Computational screening of disease associated mutations on NPC1 gene and its structural consequence in Niemann-Pick type-C1
Received date: 05 Mar 2014
Accepted date: 28 Apr 2014
Published date: 11 Oct 2014
Copyright
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
Naresh KANDAKATLA , Geetha RAMAKRISHNAN , Rajasekhar CHEKKARA , Namachivayam BALAKRISHNAN . Computational screening of disease associated mutations on NPC1 gene and its structural consequence in Niemann-Pick type-C1[J]. Frontiers in Biology, 2014 , 9(5) : 410 -421 . DOI: 10.1007/s11515-014-1314-2
1 |
Adzhubei I A, Schmidt S, Peshkin L, Ramensky V E, Gerasimova A, Bork P, Kondrashov A S, Sunyaev S R (2010). A method and server for predicting damaging missense mutations. Nat Methods, 7(4): 248–249
|
2 |
Amberger J, Bocchini C A, Scott A F, Hamosh A (2009). McKusick's online Mendelian inheritance in man (OMIM®). Nucleic Acids Res, 37(Database issue suppl 1): D793–D796
|
3 |
Balu K, Purohit R (2013). Mutational analysis of TYR gene and its structural consequences in OCA1A. Gene, 513(1): 184–195
|
4 |
Balu K, Rajendran V, Sethumadhavan R, PurohitR (2013). Investigation of binding phenomenon of NSP3 and p130Cas mutants and their effect on cell signalling. Cell Biochem Biophys, 67(2): 623–633
|
5 |
Bauer P, Knoblich R, Bauer C, Finckh U, Hufen A, Kropp J, Braun S, Kustermann-Kuhn B, Schmidt D, Harzer K, Rolfs A (2002). NPC1: Complete genomic sequence, mutation analysis, and characterization of haplotypes. Hum Mutat, 19(1): 30–38
|
6 |
Beltroy E P, Richardson J A, Horton J D, Turley S D, Dietschy J M (2005). Cholesterol accumulation and liver cell death in mice with Niemann-Pick type C disease. Hepatology, 42(4): 886–893
|
7 |
Capriotti E, Calabrese R, Casadio R (2006). Predicting the insurgence of human genetic diseases associated to single point protein mutations with support vector machines and evolutionary information. Bioinformatics, 22(22): 2729–2734
|
8 |
Carstea E D, Morris J A, Coleman K G, Loftus S K, Zhang D, Cummings C, Gu J, Rosenfeld M A, Pavan W J, Krizman D B, Nagle J, Polymeropoulos M H, Sturley S L, Ioannou Y A, Higgins M E, Comly M, Cooney A, Brown A, Kaneski C R, Blanchette-Mackie E J, Dwyer N K, Neufeld E B, Chang T Y, Liscum L, Strauss J F 3rd, Ohno K, Zeigler M, Carmi R, Sokol J, Markie D, O’Neill R R, van Diggelen O P, Elleder M, Patterson M C, Brady R O, Vanier M T, Pentchev P G, Tagle D A (1997). Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science, 277(5323): 228–231
|
9 |
Carvalho M A, Marsillac S M, Karchin R, Manoukian S, Grist S, Swaby R F, Urmenyi T P, Rondinelli E, Silva R, Gayol L, Baumbach L, Sutphen R, Pickard-Brzosowicz J L, Nathanson K L, Sali A, Goldgar D, Couch F J, Radice P, Monteiro A N A (2007). Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis. Cancer Res, 67(4): 1494–1501
|
10 |
Carvalho M, Pino M A, Karchin R, Beddor J, Godinho-Netto M, Mesquita R D, Rodarte R S, Vaz D C, Monteiro V A, Manoukian S, Colombo M, Ripamonti C B, Graeme SuthersR R, Borg A, Radice P, Grist S A, Monteiro A N A, Billack B (2009). Analysis of a set of missense, frameshift, and in-frame deletion variants of BRCA1. Mutat Res, 660(1): 1–11
|
11 |
Chasman D, Adams R M (2001). Predicting the functional consequences of non-synonymous single nucleotide polymorphisms: structure-based assessment of amino acid variation. J Mol Biol, 307(2): 683–706
|
12 |
Fernandez-Valero E M, Ballart A, Iturriaga C, Lluch M, Macias J, Vanier M T, Pineda M, Coll M J (2005). Identification of 25 new mutations in 40 unrelated Spanish Niemann-Pick type C patients: genotype-phenotype correlations. Clin Genet, 68(3): 245–254
|
13 |
Ferrer-Costa C, Gelpí J L, Zamakola L, Parraga I, de la Cruz X, Orozco M (2005). PMUT: a web-based tool for the annotation of pathological mutations on proteins. Bioinformatics, 21(14): 3176–3178
|
14 |
