Background: Phosphorus is one of the major macronutrient essential for normal growth and development of living organisms. Alkaline phosphatase (ALP) is an enzyme present in human and animals responsible for solubilization and mineralization of organic phosphate and makes it readily available for the body. The disease Hypophosphatasia (HPP) is an autosomal recessive inherited one, branded by malfunctioning mineralization of bone, dental problems, and low serum ALP levels. This study aimed to scrutinize the effect of non-synonymous SNPs (nsSNPs) of ALPL gene on protein function and structure using different computational software. Material and Methods: Different Non-Synonymous Single Nucleotide Polymorphisms (nsSNPs) and protein related sequences were attained from NCBI and ExPASY databases. Deleterious and damaging effect of nsSNPs were analyzed using SIFT, Polyphen-2, Provean and SNPs&GO software. Protein stability was inspected using I-Mutant and MUpro software. The interaction of ALPL with other genes was studied using GeneMANIA software. The structural and functional influence of point mutations was predicted using Project Hope software. Results: ALPL gene was found to have an association with 20 other genes such as TRAF3 and TPP1 using GeneMANIA. It comprises a total of 485 SNPs out of that 188 were found to be synonymous, 298 were nsSNPs. Analysis of the nsSNPs by SIFT predicts 33 as deleterious and 265 as tolerated ones. Using Provean software, 26 were deleterious while 7 nsSNPs were neutral. Taking the deleterious nsSNPSs to Polyphen-2, 24 nsSNPs were damaging, while 2 were benign. Using SNPs&GO 13 nsSNPs were predicted as disease-related while 11 were predicted to be neutral. By using PHD SNPs 11 nsSNPs were predicted as disease-related while 13 were predicted to be neutral. Project Hope analyzes the mutations according to their size, charge, hydrophobicity, and conservancy. Conclusion: This study reveals 11 nsSNPs as being possibly pathogenic variants. Seven of them were already reported from previous studies by DNA sequencing, while the remaining four were predicted in this study for the first time.
| Published in | International Journal of Genetics and Genomics (Volume 10, Issue 4) |
| DOI | 10.11648/j.ijgg.20221004.12 |
| Page(s) | 94-102 |
| Creative Commons |
This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited. |
| Copyright |
Copyright © The Author(s), 2024. Published by Science Publishing Group |
ALPL Gene, Computational Analysis, GeneMANIA, Hypophosphatasia, Non Synonymous SNP, SIFT, Polyphen-2
| [1] | Whyte, M. P., 2018. Hypophosphatasia and how alkaline phosphatase promotes mineralization. In Genetics of bone biology and skeletal disease (pp. 481-505). Academic Press. |
| [2] | Mornet, E., 2018. Hypophosphatasia. Metabolism, 82, pp. 142-155. |
| [3] | Mornet, E., 2015. Molecular genetics of hypophosphatasia and phenotype-genotype correlations. Neuronal Tissue-Nonspecific Alkaline Phosphatase (TNAP), pp. 25-43. |
| [4] | Michigami, T., Tachikawa, K., Yamazaki, M., Kawai, M., Kubota, T. and Ozono, K., 2020. Hypophosphatasia in Japan: ALPL mutation analysis in 98 unrelated patients. Calcified Tissue International, 106 (3), pp. 221-231. |
| [5] | Millán, J. L. and Whyte, M. P., 2016. Alkaline phosphatase and hypophosphatasia. Calcified tissue international, 98 (4), pp. 398-416. |
| [6] | Simao, A. M. S., Bolean, M., Hoylaerts, M. F., Millán, J. L. and Ciancaglini, P., 2013. Effects of pH on the production of phosphate and pyrophosphate by matrix vesicles’ biomimetics. Calcified tissue international, 93 (3), pp. 222-232. |
| [7] | Narisawa, S., Yadav, M. C. and Millán, J. L., 2013. In vivo overexpression of tissue-nonspecific alkaline phosphatase increases skeletal mineralization and affects the phosphorylation status of osteopontin. Journal of bone and mineral research, 28 (7), pp. 1587-1598. |
| [8] | Whyte, M. P., 2010. Physiological role of alkaline phosphatase explored in hypophosphatasia. Annals of the New York Academy of Sciences, 1192 (1), pp. 190-200. |
| [9] | Rockman-Greenberg C. Hypophosphatasia. Pediatric endocrinology reviews: PER. 2013 Jun 1; 10: 380-8. |
| [10] | Harris, H., 1990. The human alkaline phosphatases: what we know and what we don't know. Clinica chimica acta, 186 (2), pp. 133-150. |
