Identification of Novel Key Biomarkers in Simpson-Golabi-Behmel Syndrome (SGBS)
Evidence from Bioinformatics Analysis
The Simpson-Golabi-Behmel Syndrome (SGBS) or overgrowth Syndrome is an uncommon genetic X-linked disorder highlighted by macrosomia, renal defects, cardiac weaknesses and skeletal abnormalities. The purpose of the work was to classify the functional nsSNPs of GPC3 to serve as genetic biomarkers for overgrowth syndrome. The raw data of GPC3 gene were retrieved from dbSNP database and used to examine the most damaging effect using eight functional analysis tools, while we used I-mutant and MUPro to examine the effect of SNPs on GPC3 protein structure; The 3D structure of GPC3 protein is not found in the PDB, so RaptorX was used to create a 3D structural prototype to visualize the amino acids alterations by UCSF Chimera; For biophysical validation we used project HOPE; Lastly we run conservational analysis by BioEdit and Consurf web server respectively. Our results revealed three novel missense mutations (rs1460413167, rs1295603457 and rs757475450) that are that are more likely to be responsible for disturbance in the function and structure of GPC3. This work provides new insight into the molecular basis of overgrowth Syndrome by evidence from bioinformatics analysis. Three novel missense mutations (rs757475450, rs1295603457 and rs1460413167) are more likely to be responsible for disturbance in the function and structure of GPC3; therefore, they may be assisting as genetic biomarkers for overgrowth syndrome. As well as these SNPs can be used for the larger population-based studies of overgrowth syndrome.
 E. Cottereau, I. Mortemousque, M. P. Moizard, L. Burglen, D. Lacombe, B. Gilbert-Dussardier, et al., "Phenotypic spectrum of Simpson-Golabi-Behmel syndrome in a series of 42 cases with a mutation in GPC3 and review of the literature," Am J Med Genet C Semin Med Genet, vol. 163c, pp. 92-105, May 2013.
 A. Behmel, E. Plochl, and W. Rosenkranz, "A new X-linked dysplasia gigantism syndrome: identical with the Simpson dysplasia syndrome?," Hum Genet, vol. 67, pp. 409-13, 1984.
 M. Golabi and L. Rosen, "A new X-linked mental retardation-overgrowth syndrome," Am J Med Genet, vol. 17, pp. 345-58, Jan 1984.
 M. R. DeBaun, J. Ess, and S. Saunders, "Simpson Golabi Behmel syndrome: progress toward understanding the molecular basis for overgrowth, malformation, and cancer predisposition," Mol Genet Metab, vol. 72, pp. 279-86, Apr 2001.
 F. Gurrieri, M. G. Pomponi, R. Pietrobono, E. Lucci-Cordisco, E. Silvestri, G. Storniello, et al., "The Simpson-Golabi-Behmel syndrome: A clinical case and a detective story," Am J Med Genet A, vol. 155a, pp. 145-8, Jan 2011.
 J. L. Simpson, S. Landey, M. New, and J. German, "A previously unrecognized X-linked syndrome of dysmorphia," Birth Defects Orig Artic Ser, vol. 11, pp. 18-24, 1975.
 M. L. Vuillaume, M. P. Moizard, S. Rossignol, E. Cottereau, S. Vonwill, J. L. Alessandri, et al., "Mutation update for the GPC3 gene involved in Simpson-Golabi-Behmel syndrome and review of the literature," Hum Mutat, vol. 39, pp. 2110-2112, Dec 2018.
 G. Neri and M. Moscarda, "Overgrowth syndromes: a classification," Endocr Dev, vol. 14, pp. 53-60, 2009.
 J. Tenorio, P. Arias, V. Martinez-Glez, F. Santos, S. Garcia-Minaur, J. Nevado, et al., "Simpson-Golabi-Behmel syndrome types I and II," Orphanet J Rare Dis, vol. 9, p. 138, Sep 20 2014.
