MUTATION SPECTRUM ANALYSIS OF ITGA3 GENE ASSOCIATED WITH NEPHROTIC SYNDROME
Main Article Content
Keywords
Nephrotic syndrome, ITGA, Nephrogenesis, in silico, Bioinformatics
Abstract
Nephrotic syndrome is a renal disorder that affects the Glomerular Filtration Barrier (GFB). ITGA3 protein may have a pivotal function in the intricate interaction between cells, morphogens, and the extracellular matrix (ECM) that leads to the development of the kidneys (nephrogenesis). This study involves a detailed analysis of the missense mutations in the ITGA3 gene through various in silico and bioinformatics tools. Conservation score of each mutation was measured to determine the level of conservation and hence severity of the mutations with regards to the protein structure and function. 3D structural formation, phylogenetic analysis and RNA expression profiles were also constructed. Three highly deleterious mutations (G125R, R143H, P680A) were identified through these in silico tools. Molecular dynamics simulations (MDS) analysis was performed for understanding the dynamic behavior of wild type and mutant proteins. This data aims to facilitate future studies on ITGA3 protein and its role in the development of the Nephrotic syndrome, along with the implication of the mutations on the structure and function of the ITGA3 protein. This study also gives an insight on the detrimental effect on the function of the kidneys due to these mutations that ultimately results in the development of nephrotic syndrome.
References
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Capriotti E, Fariselli P, Casadio R. I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure. Nucleic Acids Res. 2005 Jul 1;33 W306-10. doi: 10.1093/nar/gki375. PMID: 15980478; PMCID: PMC1160136.
Savojardo C, Fariselli P, Martelli PL, Casadio R. INPS-MD: a web server to predict stability of protein variants from sequence and structure. Bioinformatics. 2016 Aug 15;32(16):2542-4. doi: 10.1093/bioinformatics/btw192. Epub 2016 Apr 10. PMID: 27153629.
Cheng J, Randall A, Baldi P. Prediction of protein stability changes for single-site mutations using support vector machines. Proteins. 2006 Mar 1;62(4):1125-32. doi: 10.1002/prot.20810. PMID: 16372356.
Parthiban V, Gromiha MM, Schomburg D. CUPSAT: prediction of protein stability upon point mutations. Nucleic Acids Res. 2006 Jul 1; 34:W239-42. doi: 10.1093/nar/gkl190. PMID: 16845001; PMCID: PMC1538884.
Pires DE, Ascher DB, Blundell TL. DUET: a server for predicting effects of mutations on protein stability using an integrated computational approach. Nucleic Acids Res. 2014 Jul; 42:W314-9. doi: 10.1093/nar/gku411. Epub 2014 May 14. PMID: 24829462; PMCID: PMC4086143.
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Crooks GE, Hon G, Chandonia JM, Brenner SE. WebLogo: a sequence logo generator. Genome Res. 2004 Jun;14(6):1188-90. doi: 10.1101/gr.849004. PMID: 15173120; PMCID: PMC419797.
Schultz J, Copley RR, Doerks T, Ponting CP, Bork P. SMART: a web-based tool for the study of genetically mobile domains. Nucleic Acids Res. 2000 Jan 1;28(1):231-4. doi: 10.1093/nar/28.1.231. PMID: 10592234; PMCID: PMC102444.
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McCloskey O, Maxwell AP (2017) Diagnosis and management of nephrotic syndrome. Pract 261(1801): 11-15
Gigante M, Caridi G, Montemurno E, Soccio M, d'Apolito M, Cerullo G, Gesualdo L (2011) TRPC6 mutations in children with steroid-resistant nephrotic syndrome and atypical phenotype. Clin J Am Soc Nephrol 6(7): 1626-1634
Margadant C, Charafeddine RA, Sonnenberg A (2010) Unique and redundant functions of integrins in the epidermis. FASEB J 24(11):4133-4152
Humphries JD, Byron A, Humphries MJ (2006) Integrin ligands at a glance. J Cell Sci 119(19): 3901-3903
Shen B, Delaney MK, Du X (2012) Inside-out, outside-in, and inside–outside-in: G protein signaling in integrin-mediated cell adhesion, spreading, and retraction. Curr Opin Cell Biol 24(5):600-606
Goodman SL, Picard M (2012) Integrins as therapeutic targets. Trends Pharmacol Sci 33(7):405-412
Sneha P, Doss CG (2016) Molecular Dynamics: New Frontier in Personalized Medicine. Adv Protein Chem Struct Biol 102: 181-224. https://doi.org/10.1016/bs.apcsb.2015.09.004
Adzhubei D, Jordan M, Sunyaev SR (2013) Predicting Functional Effect of Human Missense Mutations Using PolyPhen‐2. Curr Protoc 76:20
Stenson PD, et al. Human Gene Mutation Database (HGMD): 2003 update. Hum Mutat. 2003;21:577–581
The UniProt Consortium, UniProt: the universal protein knowledgebase in 2021, Nucleic Acids Res. 49 (2021) D480–D489, https://doi.org/10.1093/nar/gkaa1100.