| [11] | Nguyen, H. H., van de Laarschot, D. M., Verkerk, A. J., Milat, F., Zillikens, M. C. and Ebeling, P. R., 2018. Genetic risk factors for atypical femoral fractures (AFFs): a systematic review. JBMR plus, 2 (1), pp. 1-11. |
| [12] | Nielson, C. M., Zmuda, J. M., Carlos, A. S., Wagoner, W. J., Larson, E. A., Orwoll, E. S. and Klein, R. F., 2012. Rare coding variants in ALPL are associated with low serum alkaline phosphatase and low bone mineral density. Journal of bone and mineral research, 27 (1), pp. 93-103. |
| [13] | Matsuura, S., Kishi, F. and Kajii, T., 1990. Characterization of a 5′-flanking region of the human liver/bone/kidney alkaline phosphatase gene: two kinds of mRNA from a single gene. Biochemical and Biophysical Research Communications, 168 (3), pp. 993-1000. |
| [14] | Weiss, M. J., Ray, K., Henthorn, P. S., Lamb, B., Kadesch, T. and Harris, H., 1988. Structure of the human liver/bone/kidney alkaline phosphatase gene. Journal of Biological Chemistry, 263 (24), pp. 12002-12010. |
| [15] | Mornet, E. (Ed.), The Tissue Nonspecific Alkaline Phosphatase Gene Mutations database, University of Versailles-Saint Quentin, 2020, [updated March 31, 2020]. Available from http://www.sesep.uvsq.fr/03_hypo_mutations.php. |
| [16] | Whyte, M. P., 2016. Hypophosphatasia—aetiology, nosology, pathogenesis, diagnosis and treatment. Nature Reviews Endocrinology, 12 (4), pp. 233-246. |
| [17] | Franz, M., Rodriguez, H., Lopes, C., Zuberi, K., Montojo, J., Bader, G. D. and Morris, Q., 2018. GeneMANIA update 2018. Nucleic acids research, 46 (W1), pp. W60-W64. |
| [18] | Kumar, P., Henikoff, S. and Ng, P. C., 2009. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nature protocols, 4 (7), pp. 1073-1081. |
| [19] | Amberger, J., Bocchini, C. A., Scott, A. F. and Hamosh, A., 2009. McKusick's online Mendelian inheritance in man (OMIM®). Nucleic acids research, 37 (suppl_1), pp. D793-D796. |
| [20] | Choi, Y., Sims, G. E., Murphy, S., Miller, J. R. and Chan, A. P., 2012. Predicting the functional effect of amino acid substitutions and indels. PLoS ONE 7 (10): e46688. |
| [21] | Choi, Y., 2012, October. A fast computation of pairwise sequence alignment scores between a protein and a set of single-locus variants of another protein. In Proceedings of the ACM conference on bioinformatics, computational biology and biomedicine (pp. 414-417). |
| [22] | Ramensky, V., Bork, P. and Sunyaev, S., 2002. Human non-synonymous SNPs: server and survey. Nucleic acids research, 30 (17), pp. 3894-3900. |
| [23] | Adzhubei, I., Jordan, D. M. and Sunyaev, S. R., 2013. Predicting functional effect of human missense mutations using PolyPhen-2. Current protocols in human genetics, 76 (1), pp. 7-20. |
| [24] | Calabrese, R., Capriotti, E., Fariselli, P., Martelli, P. L. and Casadio, R., 2009. Functional annotations improve the predictive score of human disease-related mutations in proteins. Human mutation, 30 (8), pp. 1237-1244. |
| [25] | Capriotti, E., Calabrese, R. and 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), pp. 2729-2734. |
| [26] | Altschul, S. F., Madden, T. L., Schäffer, A. A., Zhang, J., Zhang, Z., Miller, W. and Lipman, D. J., 1997. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic acids research, 25 (17), pp. 3389-3402. |
| [27] | Suzek, B. E., Huang, H., McGarvey, P., Mazumder, R. and Wu, C. H., 2007. UniRef: comprehensive and non-redundant UniProt reference clusters. Bioinformatics, 23 (10), pp. 1282-1288. |
| [28] | Capriotti, E., Calabrese, R., Fariselli, P., Martelli, P. L., Altman, R. B. and Casadio, R., 2013. WS-SNPs&GO: a web server for predicting the deleterious effect of human protein variants using functional annotation. BMC genomics, 14 (3), pp. 1-7. |
| [29] | Cheng, J., Randall, A. and Baldi, P., 2006. Prediction of protein stability changes for single-site mutations using support vector machines. Proteins: Structure, Function, and Bioinformatics, 62 (4), pp. 1125-1132. |
| [30] | Venselaar H, Te Beek TA, Kuipers RK, Hekkelman ML, Vriend G. 2010. Protein structure analysis of mutations causing inheritable diseases: an e-Science approach with life scientist friendly interfaces. BMC Bioinformatics, 11, pp. 548-558. |
| [31] | Schmidt, T., Mussawy, H., Rolvien, T., Hawellek, T., Hubert, J., Rüther, W., Amling, M. and Barvencik, F., 2017. Clinical, radiographic and biochemical characteristics of adult hypophosphatasia. Osteoporosis international, 28 (9), pp. 2653-2662. |