 L. M. Brzustowicz, S. Farrell, M. B. Khan, and R. Weksberg, "Mapping of a new SGBS locus to chromosome Xp22 in a family with a severe form of Simpson-Golabi-Behmel syndrome," Am J Hum Genet, vol. 65, pp. 779-83, Sep 1999.
 D. Terespolsky, S. A. Farrell, J. Siegel-Bartelt, and R. Weksberg, "Infantile lethal variant of Simpson-Golabi-Behmel syndrome associated with hydrops fetalis," Am J Med Genet, vol. 59, pp. 329-33, Nov 20 1995.
 R. M. Hughes-Benzie, A. G. Hunter, J. E. Allanson, and A. E. Mackenzie, "Simpson-Golabi-Behmel syndrome associated with renal dysplasia and embryonal tumor: localization of the gene to Xqcen-q21," Am J Med Genet, vol. 43, pp. 428-35, Apr 15-May 1 1992.
 C. L. Garganta and J. N. Bodurtha, "Report of another family with Simpson-Golabi-Behmel syndrome and a review of the literature," Am J Med Genet, vol. 44, pp. 129-35, Sep 15 1992.
 C. B. Griffith, R. C. Probert, and G. H. Vance, "Genital anomalies in three male siblings with Simpson-Golabi-Behmel syndrome," Am J Med Genet A, vol. 149a, pp. 2484-8, Nov 2009.
 A. Vaisfeld, M. G. Pomponi, R. Pietrobono, E. Tabolacci, and G. Neri, "Simpson-Golabi-Behmel syndrome in a female: A case report and an unsolved issue," Am J Med Genet A, vol. 173, pp. 285-288, Jan 2017.
 S. Halayem, M. Hamza, F. Maazoul, H. Ben Turkia, M. Touati, N. Tebib, et al., "Distinctive findings in a boy with Simpson-Golabi-Behmel syndrome," Am J Med Genet A, vol. 170a, pp. 1035-9, Apr 2016.
 M. Li, C. Shuman, Y. L. Fei, E. Cutiongco, H. A. Bender, C. Stevens, et al., "GPC3 mutation analysis in a spectrum of patients with overgrowth expands the phenotype of Simpson-Golabi-Behmel syndrome," Am J Med Genet, vol. 102, pp. 161-8, Aug 1 2001.
 S. Mariani, L. Iughetti, R. Bertorelli, D. Coviello, M. Pellegrini, A. Forabosco, et al., "Genotype/phenotype correlations of males affected by Simpson-Golabi-Behmel syndrome with GPC3 gene mutations: patient report and review of the literature," J Pediatr Endocrinol Metab, vol. 16, pp. 225-32, Feb 2003.
 M. Veugelers, B. D. Cat, S. Y. Muyldermans, G. Reekmans, N. Delande, S. Frints, et al., "Mutational analysis of the GPC3/GPC4 glypican gene cluster on Xq26 in patients with Simpson-Golabi-Behmel syndrome: identification of loss-of-function mutations in the GPC3 gene," Hum Mol Genet, vol. 9, pp. 1321-8, May 22 2000.
 G. Pilia, R. M. Hughes-Benzie, A. MacKenzie, P. Baybayan, E. Y. Chen, R. Huber, et al., "Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome," Nat Genet, vol. 12, pp. 241-7, Mar 1996.
 K. Ridnoi, E. Kurvinen, S. Pajusalu, T. Reimand, and K. Ounap, "Two Consecutive Pregnancies with Simpson-Golabi-Behmel Syndrome Type 1: Case Report and Review of Published Prenatal Cases," Mol Syndromol, vol. 9, pp. 205-213, Jul 2018.
 H. K. Stove, N. Becher, V. Gjorup, M. Ramsing, I. Vogel, and E. M. Vestergaard, "First reported case of Simpson-Golabi-Behmel syndrome in a female fetus diagnosed prenatally with chromosomal microarray," Clin Case Rep, vol. 5, pp. 608-612, May 2017.