Garver W S, Francis G A, Jelinek D, Shepherd G, Flynn J, Castro G, Walsh Vockley C, Coppock D L, Pettit K M, Heidenreich R A, Meaney F J (2007). The National Niemann-Pick C1 disease database: report of clinical features and health problems. Am J Med Genet A, 143A(11): 1204–1211
|
15 |
Garver W S, Heidenreich R A (2002). The Niemann-Pick C proteins and trafficking of cholesterol through the late endosomal/lysosomal system. Curr Mol Med, 2(5): 485–505
|
16 |
Garver W S, Jelinek D, Meaney F J, Flynn J, Pettit K M, Shepherd G, Heidenreich R A, Vockley C M W, Castro G, Francis G A (2010). The National Niemann-Pick Type C1 Disease Database: correlation of lipid profiles, mutations, and biochemical phenotypes. J Lipid Res, 51(2): 406–415
|
17 |
Goldgar D E, Easton D F, Deffenbaugh A M, Monteiro A N, Tavtigian S V, Couch F J, the Breast Cancer Information Core (BIC) Steering Committee (2004). Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2. Am J Hum Genet, 75(4): 535–544
|
18 |
Goldstein J L, Brown M S (1992). Lipoprotein receptors and the control of plasma LDL cholesterol levels. Eur Heart J, 13(Suppl B): 34–36
|
19 |
Greer W L, Dobson M J, Girouard G S, Byers D M, Riddell D C, Neumann P E (1999). Mutations in NPC1 highlight a conserved NPC1-specific cysteine-rich domain, Am J Hum Genet, 65(5): 1252–1260
|
20 |
Harpaz Y, Gerstein M, Chothia C (1994). Volume changes on protein folding. Structure, 2(7): 641–649
|
21 |
Hess B, Kutzner C, Van Der Spoel D, Lindahl E (2008). GROMACS 4: Algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput, 4(3): 435–447
|
22 |
Hollup S M, Salensminde G, Reuter N (2005). WEBnm@: a web application for normal mode analyses of proteins. BMC Bioinformatics, 6(1): 52
|
23 |
Ioannou Y A (2000). The structure and function of the Niemann-Pick C1 protein. Mol Genet Metab, 71(1-2): 175–181
|
24 |
Kamaraj B, Purohit R (2014). Computational screening of disease-associated mutations in OCA2 gene. Cell Biochem Biophys, 68(1): 97–109
|
25 |
Kamaraj B, Purohit R (2013). In silico screening and molecular dynamics simulation of disease-associated nssnp in tyrp1 gene and its structural consequences in OCA3. BioMed Res Int, 2013: Article ID 697051
|
26 |
Kaplan W, Littlejohn T G (2001). Swiss-PDB viewer (deep view). Brief Bioinform, 2(2): 195–197
|
27 |
Karchin R (2009). Next generation tools for the annotation of human SNPs. Brief Bioinform, 10(1): 35–52
|
28 |
Kobayashi T, Beuchat M H, Lindsay M, Frias S, Palmiter R D, Sakuraba H, Parton R G, Gruenberg J (1999). Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport. Nat Cell Biol, 1(2): 113–118
|
29 |
Kumar A, Purohit R (2012a). Computational centrosomics: an approach to understand the dynamic behaviour of centrosome. Gene, 511(1): 125–126
|
30 |
Kumar A, Purohit R (2012c). Computational investigation of pathogenic nsSNPs in CEP63 protein. Gene, 503(1): 75–82
|
31 |
Kumar A, Purohit R (2013). Cancer associated E17K mutation causes rapid conformational drift in AKT1 pleckstrin homology (PH) domain. PLoS One, 8(5): e64364
|
32 |
Kumar A, Purohit R (2014). Use of Long Term Molecular Dynamics Simulation in Predicting Cancer Associated SNPs. PLoS Comput Biol, 10(4): e1003318
|
33 |
Kumar A, Rajendran V, Sethumadhavan R, Purohit R (2013). Molecular dynamic simulation reveals damaging impact of RAC1 F28L mutation in the switch I region. PLoS One, 8(10): e77453
|
34 |
Kumar A, Rajendran V, Sethumadhavan R, Purohit R (2013a). Computational investigation of cancer-associated molecular mechanism in Aurora A (S155R) mutation. Cell Biochem Biophys, 66(3): 787–796
|
35 |
Kumar A, Rajendran V, Sethumadhavan R, Purohit R (2013b). Evidence of colorectal cancer-associated mutation in MCAK: a computational report. Cell Biochem Biophys, 67(3): 837–851
|
36 |
