Document Type : Original Research

Authors

1 MD, PhD, Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

2 MD, PhD, legal medicine research center, legal medicine organization, Tehran , iran

3 MD, Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

4 PhD, Department of Biotechnology, Institute of Science and High Technology and Environmental Science, Graduate University of Advanced Technology, Kerman, Iran

5 MD, Genetic Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

Abstract

Background: Progressive familial intrahepatic cholestases (PFIC) are a spectrum of autosomal progressive liver diseases developing to end-stage liver disease. ATP8B1 deficiency caused by mutations in ATP8B1 gene encoding a P-type ATPase leads to PFIC1. The gene for PFIC1 has been mapped on a 19-cM region of 18q21-q22, and a gene defect in ATP8B1 can cause deregulations in bile salt transporters through decreased expression and/or activity of FXR. Point mutations are the most common, with the majority being missense or nonsense mutations. In addition, approximately 15% of disease-causing ATP8B1 mutations are annotated as splicing disrupting alteration given that they are located at exon-intron borders.
Objective: Here, we describe the hidden layer of computational biology information of rare codons in ATP8B1, which can help us for drug design.
Methods: Some rare codons in different locations of ATP8b1 gene were identified using several web servers and by in-silico modelling of ATP8b1 in Phyre2 and I-TASSER server, some rare codons were evaluated.
Results: Some of these rare codons were located at special positions which seem to have a critical role in proper folding of ATP8b1 protein. Structural analysis showed that some of rare codons are related to mutations in ATP8B1 that are responsible for PFIC1 disease, which may have a critical role in ensuring the correct folding.
Conclusion: Investigation of such hidden information can enhance our understanding of ATP8b1 folding. Moreover, studies of these rare codons help us to clarify their role in rational design of new and effective drugs.