 G. Jedraszak, M. Girard, A. Mellos, D. D. Djeddi, C. Chardot, A. Vanrenterghem, et al., "A patient with Simpson-Golabi-Behmel syndrome, biliary cirrhosis and successful liver transplantation," Am J Med Genet A, vol. 164a, pp. 774-7, Mar 2014.
 R. Kosaki, T. Takenouchi, N. Takeda, M. Kagami, K. Nakabayashi, K. Hata, et al., "Somatic CTNNB1 mutation in hepatoblastoma from a patient with Simpson-Golabi-Behmel syndrome and germline GPC3 mutation," Am J Med Genet A, vol. 164a, pp. 993-7, Apr 2014.
 R. Huber, L. Crisponi, R. Mazzarella, C. N. Chen, Y. Su, H. Shizuya, et al., "Analysis of exon/intron structure and 400 kb of genomic sequence surrounding the 5'-promoter and 3'-terminal ends of the human glypican 3 (GPC3) gene," Genomics, vol. 45, pp. 48-58, Oct 1 1997.
 J. Schmidt, R. Hollstein, F. J. Kaiser, and G. Gillessen-Kaesbach, "Molecular analysis of a novel intragenic deletion in GPC3 in three cousins with Simpson-Golabi-Behmel syndrome," Am J Med Genet A, vol. 173, pp. 1400-1405, May 2017.
 D. D. Villarreal, H. Villarreal, A. M. Paez, D. Peppas, J. Lynch, E. Roeder, et al., "A patient with a unique frameshift mutation in GPC3, causing Simpson-Golabi-Behmel syndrome, presenting with craniosynostosis, penoscrotal hypospadias, and a large prostatic utricle," Am J Med Genet A, vol. 161a, pp. 3121-5, Dec 2013.
 S. Yano, B. Baskin, A. Bagheri, Y. Watanabe, K. Moseley, A. Nishimura, et al., "Familial Simpson-Golabi-Behmel syndrome: studies of X-chromosome inactivation and clinical phenotypes in two female individuals with GPC3 mutations," Clin Genet, vol. 80, pp. 466-71, Nov 2011.
 E. Chiao, P. Fisher, L. Crisponi, M. Deiana, I. Dragatsis, D. Schlessinger, et al., "Overgrowth of a mouse model of the Simpson-Golabi-Behmel syndrome is independent of IGF signaling," Dev Biol, vol. 243, pp. 185-206, Mar 1 2002.
 P. Lapunzina, I. Badia, C. Galoppo, E. De Matteo, P. Silberman, A. Tello, et al., "A patient with Simpson-Golabi-Behmel syndrome and hepatocellular carcinoma," J Med Genet, vol. 35, pp. 153-6, Feb 1998.
 R. Savarirayan and A. Bankier, "Simpson-Golabi-Behmel syndrome and attention deficit hyperactivity disorder in two brothers," J Med Genet, vol. 36, pp. 574-6, Jul 1999.
 W. X. Bai, J. Gao, C. Qian, and X. Q. Zhang, "[A bioinformatics analysis of differentially expressed genes associated with liver cancer]," Zhonghua Gan Zang Bing Za Zhi, vol. 25, pp. 435-439, Jun 20 2017.
 F. Cartier, E. Indersie, S. Lesjean, J. Charpentier, K. B. Hooks, A. Ghousein, et al., "New tumor suppressor microRNAs target glypican-3 in human liver cancer," Oncotarget, vol. 8, pp. 41211-41226, Jun 20 2017.
 Y. Wu, H. Liu, and H. Ding, "GPC-3 in hepatocellular carcinoma: current perspectives," J Hepatocell Carcinoma, vol. 3, pp. 63-67, 2016.
 J. Filmus, "Glypicans in growth control and cancer," Glycobiology, vol. 11, pp. 19r-23r, Mar 2001.
 H. Lin, R. Huber, D. Schlessinger, and P. J. Morin, "Frequent silencing of the GPC3 gene in ovarian cancer cell lines," Cancer Res, vol. 59, pp. 807-10, Feb 15 1999.
