wet laboratory scientists to understand the structural and functional effect of NPC1 gene upon mutation.

Key words： Niemann-Pick disease type C1; SNPs; gene mutation

Compliance with ethics guidelines

Naresh Kandakatla, Rajasekhar Chekkara, Namachivayam Balakrishnan and Geetha Ramakrishnan declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors.

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