Keywords

  1. Jacquemin E. Progressive familial intrahepatic cholestasis. Clinics and research in hepatology and gastroenterology. 2012;36:S26-S35. doi.org/10.1016/S2210-7401(12)70018-9.
  2. Sira AM, Sira MM. Progressive familial intrahepatic cholestasis: INTECH Open Access Publisher; 2013.
  3. Srivastava A. Progressive familial intrahepatic cholestasis. J Clin Exp Hepatol. 2014;4:25-36. doi.org/10.1016/j.jceh.2013.10.005. PubMed PMID: 25755532. PubMed PMCID: 4017198.
  4. Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E. Progressive familial intrahepatic cholestasis. Orphanet J Rare Dis. 2009;4:1. doi.org/10.1186/1750-1172-4-1. PubMed PMID: 19133130. PubMed PMCID: 2647530.
  5. Engelmann G, Wenning D, Herebian D, Sander O, Droge C, Kluge S, et al. Two Case Reports of Successful Treatment of Cholestasis With Steroids in Patients With PFIC-2. Pediatrics. 2015;135:e1326-32. doi.org/10.1542/peds.2014-2376. PubMed PMID: 25847799.
  6. Groen A, Romero MR, Kunne C, Hoosdally SJ, Dixon PH, Wooding C, et al. Complementary functions of the flippase ATP8B1 and the floppase ABCB4 in maintaining canalicular membrane integrity. Gastroenterology. 2011;141(5):1927-37. e4. https://doi.org/10.1053/j.gastro.2011.07.042.
  7. Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E, editors. The spectrum of liver diseases related to ABCB4 gene mutations: pathophysiology and clinical aspects. Seminars in liver disease; 2010: © Thieme Medical Publishers.
  8. Dröge C, Kluge S, Häussinger D, Kubitz R, Keitel V. Sequencing of ATP8B1, ABCB11 and ABCB4 revealed 135 genetic variants in 374 unrelated patients with suspected intrahepatic cholestasis. Zeitschrift für Gastroenterologie. 2015;53:A3_27.
  9. Park JS, Ko JS, Seo JK, Moon JS, Park SS. Clinical and ABCB11 profiles in Korean infants with progressive familial intrahepatic cholestasis. World J Gastroenterol. 2016;22:4901-7. doi.org/10.3748/wjg.v22.i20.4901. PubMed PMID: 27239116. PubMed PMCID: 4873882.
  10. Carlton VE, Knisely AS, Freimer NB. Mapping of a locus for progressive familial intrahepatic cholestasis (Byler disease) to 18q21-q22, the benign recurrent intrahepatic cholestasis region. Hum Mol Genet. 1995;4:1049-53. doi.org/10.1093/hmg/4.6.1049. PubMed PMID: 7655458.
  11. Fathy M, Kamal M, Al-Sharkawy M, Al-Karaksy H, Hassan N. Molecular characterization of exons 6, 8 and 9 of ABCB4 gene in children with Progressive Familial Intrahepatic Cholestasis type 3. Biomarkers. 2016;21:573-7. doi.org/10.3109/1354750X.2016.1166264. PubMed PMID: 27075526.
  12. Kane JF. Effects of rare codon clusters on high-level expression of heterologous proteins in Escherichia coli. Curr Opin Biotechnol. 1995;6:494-500. doi.org/10.1016/0958-1669(95)80082-4. PubMed PMID: 7579660.
  13. Nakamura Y, Gojobori T, Ikemura T. Codon usage tabulated from international DNA sequence databases: status for the year 2000. Nucleic Acids Res. 2000;28:292. doi.org/10.1093/nar/28.1.292. PubMed PMID: 10592250. PubMed PMCID: 102460.
  14. Chartier M, Gaudreault F, Najmanovich R. Large-scale analysis of conserved rare codon clusters suggests an involvement in co-translational molecular recognition events. Bioinformatics. 2012;28:1438-45. doi.org/10.1093/bioinformatics/bts149. PubMed PMID: 22467916. PubMed PMCID: 3465090.
  15. Thanaraj TA, Argos P. Protein secondary structural types are differentially coded on messenger RNA. Protein Sci. 1996;5:1973-83. doi.org/10.1002/pro.5560051003. PubMed PMID: 8897597. PubMed PMCID: 2143259.
  16. Zhang Y. I-TASSER server for protein 3D structure prediction. BMC Bioinformatics. 2008;9:40. doi.org/10.1186/1471-2105-9-40. PubMed PMID: 18215316. PubMed PMCID: 2245901.
  17. Kaplan W, Littlejohn TG. Swiss-PDB Viewer (Deep View). Brief Bioinform. 2001;2:195-7. doi.org/10.1093/bib/2.2.195. PubMed PMID: 11465736.
  18. Theodosiou A, Promponas VJ. LaTcOm: a web server for visualizing rare codon clusters in coding sequences. Bioinformatics. 2012;28:591-2. doi.org/10.1093/bioinformatics/btr706. PubMed PMID: 22199385.