 G. Shaw, "Polymorphism and single nucleotide polymorphisms (SNPs)," BJU Int, vol. 112, pp. 664-5, Sep 2013.
 Y. Chen, F. Cunningham, D. Rios, W. M. McLaren, J. Smith, B. Pritchard, et al., "Ensembl variation resources," BMC Genomics, vol. 11, p. 293, May 11 2010.
 C. George Priya Doss, C. Sudandiradoss, R. Rajasekaran, P. Choudhury, P. Sinha, P. Hota, et al., "Applications of computational algorithm tools to identify functional SNPs," Funct Integr Genomics, vol. 8, pp. 309-16, Nov 2008.
 J. D. Tenenbaum, "Translational Bioinformatics: Past, Present, and Future," Genomics Proteomics Bioinformatics, vol. 14, pp. 31-41, Feb 2016.
 J. Vamathevan and E. Birney, "A Review of Recent Advances in Translational Bioinformatics: Bridges from Biology to Medicine," Yearb Med Inform, vol. 26, pp. 178-187, Aug 2017.
 P. Katara, "Single nucleotide polymorphism and its dynamics for pharmacogenomics," Interdiscip Sci, vol. 6, pp. 85-92, Jun 2014.
 J. Wang, G. S. Pang, S. S. Chong, and C. G. Lee, "SNP web resources and their potential applications in personalized medicine," Curr Drug Metab, vol. 13, pp. 978-90, Sep 1 2012.
 D. Gefel, I. Maslovsky, and J. Hillel, "[Application of single nucleotide polymorphisms (SNPs) for the detection of genes involved in the control of complex diseases]," Harefuah, vol. 147, pp. 449-54, 476, May 2008.
 D. A. Benson, M. Cavanaugh, K. Clark, I. Karsch-Mizrachi, D. J. Lipman, J. Ostell, et al., "GenBank," Nucleic Acids Res, vol. 45, pp. D37-d42, Jan 4 2017.
 "NCBI website."
 "UniProt: the universal protein knowledgebase," Nucleic Acids Res, vol. 45, pp. D158-d169, Jan 4 2017.
 N. L. Sim, P. Kumar, J. Hu, S. Henikoff, G. Schneider, and P. C. Ng, "SIFT web server: predicting effects of amino acid substitutions on proteins," Nucleic Acids Res, vol. 40, pp. W452-7, Jul 2012.
 SIFT server. Available: https://sift.bii.a-star.edu.sg/
 E. Capriotti and R. B. Altman, "Improving the prediction of disease-related variants using protein three-dimensional structure," BMC Bioinformatics, vol. 12 Suppl 4, p. S3, 2011.
 PolyPhen-2 server. Available: http://genetics.bwh.harvard.edu/pph2/
 Y. Choi, G. E. Sims, S. Murphy, J. R. Miller, and A. P. Chan, "Predicting the functional effect of amino acid substitutions and indels," PLoS One, vol. 7, p. e46688, 2012.
 M. Hecht, Y. Bromberg, and B. Rost, "Better prediction of functional effects for sequence variants," BMC Genomics, vol. 16 Suppl 8, p. S1, 2015.
 SNAP2 server. Available: https://rostlab.org/services/snap2web/
 R. Calabrese, E. Capriotti, P. Fariselli, P. L. Martelli, and R. Casadio, "Functional annotations improve the predictive score of human disease-related mutations in proteins," Hum Mutat, vol. 30, pp. 1237-44, Aug 2009.
 SNPs&Go server. Available: http://snps.biofold.org/snps-and-go/snps-and-go.html
 V. Lopez-Ferrando, A. Gazzo, X. de la Cruz, M. Orozco, and J. L. Gelpi, "PMut: a web-based tool for the annotation of pathological variants on proteins, 2017 update," Nucleic Acids Res, vol. 45, pp. W222-w228, Jul 3 2017.