Paul D. Thomas, Michael J. Campbell, Anish Kejariwal, Huaiyu Mi, Brian Karlak, Robin Daverman, Karen Diemer, Anushya Muruganujan, Apurva Narechania. 2003. PANTHER: a library of protein families and subfamilies indexed by function. Genome Res., 13: 2129-2141 doi: 10.1101/gr.772403. PMID: 12952881; PMCID: PMC403709
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–249
Capriotti E, Altman RB, Bromberg Y. Collective judgment predicts disease-associated single nucleotide variants. BMC Genomics. 2013;14 Suppl 3(Suppl 3):S2. doi: 10.1186/1471-2164-14-S3-S2. Epub 2013 May 28. PMID: 23819846; PMCID: PMC3839641
Bendl J, Stourac J, Salanda O, Pavelka A, Wieben ED, Zendulka J, Brezovsky J, Damborsky J. PredictSNP: robust and accurate consensus classifier for prediction of disease-related mutations. PLoS Comput Biol. 2014 Jan;10(1):e1003440. doi: 10.1371/journal.pcbi.1003440. Epub 2014 Jan 16. PMID: 24453961; PMCID: PMC3894168
Ng PC, Henikoff S. SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003 Jul 1;31(13):3812-4. doi: 10.1093/nar/gkg509. PMID: 12824425; PMCID: PMC168916
Stone E.A., Sidow A. Physicochemical constraint violation by missense substitution mediates impairment of protein function and disease severity. Genome Research (2005) 15 978-986
López-Ferrando V, Gazzo A, de la Cruz X, Orozco M, Gelpí JL. PMut: a web-based tool for the annotation of pathological variants on proteins, 2017 update. Nucleic Acids Res. 2017 Jul 3;45(W1):W222-W228. doi: 10.1093/nar/gkx313. PMID: 28453649; PMCID: PMC5793831
Johnson AD, Handsaker RE, Pulit SL, Nizzari MM, O'Donnell CJ, de Bakker PI "SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap." Bioinformatics 2008; 24(24):2938-9 https://doi.org/10.1093/bioinformatics/btn564 PMID: 18974171 PMCID: PMC2720775
Capriotti E, Fariselli P. PhD-SNPg: a webserver and lightweight tool for scoring single nucleotide variants. Nucleic Acids Res. 2017 Jul 3;45(W1):W247-W252. doi: 10.1093/nar/gkx369. PMID: 28482034; PMCID: PMC5570245
Capriotti E, Calabrese R, Fariselli P, Martelli PL, Altman RB, Casadio R. WS-SNPs&GO: a web server for predicting the deleterious effect of human protein variants using functional annotation. BMC Genomics. 2013;14 Suppl 3(Suppl 3):S6. doi: 10.1186/1471-2164-14-S3-S6. Epub 2013 May 28. PMID: 23819482; PMCID: PMC3665478
Wiel L, Baakman C, Gilissen D, Veltman JA, Vriend G, Gilissen C. MetaDome: Pathogenicity analysis of genetic variants through aggregation of homologous human protein domains. Hum Mutat. 2019 Aug;40(8):1030-1038. doi: 10.1002/humu.23798. Epub 2019 Jun 18. PMID: 31116477; PMCID: PMC6772141.
Capriotti E, Fariselli P, Casadio R. I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure. Nucleic Acids Res. 2005 Jul 1;33 W306-10. doi: 10.1093/nar/gki375. PMID: 15980478; PMCID: PMC1160136.
Savojardo C, Fariselli P, Martelli PL, Casadio R. INPS-MD: a web server to predict stability of protein variants from sequence and structure. Bioinformatics. 2016 Aug 15;32(16):2542-4. doi: 10.1093/bioinformatics/btw192. Epub 2016 Apr 10. PMID: 27153629.
Cheng J, Randall A, Baldi P. Prediction of protein stability changes for single-site mutations using support vector machines. Proteins. 2006 Mar 1;62(4):1125-32. doi: 10.1002/prot.20810. PMID: 16372356.
Parthiban V, Gromiha MM, Schomburg D. CUPSAT: prediction of protein stability upon point mutations. Nucleic Acids Res. 2006 Jul 1; 34:W239-42. doi: 10.1093/nar/gkl190. PMID: 16845001; PMCID: PMC1538884.
Pires DE, Ascher DB, Blundell TL. DUET: a server for predicting effects of mutations on protein stability using an integrated computational approach. Nucleic Acids Res. 2014 Jul; 42:W314-9. doi: 10.1093/nar/gku411. Epub 2014 May 14. PMID: 24829462; PMCID: PMC4086143.
Ashkenazy H, Abadi S, Martz E, Chay O, Mayrose I, Pupko T, Ben-Tal N. ConSurf 2016: an improved methodology to estimate and visualize evolutionary conservation in macromolecules. Nucleic Acids Res. 2016 Jul 8;44(W1):W344-50. doi: 10.1093/nar/gkw408. Epub 2016 May 10. PMID: 27166375; PMCID: PMC4987940.