  19. Dong H, Nilsson L, Kurland CG. Co-variation of tRNA abundance and codon usage in Escherichia coli at different growth rates. J Mol Biol. 1996;260:649-63. doi.org/10.1006/jmbi.1996.0428. PubMed PMID: 8709146.
  20. Wu S, Zhang Y. LOMETS: a local meta-threading-server for protein structure prediction. Nucleic Acids Res. 2007;35:3375-82. doi.org/10.1093/nar/gkm251. PubMed PMID: 17478507. PubMed PMCID: 1904280.
  21. Guex N, Peitsch M. Swiss-PdbViewer: a fast and easy-to-use PDB viewer for Macintosh and PC. Protein Data Bank Quaterly Newsletter. 1996;77(7).
  22. DeLano WL. The PyMOL molecular graphics system. 2002.
  23. Vriend G. WHAT IF: a molecular modeling and drug design program. J Mol Graph. 1990;8:52-6, 29. PubMed PMID: 2268628.
  24. Tina KG, Bhadra R, Srinivasan N. PIC: Protein Interactions Calculator. Nucleic Acids Res. 2007;35:W473-6. doi.org/10.1093/nar/gkm423. PubMed PMID: 17584791. PubMed PMCID: 1933215.
  25. Sonnhammer EL, Eddy SR, Durbin R. Pfam: a comprehensive database of protein domain families based on seed alignments. Proteins. 1997;28:405-20. doi.org/10.1002/(SICI)1097-0134(199707)28:33.0.CO;2-L. PubMed PMID: 9223186.
  26. Widmann M, Clairo M, Dippon J, Pleiss J. Analysis of the distribution of functionally relevant rare codons. BMC Genomics. 2008;9:207. doi.org/10.1186/1471-2164-9-207. PubMed PMID: 18457591. PubMed PMCID: 2391168.
  27. Nicolaou M, Andress EJ, Zolnerciks JK, Dixon PH, Williamson C, Linton KJ. Canalicular ABC transporters and liver disease. J Pathol. 2012;226:300-15. doi.org/10.1002/path.3019. PubMed PMID: 21984474.
  28. Erlinger S, Arias IM, Dhumeaux D. Inherited disorders of bilirubin transport and conjugation: new insights into molecular mechanisms and consequences. Gastroenterology. 2014;146:1625-38. doi.org/10.1053/j.gastro.2014.03.047. PubMed PMID: 24704527.
  29. Bull LN, van Eijk MJ, Pawlikowska L, DeYoung JA, Juijn JA, Liao M, et al. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat Genet. 1998;18:219-24. doi.org/10.1038/ng0398-219. PubMed PMID: 9500542.
  30. van der Woerd WL, van Mil SW, Stapelbroek JM, Klomp LW, van de Graaf SF, Houwen RH. Familial cholestasis: progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy. Best Pract Res Clin Gastroenterol. 2010;24:541-53. doi.org/10.1016/j.bpg.2010.07.010. PubMed PMID: 20955958.
  31. Morris AL, Bukauskas K, Sada RE, Shneider BL. Byler disease: early natural history. J Pediatr Gastroenterol Nutr. 2015;60:460-6. doi.org/10.1097/MPG.0000000000000650. PubMed PMID: 25825852.
  32. Cheng T, Li Q, Zhou Z, Wang Y, Bryant SH. Structure-based virtual screening for drug discovery: a problem-centric review. AAPS J. 2012;14:133-41. doi.org/10.1208/s12248-012-9322-0. PubMed PMID: 22281989. PubMed PMCID: 3282008.
  33. Mortazavi M, Zarenezhad M, Alavian SM, Gholamzadeh S, Malekpour A, Ghorbani M, et al. Bioinformatic Analysis of Codon Usage and Phylogenetic Relationships in Different Genotypes of the Hepatitis C Virus. Hepatitis monthly. 2016;16(10). doi: 10.5812/hepatmon.39196 PMCID: PMC5111459, PMID: 27882066
  34. Mortazavi M, Zarenezhad M, Gholamzadeh S, Alavian SM, Ghorbani M, Dehghani R, et al. Bioinformatic Identification of Rare Codon Clusters (RCCs) in HBV Genome and Evaluation of RCCs in Proteins Structure of Hepatitis B Virus. Hepatitis monthly. 2016;16(10). doi: 10.5812/hepatmon.39909, PMCID: PMC5116127, PMID: 27882067
  35. Fattahi M, Malekpour A, Mortazavi M, Safarpour A, Naseri N. The characteristics of rare codon clusters in the genome and proteins of hepatitis C virus; a bioinformatics look. Middle East journal of digestive diseases. 2014;6(4):214. PMCID: PMC4208930, PMID: 25349685
  36. Mortazavi M, Hosseinkhani S. Design of thermostable luciferases through arginine saturation in solvent-exposed loops. Protein Engineering, Design & Selection. 2011;24(12):893-903. https://doi.org/10.1093/protein/gzr051