 P-Mut server. Available: http://mmb.irbbarcelona.org/PMut
 E. Capriotti, P. Fariselli, and R. Casadio, "I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure," Nucleic Acids Res, vol. 33, pp. W306-10, Jul 1 2005.
 I-Mutant server. Available: http://gpcr2.biocomp.unibo.it/cgi/predictors/I-Mutant3.0/I-Mutant3.0.cgi
 J. Cheng, A. Randall, and P. Baldi, "Prediction of protein stability changes for single-site mutations using support vector machines," Proteins, vol. 62, pp. 1125-32, Mar 1 2006.
 MUPro server. Available: http://mupro.proteomics.ics.uci.edu/
 project HOPE server. Available: http://www.cmbi.ru.nl/hope
 RaptorX server. Available: (http://raptorx.uchicago.edu/
 S. Wang, W. Li, S. Liu, and J. Xu, "RaptorX-Property: a web server for protein structure property prediction," Nucleic Acids Res, vol. 44, pp. W430-5, Jul 8 2016.
 E. F. Pettersen, T. D. Goddard, C. C. Huang, G. S. Couch, D. M. Greenblatt, E. C. Meng, et al., "UCSF Chimera--a visualization system for exploratory research and analysis," J Comput Chem, vol. 25, pp. 1605-12, Oct 2004.
 UCSF Chimera. Available: http://www.cgl.ucsf.edu/chimera/
 BioEdit. Available: http://www.mbio.ncsu.edu/bioedit/bioedit.html
 H. Ashkenazy, S. Abadi, E. Martz, O. Chay, I. Mayrose, T. Pupko, et al., "ConSurf 2016: an improved methodology to estimate and visualize evolutionary conservation in macromolecules," Nucleic Acids Res, vol. 44, pp. W344-50, Jul 8 2016.
 ConSurf server. Available: http://consurf.tau.ac.il/).
 B. Sun, Z. Huang, B. Wang, Y. Yu, S. Lin, L. Luo, et al., "Significance of Glypican-3 (GPC3) Expression in Hepatocellular Cancer Diagnosis," Med Sci Monit, vol. 23, pp. 850-855, Feb 16 2017.
 C. Chen, X. Huang, Z. Ying, D. Wu, Y. Yu, X. Wang, et al., "Can glypican-3 be a disease-specific biomarker?," Clin Transl Med, vol. 6, p. 18, Dec 2017.
 P. Mochalski, E. Diem, K. Unterkofler, A. Mundlein, H. Drexel, C. A. Mayhew, et al., "In vitro profiling of volatile organic compounds released by Simpson-Golabi-Behmel syndrome adipocytes," J Chromatogr B Analyt Technol Biomed Life Sci, vol. 1104, pp. 256-261, Jan 1 2019.
 A. X. Zhu, P. J. Gold, A. B. El-Khoueiry, T. A. Abrams, H. Morikawa, N. Ohishi, et al., "First-in-man phase I study of GC33, a novel recombinant humanized antibody against glypican-3, in patients with advanced hepatocellular carcinoma," Clin Cancer Res, vol. 19, pp. 920-8, Feb 15 2013.
 A. Das Bhowmik and A. Dalal, "Whole exome sequencing identifies a novel frameshift mutation in GPC3 gene in a patient with overgrowth syndrome," Gene, vol. 572, pp. 303-6, Nov 10 2015.
 C. Kehrer, A. Hoischen, R. Menkhaus, E. Schwab, A. Muller, S. Kim, et al., "Whole exome sequencing and array-based molecular karyotyping as aids to prenatal diagnosis in fetuses with suspected Simpson-Golabi-Behmel syndrome," Prenat Diagn, vol. 36, pp. 961-965, Oct 2016.
 Z. B. Alwi, "The Use of SNPs in Pharmacogenomics Studies," Malays J Med Sci, vol. 12, pp. 4-12, Jul 2005.
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