| [32] | Hofmann, C., Girschick, H., Mornet, E., Schneider, D., Jakob, F. and Mentrup, B., 2014. Unexpected high intrafamilial phenotypic variability observed in hypophosphatasia. European Journal of Human Genetics, 22 (10), pp. 1160-1164. |
| [33] | Högler, W., Langman, C., Gomes da Silva, H., Fang, S., Linglart, A., Ozono, K., Petryk, A., Rockman-Greenberg, C., Seefried, L. and Kishnani, P. S., 2019. Diagnostic delay is common among patients with hypophosphatasia: initial findings from a longitudinal, prospective, global registry. BMC Musculoskeletal Disorders, 20 (1), pp. 1-9. |
| [34] | Horiike T. Invited Mini-Review an Introduction To Molecular. Rev. Agric. Sci. 2016; 4: 36–45. |
| [35] | Mishra, S. K. and Jernigan, R. L., 2018. Protein dynamic communities from elastic network models align closely to the communities defined by molecular dynamics. PLoS One, 13 (6), p. e0199225. |
| [36] | Nielsen, S. V., Stein, A., Dinitzen, A. B., Papaleo, E., Tatham, M. H., Poulsen, E. G., Kassem, M. M., Rasmussen, L. J., Lindorff-Larsen, K. and Hartmann-Petersen, R., 2017. Predicting the impact of Lynch syndrome-causing missense mutations from structural calculations. PLoS Genetics, 13 (4), p. e1006739. |
| [37] | Zurutuza, L., Muller, F., Gibrat, J. F., Taillandier, A., Simon-Bouy, B., Serre, L. and Mornet, E., 1999. Correlations of genotype and phenotype in hypophosphatasia. Human Molecular Genetics, 8 (6), pp. 1039-1046. |
| [38] | Fauvert, D., Brun-Heath, I., Lia-Baldini, A. S., Bellazi, L., Taillandier, A., Serre, J. L., De Mazancourt, P. and Mornet, E., 2009. Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles. BMC medical genetics, 10 (1), pp. 1-8. |
| [39] | Silvent, J., Gasse, B., Mornet, E. and Sire, J. Y., 2014. Molecular evolution of the tissue-nonspecific alkaline phosphatase allows prediction and validation of missense mutations responsible for hypophosphatasia. Journal of Biological Chemistry, 289 (35), pp. 24168-24179. |
| [40] | Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W. W., Hegde, M., Lyon, E., Spector, E. and Voelkerding, K., 2015. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in medicine, 17 (5), pp. 405-423. |
| [41] | Kato, M., Michigami, T., Tachikawa, K., Kato, M., Yabe, I., Shimizu, T., Asaka, T., Kitagawa, Y. and Atsumi, T., 2021. Novel mutation in the ALPL gene with a dominant negative effect in a Japanese family. Journal of Bone and Mineral Metabolism, 39 (5), pp. 804-809. |
| [42] | Martins, L., de Almeida, A. B., Dos Santos, E. J. L., Foster, B. L., Machado, R. A., Kantovitz, K. R., Coletta, R. D. and Nociti Jr, F. H., 2019. A novel combination of biallelic ALPL mutations associated with adult hypophosphatasia: A phenotype-genotype association and computational analysis study. Bone, 125, pp. 128-139. |
APA Style
Nabaa Kamal Alshafei, Intisar Hassan Saeed, Mona Abdelrahman Mohamed Khaier. (2022). The Effect of Non-synonymous Single Nucleotide Polymorphisms Variants in ALPL Gene, a Computational Approach. International Journal of Genetics and Genomics, 10(4), 94-102. https://doi.org/10.11648/j.ijgg.20221004.12
ACS Style
Nabaa Kamal Alshafei; Intisar Hassan Saeed; Mona Abdelrahman Mohamed Khaier. The Effect of Non-synonymous Single Nucleotide Polymorphisms Variants in ALPL Gene, a Computational Approach. Int. J. Genet. Genomics 2022, 10(4), 94-102. doi: 10.11648/j.ijgg.20221004.12
Share This Article
Twitter
Linked In
Facebook
Copy
Download@article{10.11648/j.ijgg.20221004.12,
author = {Nabaa Kamal Alshafei and Intisar Hassan Saeed and Mona Abdelrahman Mohamed Khaier},
title = {The Effect of Non-synonymous Single Nucleotide Polymorphisms Variants in ALPL Gene, a Computational Approach},
journal = {International Journal of Genetics and Genomics},
volume = {10},
number = {4},
pages = {94-102},
doi = {10.11648/j.ijgg.20221004.12},
url = {https://doi.org/10.11648/j.ijgg.20221004.12},
eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ijgg.20221004.12},