Laskowski RA, Jabłońska J, Pravda L, Vařeková RS, Thornton JM. PDBsum: Structural summaries of PDB entries. Protein Sci. 2018 Jan;27(1):129-134. doi: 10.1002/pro.3289. Epub 2017 Oct 27. PMID: 28875543; PMCID: PMC5734310.
Madeira F, Park YM, Lee J, Buso N, Gur T, Madhusoodanan N, Basutkar P, Tivey ARN, Potter SC, Finn RD, Lopez R. The EMBL-EBI search and sequence analysis tools APIs in 2019. Nucleic Acids Res. 2019 Jul 2;47(W1):W636-W641. doi: 10.1093/nar/gkz268. PMID: 30976793; PMCID: PMC6602479.
Crooks GE, Hon G, Chandonia JM, Brenner SE. WebLogo: a sequence logo generator. Genome Res. 2004 Jun;14(6):1188-90. doi: 10.1101/gr.849004. PMID: 15173120; PMCID: PMC419797.
Schultz J, Copley RR, Doerks T, Ponting CP, Bork P. SMART: a web-based tool for the study of genetically mobile domains. Nucleic Acids Res. 2000 Jan 1;28(1):231-4. doi: 10.1093/nar/28.1.231. PMID: 10592234; PMCID: PMC102444.
C. Geourjon, G. Deléage, SOPMA: significant improvements in protein secondary structure prediction by consensus prediction from multiple alignments, Bioinformatics, Volume 11, Issue 6, December 1995, Pages 681–684, https://doi.org/10.1093/bioinformatics/11.6.681
Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJ. The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc. 2015 Jun;10(6):845-58. doi: 10.1038/nprot.2015.053. Epub 2015 May 7. PMID: 25950237; PMCID: PMC5298202.
Schrödinger, L., & DeLano, W. (2020). PyMOL. Retrieved from http://www.pymol.org/pymol
Blom N, Sicheritz-Pontén T, Gupta R, Gammeltoft S, Brunak S. Prediction of post-translational glycosylation and phosphorylation of proteins from the amino acid sequence. Proteomics. 2004 Jun;4(6):1633-49. doi: 10.1002/pmic.200300771. PMID: 15174133.
Szklarczyk D, Gable AL, Nastou KC, Lyon D, Kirsch R, Pyysalo S, Doncheva NT, Legeay M, Fang T, Bork P, Jensen LJ, von Mering C. The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2021 Jan 8;49(D1):D605-D612. doi: 10.1093/nar/gkaa1074. Erratum in: Nucleic Acids Res. 2021 Oct 11;49(18):10800. PMID: 33237311; PMCID: PMC7779004.
Warde-Farley D, Donaldson SL, Comes O, Zuberi K, Badrawi R, Chao P, Franz M, Grouios C, Kazi F, Lopes CT, Maitland A, Mostafavi S, Montojo J, Shao Q, Wright G, Bader GD, Morris Q. The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res. 2010 Jul;38(Web Server issue):W214-20. doi: 10.1093/nar/gkq537. PMID: 20576703; PMCID: PMC2896186.
Mark Johnson, Irena Zaretskaya, Yan Raytselis, Yuri Merezhuk, Scott McGinnis, Thomas L. Madden, NCBI BLAST: a better web interface, Nucleic Acids Research, Volume 36, Issue suppl_2, 1 July 2008, Pages W5–W9, https://doi.org/10.1093/nar/gkn201
Olena Morozova, Yulia Newton, Melissa Cline, Jingchun Zhu, Katrina Learned, Josh Stuart, Sofie Salama, Robert Arceci, David Haussler. Treehouse Childhood Cancer Project: a resource for sharing and multiple cohort analysis of pediatric cancer genomics data. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015
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May 25, 2024
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Quratul Ain Nazir, Wasim Shehzad, Muhammad Asad Ali, & Muhammad YasirZahoor. (2024). MUTATION SPECTRUM ANALYSIS OF ITGA3 GENE ASSOCIATED WITH NEPHROTIC SYNDROME. Journal of Population Therapeutics and Clinical Pharmacology, 31(5), 2024-2046. https://doi.org/10.53555/jptcp.v31i5.7127
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Author Biographies
Quratul Ain Nazir
Institute of Biochemistry and Biotechnology, University of Veterinary and Animal Sciences Lahore, Pakistan.
Wasim Shehzad
Institute of Biochemistry and Biotechnology, University of Veterinary and Animal Sciences Lahore, Pakistan.
Muhammad Asad Ali
Department of Microbiology, University of Veterinary and Animal Sciences Lahore, Pakistan.
Muhammad YasirZahoor
Institute of Biochemistry and Biotechnology, University of Veterinary and Animal Sciences Lahore, Pakistan.
How to Cite
Quratul Ain Nazir, Wasim Shehzad, Muhammad Asad Ali, & Muhammad YasirZahoor. (2024). MUTATION SPECTRUM ANALYSIS OF ITGA3 GENE ASSOCIATED WITH NEPHROTIC SYNDROME. Journal of Population Therapeutics and Clinical Pharmacology, 31(5), 2024-2046. https://doi.org/10.53555/jptcp.v31i5.7127