Kumar A, Rajendran V, Sethumadhavan R, Purohit R (2014). Relationship between a point mutation S97C in CK1δ protein and its affect on ATP-binding affinity. J Biomol Struct Dyn, 32(3): 394–405
|
37 |
Kumar A, Rajendran V, Sethumadhavan R, Shukla P, Tiwari S, Purohit R (2014). Computational SNP analysis: current approaches and future prospects. Cell Biochem Biophys, 68(2): 233–239
|
38 |
Kumar P, Henikoff S, Ng P C (2009). Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc, 4(7): 1073–1081
|
39 |
Kumar A, Purohit R (2012b). Computational screening and molecular dynamics simulation of disease associated nsSNPs in CENP-E. Mutat Res, 738–739: 28–37
|
40 |
Kumar A, Rajendran V, Sethumadhavan R, Purohit R (2012). In silico prediction of a disease-associated STIL mutant and its affect on the recruitment of centromere protein J (CENPJ). FEBS Open Bio, 2: 285–293
|
41 |
Laskowski R A, Rullmannn J A, MacArthur M W, Kaptein R, Thornton J M (1996). AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR. J Biomol NMR, 8(4): 477–486
|
42 |
Li B, Krishnan V G, Mort M E, Xin F, Kamati K K, Cooper D N, Mooney S D, Radivojac P (2009). Automated inference of molecular mechanisms of disease from amino acid substitutions. Bioinformatics, 25(21): 2744–2750
|
43 |
Liscum L (2000). Niemann-Pick type C mutations cause lipid traffic jam. Traffic, 1(3): 218–225
|
44 |
Millat G, Baïlo N, Molinero S, Rodriguez C, Chikh K, Vanier M T (2005). Niemann-Pick C disease: use of denaturing high performance liquid chromatography for the detection of NPC1 and NPC2 genetic variations and impact on management of patients and families. Mol Genet Metab, 86(1-2): 220–232
|
45 |
Millat G, Marçais C, Rafi M A, Yamamoto T, Morris J A, Pentchev P G, Ohno K, Wenger D A, Vanier M T (1999). Niemann-Pick C1 disease: the I1061T substitution is a frequent mutant allele in patients of Western European descent and correlates with a classic juvenile phenotype. Am J Hum Genet, 65(5): 1321–1329
|
46 |
Millat G, Marçais C, Tomasetto C, Chikh K, Fensom A H, Harzer K, Wenger D A, Ohno K, Vanier M T (2001). Niemann-Pick C1 disease: correlations between NPC1 mutations, levels of NPC1 protein, and phenotypes emphasize the functional significance of the putative sterol-sensing domain and of the cysteine-rich luminal loop. Am J Hum Genet, 68(6): 1373–1385
|
47 |
Mooney S (2005). Bioinformatics approaches and resources for single nucleotide polymorphism functional analysis. Brief Bioinform, 6(1): 44–56
|
48 |
Morris J A, Zhang D, Coleman K G, Nagle J, Pentchev P G, Carstea E D (1999). The genomic organization and polymorphism analysis of the human Niemann-Pick C1 gene. Biochem Biophys Res Commun, 261(2): 493–498
|
49 |
Ng P C, Henikoff S (2006). Predicting the effects of amino acid substitutions on protein function. Annu Rev Genomics Hum Genet, 7(1): 61–80
|
50 |
Pipalia N H, Huang A, Ralph H, Rujoi M, Maxfield F R (2006). Automated microscopy screening for compounds that partially revert cholesterol accumulation in Niemann-Pick C cells. J Lipid Res, 47(2): 284–301
|
51 |
Puri V, Watanabe R, Dominguez M, Sun X, Wheatley C L, Marks D L, Pagano R E (1999). Cholesterol modulates membrane traffic along the endocytic pathway in sphingolipid-storage diseases. Nat Cell Biol, 1(6): 386–388
|
52 |
Purohit R (2014). Role of ELA region in auto-activation of mutant KIT receptor: a molecular dynamics simulation insight. J Biomol Struct Dyn, 32(7): 1033–1046
|
53 |
Purohit R, Rajendran V, Sethumadhavan R (2011a). Studies on adaptability of binding residues and flap region of TMC-114 resistance HIV-1 protease mutants. J Biomol Struct Dyn, 29(1): 137–152
|
54 |
Purohit R, Rajendran V, Sethumadhavan R (2011b). Relationship between mutation of serine residue at 315th position in M. tuberculosis catalase-peroxidase enzyme and Isoniazid susceptibility: an in silico analysis. J Mol Model, 17(4): 869–877
|
55 |