abstract = {Background: Phosphorus is one of the major macronutrient essential for normal growth and development of living organisms. Alkaline phosphatase (ALP) is an enzyme present in human and animals responsible for solubilization and mineralization of organic phosphate and makes it readily available for the body. The disease Hypophosphatasia (HPP) is an autosomal recessive inherited one, branded by malfunctioning mineralization of bone, dental problems, and low serum ALP levels. This study aimed to scrutinize the effect of non-synonymous SNPs (nsSNPs) of ALPL gene on protein function and structure using different computational software. Material and Methods: Different Non-Synonymous Single Nucleotide Polymorphisms (nsSNPs) and protein related sequences were attained from NCBI and ExPASY databases. Deleterious and damaging effect of nsSNPs were analyzed using SIFT, Polyphen-2, Provean and SNPs&GO software. Protein stability was inspected using I-Mutant and MUpro software. The interaction of ALPL with other genes was studied using GeneMANIA software. The structural and functional influence of point mutations was predicted using Project Hope software. Results: ALPL gene was found to have an association with 20 other genes such as TRAF3 and TPP1 using GeneMANIA. It comprises a total of 485 SNPs out of that 188 were found to be synonymous, 298 were nsSNPs. Analysis of the nsSNPs by SIFT predicts 33 as deleterious and 265 as tolerated ones. Using Provean software, 26 were deleterious while 7 nsSNPs were neutral. Taking the deleterious nsSNPSs to Polyphen-2, 24 nsSNPs were damaging, while 2 were benign. Using SNPs&GO 13 nsSNPs were predicted as disease-related while 11 were predicted to be neutral. By using PHD SNPs 11 nsSNPs were predicted as disease-related while 13 were predicted to be neutral. Project Hope analyzes the mutations according to their size, charge, hydrophobicity, and conservancy. Conclusion: This study reveals 11 nsSNPs as being possibly pathogenic variants. Seven of them were already reported from previous studies by DNA sequencing, while the remaining four were predicted in this study for the first time.},
year = {2022}
}
TY - JOUR T1 - The Effect of Non-synonymous Single Nucleotide Polymorphisms Variants in ALPL Gene, a Computational Approach AU - Nabaa Kamal Alshafei AU - Intisar Hassan Saeed AU - Mona Abdelrahman Mohamed Khaier Y1 - 2022/12/29 PY - 2022 N1 - https://doi.org/10.11648/j.ijgg.20221004.12 DO - 10.11648/j.ijgg.20221004.12 T2 - International Journal of Genetics and Genomics JF - International Journal of Genetics and Genomics JO - International Journal of Genetics and Genomics SP - 94 EP - 102 PB - Science Publishing Group SN - 2376-7359 UR - https://doi.org/10.11648/j.ijgg.20221004.12 AB - Background: Phosphorus is one of the major macronutrient essential for normal growth and development of living organisms. Alkaline phosphatase (ALP) is an enzyme present in human and animals responsible for solubilization and mineralization of organic phosphate and makes it readily available for the body. The disease Hypophosphatasia (HPP) is an autosomal recessive inherited one, branded by malfunctioning mineralization of bone, dental problems, and low serum ALP levels. This study aimed to scrutinize the effect of non-synonymous SNPs (nsSNPs) of ALPL gene on protein function and structure using different computational software. Material and Methods: Different Non-Synonymous Single Nucleotide Polymorphisms (nsSNPs) and protein related sequences were attained from NCBI and ExPASY databases. Deleterious and damaging effect of nsSNPs were analyzed using SIFT, Polyphen-2, Provean and SNPs&GO software. Protein stability was inspected using I-Mutant and MUpro software. The interaction of ALPL with other genes was studied using GeneMANIA software. The structural and functional influence of point mutations was predicted using Project Hope software. Results: ALPL gene was found to have an association with 20 other genes such as TRAF3 and TPP1 using GeneMANIA. It comprises a total of 485 SNPs out of that 188 were found to be synonymous, 298 were nsSNPs. Analysis of the nsSNPs by SIFT predicts 33 as deleterious and 265 as tolerated ones. Using Provean software, 26 were deleterious while 7 nsSNPs were neutral. Taking the deleterious nsSNPSs to Polyphen-2, 24 nsSNPs were damaging, while 2 were benign. Using SNPs&GO 13 nsSNPs were predicted as disease-related while 11 were predicted to be neutral. By using PHD SNPs 11 nsSNPs were predicted as disease-related while 13 were predicted to be neutral. Project Hope analyzes the mutations according to their size, charge, hydrophobicity, and conservancy. Conclusion: This study reveals 11 nsSNPs as being possibly pathogenic variants. Seven of them were already reported from previous studies by DNA sequencing, while the remaining four were predicted in this study for the first time. VL - 10 IS - 4 ER -
Email: