Skip to main content

Advertisement

SpringerLink
Log in

Mutational analysis of exon 8 and exon 14 of ATP7B gene in Bangladeshi children with Wilson disease

  • Original Article
  • Published:
Indian Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background 

Wilson disease (WD) is an autosomal recessive disorder caused by mutation in the Adenosine Triphosphate 7B (ATP7B) gene. The spectrum of ATP7B mutation varies in different populations. The objective of this study was to identify the mutation in exon 8 and exon 14 of ATP7B gene in Bangladeshi children clinically diagnosed as WD. We also aimed to explore the phenotypic presentation.

Methods

It was a cross sectional observational study. The study was conducted at the Department of Paediatric Gastroenterology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from January 2017 to June 2018. A total of 37 patients diagnosed with WD were enrolled for the study. Venous blood (about 3 mL) was drawn aseptically from each patient into tube containing ethyline diamine tetraacetic acid (EDTA) and preserved at −30°C for long-term preservation. The peripheral blood leukocytes of the patients and genomic DNAs were extracted. Exons 14 and 8 of ATP7B and their associated splice-site junctions were amplified by the polymerase chain reaction (PCR). The size and quantity of PCR products were verified by electrophoresis in 1.5% (w/v) agarose gel. 74 (37 × 2) PCR products were sent for Sanger Sequencing. The sequences were analyzed by Chromas version 2.6.6 software and the nucleotide blast was done by National Center for Biotechnology Information (NCBI) nucleoblast. Finally, the sequences were analyzed using AB Applied Bio systems and were matched with the reference sequences using MEGA software.

Results

In this study, a single novel homozygous mutation pLeu.1071Val in the exon 14 was found in every (100%) studied child clinically diagnosed with WD. Heterozygous mutation p.Gly1061Glu in exon14 was also found in 6 patients (11%) with WD, which is one of the common mutations in this disease. In exon 8, p.Arg778Leu mutation was detected in one patient (2.7%), which is common in the Chinese and the South Asian populations and was heterozygous. Two novel heterozygous missense mutations p.K785R (2.7%) and p.S744F (2.7%) were also found in two other children in the exon 8.

Conclusion

We found three novel mutations in Bangladeshi children with WD, one of which may be tagged as founder mutation for Bangladeshi population. This finding indicates the necessity to study the mutation profiles of the whole ATP7B gene in our population for risk prediction. A further large-scale study will help in the development of a Mutational Data Base of Bangladeshi population with WD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Patil M, Sheth KA, Krishnamurthy AC, Devarbhavi H. A review and current perspective on Wilson Disease. J Clin Exp Hepatol. 2013;3:321–36.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Chen C, Shen B, Xiao JJ, et al. Currently clinical views on Genetics of Wilson Disease. Chin Med J (Engl). 2015;128:1826–30.

    Article  CAS  PubMed  Google Scholar 

  3. Członkowska A, Litwin T, Dusek P, et al. Wilson disease. Nat Rev Dis Primers. 2018;4:21.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Walshe JM, Yealland M. Chelation treatment of neurological Wilson’s disease. Q J Med. 1993;86:197–204.

    CAS  PubMed  Google Scholar 

  5. Ferenci P. Diagnosis of Wilson disease. Handb Clin Neurol. 2017;142:171–80.

    Article  PubMed  Google Scholar 

  6. Sternlieb I, Scheinberg IH. Prevention of Wilson’s disease in asymptomatic patients. New Engl J Med. 1968;278:352–9.

    Article  CAS  PubMed  Google Scholar 

  7. Nakayama K, Kubota M, Katoh Y, et al. Early and pre-symptomatic detection of Wilson’s disease at the mandatory 3-year-old medical health care examination in Hokkaido Prefecture with the use of a novel automated urinary ceruloplasmin assay. Mol Genet Metab. 2008;94:363–7.

    Article  CAS  PubMed  Google Scholar 

  8. Chang IJ, Hahn SH. Genetics of Wilson disease. Handb Clin Neurol. 2017;142:19–34.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Wang L-H, Huang YQ, Shang X, et al. Mutation analysis of 73 southern Chinese Wilson’s disease patients: identification of 10 novel mutations and its clinical correlation. J Hum Genet. 2011;56:660–5.

    Article  CAS  PubMed  Google Scholar 

  10. Stenson PD, Mort M, Ball EV, Shaw K, Phillips A, Cooper DN. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet. 2014;133:1–9.

    Article  CAS  PubMed  Google Scholar 

  11. Payne AS, Kelly EJ, Gitlin JD. Functional expression of the Wilson disease protein reveals mis-localization and impaired copper-dependent trafficking of the common H1069Q mutation. Proc Natl Acad Sci USA. 1998;95:10854–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bie PD, Sluis BVD, Burstein E, et al. Distinct Wilson's disease mutations in ATP7B are associated with enhanced binding to COMMD1 and reduced stability of ATP7B. J Gastroenterol. 2007;133:1316–126.

    Google Scholar 

  13. van den Berghe PVE, Stapelbroek JM, Krieger E, et al. Reduced expression of ATP7B affected by Wilson disease-causing mutations is rescued by pharmacological folding chaperones 4-phenylbutyrate and curcumin. J Hepatol. 2009;50:1783–95.

    Article  Google Scholar 

  14. Leggio L, Addolorato G, Loudianos G, Abenavoli L, Gasbarrini G. Genotype-phenotype correlation of the Wilson disease ATP7B gene. Am J Med Genet A. 2006;140:933.

    Article  PubMed  Google Scholar 

  15. Li X, Lu Y, Ling Y, et al. Clinical and molecular characterization of Wilsons disease in China: identification of 14 Novel mutations. BMC Med Genet. 2011;12:6.

  16. Stapelbroek JM, Bollen CW, van Amstel JK, et al. The H1069Q mutation in ATP7B is associated with late and neurologic presentation in Wilson disease: results of a meta-analysis. J Hepatol. 2004;41:758–63.

    Article  CAS  PubMed  Google Scholar 

  17. Kalita J, Somarajan BI, Misra UK, Mittal B. R778L, H1069Q, and I1102T mutation study in neurologic Wilson disease. Neurol India. 2010;58:627–30.

    Article  PubMed  Google Scholar 

  18. Folhoffer A, Ferenci P, Csak T, et al. Novel mutations of the ATP7B gene among 109 Hungarian patients with Wilson’s disease. Eur J Gastroenterol Hepatol. 2007;19:105–11.

    Article  CAS  PubMed  Google Scholar 

  19. Kuppala D, Deng J, Brewer GJ, Wang MM, Borjigin J. Wilson disease mutations in the American population: identification of five novel mutations in ATP7B. The Open Hepatology J. 2009;1:1–4.

  20. Hua R, Hua F, Jiao Y, et al. Mutational analysis of ATP7B in Chinese Wilson disease patients. Am J Transl Res. 2016;8:2851–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Deguti MM, Genschel J, Cancado EL, et al. Wilson disease. Novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Hum Mutat. 2004;23:398.

    Article  PubMed  Google Scholar 

  22. Tomic A, Dobricic V. NovakovicI, et al. Mutation analysis of ATP7B gene and the genotype-phenotype correlation in patients with Wilson’s disease in Serbia. Vojnosanit Pregl. 2013;70:457–62.

    Article  PubMed  Google Scholar 

  23. Coffey AJ, Durkie M, Hague S, et al. A genetic study of Wilson’s disease in the United Kingdom. Brain. 2013;136:1476–87.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Kieffer DA, Medici V. Wilson disease: At the crossroads between genetics and epigenetics-a review of the evidence. Liver Res. 2017;1:121–30.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Aggarwal A, Bhatt M. The pragmatic treatment of Wilson’s disease. Mov Dis Clinl Pract. 2013;1:14–23.

  26. Margarit E, Bach V, Gomez D, et al. Mutation analysis of Wilson disease in the Spanish population - identification of a prevalent substitution and eight novel mutations in the ATP7B gene. Clin Genet. 2005;68:61–8.

    Article  CAS  PubMed  Google Scholar 

  27. Dmitriev OY, Bhattacharjee A, Nokhrin S, Uhlemann EM, Lutsenko S. Difference in stability of the N-domain underlies distinct intracellular properties of the E1064A and H1069Q mutants of copper-transporting ATPase ATP7B. J Biol Chem. 2011;286:16355–62.

  28. Devarbhavi H, Singh R, Adarsh CK, Sheth K, Kiran R, Patil M. Factors that predict mortality in children with Wilson disease associated acute liver failure and comparison of Wilson disease specific prognostic indices. J Gastroenterol Hepatol. 2013;29:380–6.

  29. Iacob R, Iacob S, Nastase A, et al. The His1069Gln mutation in the ATP7B gene in Romanian patients with Wilson’s disease referred to a tertiary gastroenterology centre. J Gastrointestin Liver Dis. 2012;21:181–5.

    PubMed  Google Scholar 

  30. Mazumder MW, Karim MB, Rukunuzzaman M. Penicillamine challenge in the diagnosis of Wilson disease: a valuable diagnostic test. Mymensingh Med J. 2014;23:489–95.

    CAS  PubMed  Google Scholar 

  31. Karim MB, Rahman MM, Islam MS. Wilson’s disease with hepatic presentation in childhood. Mymensingh Med J. 2007;16:29–32.

    Article  CAS  PubMed  Google Scholar 

  32. Taly AB, Meenakshi-Sundaram S, Sinha S, Swamy HS, Arunodaya GR. Wilson disease: description of 282 patients evaluated over 3 decades. Medicine (Baltimore).. 2007;86:112–21.

  33. Rukunuzzaman M. Wilson’s disease in Bangladeshi children: analysis of 100 cases. Pediatr Gastroenterol Hepatol Nutr. 2015;18:121–7.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Jumah M, Majumdar R, Rajeh SA, et al. A clinical and genetic study of 56 Saudi Wilson disease patients: identification of Saudi-specific mutations. Eur J Neurol. 2004;11:121–4.

    Article  PubMed  Google Scholar 

  35. Scheinberg IH, Sternlieb I, Schilsky M, Stockert RJ. Penicillamine may detoxify copper in Wilson’s disease. Lancet. 1987;2:95.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge the authority of BSMMU for funding support of this study (Research Grant for Teachers, BSMMU). We thank the Department of Anatomy, BSMMU, for providing the infrastructure, and other research facilities. We also express our gratitude to the patients participated in our research.

Funding

The study was funded by the University and Grant Commission and Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh.

Author information

Authors and Affiliations

  1. Department of Paediatric Gastroenterology and Nutrition, Bangabandhu Sheikh Mujib Medical University, Apartment No.-E3, Total Tomiz, 41, Dilu Road, Ramna, Dhaka, 1000, Bangladesh

    Ruhina Tasmeen, A. S. M. Bazlul Karim, Md. Rokunuzzaman, Wahiduzzaman Majumder, Rafia Rasid, Md. Benzamin & Md. Sharif Hasan

  2. Department of Anatomy, Bangabandhu Sheikh Mujib Medical University, Dhaka, 1000, Bangladesh

    Laila Anjuman Banu

  3. International Centre for Diarrhoeal Disease Research, Bangladesh, Dhaka, Bangladesh

    Enayet Hossain

  4. Department of Paediatric Neurology, Bangabandhu Sheikh Mujib Medical University, Dhaka, 1000, Bangladesh

    Syeda Tabassum Alam

Authors
  1. Ruhina Tasmeen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. S. M. Bazlul Karim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laila Anjuman Banu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Enayet Hossain
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Md. Rokunuzzaman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wahiduzzaman Majumder
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Syeda Tabassum Alam
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rafia Rasid
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Md. Benzamin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Md. Sharif Hasan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ruhina Tasmeen.

Ethics declarations

Conflict of interest

RT, ASMBK, LAB, EH, MR, WM, STA, RR, MB, and MSH declare no competing interests.

Ethics statement

The study was performed conforming to the Helsinki declaration of 1975, as revised in 2000 and 2008 concerning human and animal rights, and the authors followed the policy concerning informed consent as shown on Springer.com.

Disclaimer

The authors are solely responsible for the data and the contents of the paper. In no way, the Honorary Editor-in-Chief, Editorial Board Members, the Indian Society of Gastroenterology or the printer/publishers are responsible for the results/findings and content of this article.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tasmeen, R., Karim, A.S.M.B., Banu, L.A. et al. Mutational analysis of exon 8 and exon 14 of ATP7B gene in Bangladeshi children with Wilson disease. Indian J Gastroenterol 41, 456–464 (2022). https://doi.org/10.1007/s12664-022-01276-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12664-022-01276-x

Keywords

Search

Navigation