Purohit R, Sethumadhavan R (2009). Structural basis for the resilience of Darunavir (TMC114) resistance major flap mutations of HIV-1 protease. Interdiscip Sci, 1(4): 320–328
|
56 |
Rajendran V, Purohit R, Sethumadhavan R (2012). In silico investigation of molecular mechanism of laminopathy caused by a point mutation (R482W) in lamin A/C protein. Amino Acids, 43(2): 603–615
|
57 |
Rajendran V, Sethumadhavan R (2014). Drug resistance mechanism of PncA in Mycobacterium tuberculosis. J Biomol Struct Dyn, 32(2): 209–221
|
58 |
Ribeiro I, Marcão A, Amaral O, Sá Miranda M C, Vanier M T, Millat G (2001). Niemann-Pick type C disease: NPC1 mutations associated with severe and mild cellular cholesterol trafficking alterations. Hum Genet, 109(1): 24–32
|
59 |
Runz H, Dolle D, Schlitter A M, Zschocke J (2008). NPC-db, a Niemann-Pick type C disease gene variation database. Hum Mutat, 29(3): 345–350
|
60 |
Scott C, Ioannou Y A(2004). The NPC1 protein: structure implies function. Biochimica et Biophysica Acta (BBA)-Mol Cell Biol L, 1685(1): 8–13
|
61 |
Sherry S T, Ward M H, Kholodov M, Baker J, Phan L, Smigielski E M, Sirotkin K (2001). dbSNP: the NCBI database of genetic variation. Nucleic Acids Res, 29(1): 308–311
|
62 |
Steward R E, MacArthur M W, Laskowski R A, Thornton J M (2003). Molecular basis of inherited diseases: a structural perspective. Trends Genet, 19(9): 505–513
|
63 |
Sun X, Marks D L, Park W D, Wheatley C L, Puri V, O’Brien J F, Kraft D L, Lundquist P A, Patterson M C, Pagano R E, Snow K (2001). Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1. Am J Hum Genet, 68(6): 1361–1372
|
64 |
Sun X, Marks D L, Park W D, Wheatley C L, Puri V, O’Brien J F, Kraft D L, Lundquist P A, Patterson M C, Pagano R E, Snow K (2001). Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1. Am J Hum Genet, 68(6): 1361–1372
|
65 |
Sunyaev S, Ramensky V, Bork P (2000). Towards a structural basis of human non-synonymous single nucleotide polymorphisms. Trends Genet, 16(5): 198–200
|
66 |
Tamura H, Takahashi T, Ban N, Torisu H, Ninomiya H, Takada G, Inagaki N (2006). Niemann-Pick type C disease: novel NPC1 mutations and characterization of the concomitant acid sphingomyelinase deficiency. Mol Genet Metab, 87(2): 113–121
|
67 |
Tarugi P, Ballarini G, Bembi B, Battisti C, Palmeri S, Panzani F, Di Leo E, Martini C, Federico A, Calandra S (2002). Niemann-Pick type C disease: mutations of NPC1 gene and evidence of abnormal expression of some mutant alleles in fibroblasts. J Lipid Res, 43(11): 1908–1919
|
68 |
Thomas P D, Campbell M J, Kejariwal A, Mi H, Karlak B, Daverman R, Diemer K, Muruganujan A, Narechania A (2003). PANTHER: a library of protein families and subfamilies indexed by function. Genome Res, 13(9): 2129–2141
|
69 |
Vanier M T, Suzuki K (1998). Recent advances in elucidating Niemann-Pick C disease. Brain Pathol, 8(1): 163–174
|
70 |
Wiederstein M, Sippl M J (2007). ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res, 35(Web Server issue suppl 2): W407-10
|
71 |
Willard L, Ranjan A, Zhang H, Monzavi H, Boyko R F, Sykes B D, Wishart D S (2003). VADAR: a web server for quantitative evaluation of protein structure quality. Nucleic Acids Res, 31(13): 3316–3319
|
72 |
Xiong H, Higaki K, Wei C J, Bao X H, Zhang Y H, Fu N, Qin J, Adachi K, Kumura Y, Ninomiya H, Nanba E, Wu X R (2012). Genotype/phenotype of 6 Chinese cases with Niemann-Pick disease type C. Gene, 498(2): 332–335
|
73 |
Yamamoto T, Ninomiya H, Matsumoto M, Ohta Y, Nanba E, Tsutsumi Y, Yamakawa K, Millat G, Vanieer M, Pentchev P G, Ohno K (2000). Genotype-phenotype relationship of Niemann-Pick disease type C: a possible correlation between clinical onset and levels of NPC1 protein in isolated skin fibroblasts. J Med Genet, 37(9): 707–712
|
74 |
Zhang Y (2008). I-TASSER server for protein 3D structure prediction. BMC Bioinformatics, 9(1): 40
|
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