ISSN 0564-3783  
Main page
Preview papers  
Information to authors
Editorial board
Standard version

In Ukrainian

Export citations   UNIMARC   BibTeX   RIS

Mutations in gene ATP7B in ukrainian patients with high risk of Wilsons disease

Makukh H., Hayboniuk I., Zarina A., Semeriak O.M., Gailite L.


SUMMARY. SI Institute of Hereditary Pathology of Ukrainian National Academy of Medical Wilsons disease (WD) is an autosomal recessive con-dition, caused by the impaired metabolism of copper due to hereditary mutations in the gene ATP7, the spectrum and frequency of mutations are considerably different in different populations. To define the list of the most frequent mutations in the gene ATP7B in patients from Ukraine with the purpose of introducing the genetic testing into the practice of medical and genetic consulting. The materials for the study were DNA samples, isolated from leukocytes of 90 patients (41 males and 49 females), aged 360, with clinical and biochemical signs of the disease. The molecular and genetic analysis of the mutation c.3207C > A (H1069Q), the most common among Europeans, was conducted by the method of PCR Bi-PASA. The sequencing of exons of the gene ATP7B was conducted for 23 patients, who had scored 3 by the Leipzig scoring system. The molecular and genetic analysis of the mutations in the gene ATP7B verified Wilsons disease genetically in 23.3 % of patients with clinical signs of the disease. Five different mutations and five single-nucleotide polymorphisms in the gene ATP7B were determined in the patients of the investigated sampling. The mutation (c.3207C > A), most common for Europeans, was determined in 28 patients, including 15 cases of homozygosity. In 6 cases the mutation c.3207C > A was in compound heterozygous state with other mutations in the gene ATP7B: 3 c.2304dupC (8 exon), 1 c.2128G > A (8 exon), 1 c.3011A > C (13 exon), 1 c.3402delC (15 exon). No other transformations, except for mutation H1069Q, were found in 7 persons. The frequency of the pathogenic allele c.3207C > A (H1069Q) of the gene ATP7B, most widespread in Europe, among patients who scored 3 and more points according to the scoring system of diagnostic tests, was 76.8 %. The frequency of allele c.2304dupC among genetically verified cases was 7 %. The genetic testing of two mutations in the gene ATP7B (c.3207C > A and c.2304dupC), which are frequent among patients with Wilsons disease from Ukraine, was introduced into practice. The third of patients did not have pathogenic alleles in exon sequences of the gene ATP7B but had one or several single nucleotide polymorphisms, including several non-pathogenic variants and one polymorphism associated with the increased risk of developing Alzheimers disease (c.2495A > G). The obtained results indicate high informative value of genetic testing of mutations c.3207C > A and c.2304dupC in the gene ATP7B among Ukrainian patients with Wilsons disease.

Key words: ATP7B gene, mutation, Wilson disease, Ukraine

Tsitologiya i Genetika 2020, vol. 54, no. 4, pp. 53-62

  1. SI Institute of Hereditary Pathology of Ukrainian National Academy of Medical Science, 31-a, Lysenko str., Lviv, Ukraine
  2. Riga Stradins University, 16 Dzirciema str., Riga, Latvia, LV-1007
  3. KI LOR Lviv Regional Clinical Hospital, 4, Nekrasova str., Lviv, Ukraine, 79008

E-mail: makukh.h, ivankagaiboniuk, zarina.agnese, dr.orchyk, linda.gailite

Makukh H., Hayboniuk I., Zarina A., Semeriak O.M., Gailite L. Mutations in gene ATP7B in ukrainian patients with high risk of Wilsons disease, Tsitol Genet., 2020, vol. 54, no. 4, pp. 53-62.

In "Cytology and Genetics":
H. Makukh, I. Hayboniuk, A. Zarina, O. M. Semeriak & L. Gailite Mutations in the ATP7B Gene in Ukrainian Patients with High Risk of Wilsons Disease, Cytol Genet., 2020, vol. 54, no. 4, pp. 324332
DOI: 10.3103/S009545272004009X


1. Bhargava, K., Bahde, R., Kapoor, S., Palestro1, C., and Gupta, S., Evaluation of biliary copper excretion in a rat model of Wilsons disease by PET imaging with 64Cu-asialofetuin, J. Nucl. Med., 2012, vol. 53, suppl. no. 1.

2. Langley, A. and Dameron, C.T., Copper and anesthesia: clinical relevance and management of copper related disorders, Anesthesiol. Res. Pract., 2013, vol. 2013, p. 750 901.

3. Yu, C.H., Lee, W., Nokhrin, S., and Dmitriev, O.Y., The structure of metal binding domain 1 of the copper transporter ATP7B reveals mechanism of a singular Wilson disease mutation, Sci. Rep., 2018, vol. 12, no. 8, pp. 581582.

4. Candan, A., Yaozong, L., and Pernilla, W-S., The six metal binding domains in human copper transporter, ATP7B: molecular biophysics and disease-causing mutations, Biometals, 2017, vol. 30, no. 6, pp. 823840.

5. Huster, D., Kühne, A., Bhattacharjee, A., Raines, L., Jantsch, V., Noe, J., Schirrmeister, W., Sommerer, I., Sabri, O., Berr, F., Mössner, J., Stieger, B., Caca, K., and Lutsenko, S., Diverse functional properties of Wilson disease ATP7B variants, Gastroenterology, 2012, vol. 142, no. 4, pp. 947956.

6. Shanmugavel, K.P. and Wittung-Stafshede P., Copper relay path through the N-terminus of Wilson disease protein, ATP7B, Metallomics, 2019, vol. 11, pp. 1472 1480.

7. Yu, C.H., Yang, N., Bothe, J., Tonelli, M., Nokhrin, S., Dolgova, N.V., Braiterman, L., Lutsenko, S., and Dmitriev, O.Y., The metal chaperone Atox1 regulates the activity of the human copper transporter ATP7B by modulating domain dynamics, J. Biol. Chem., 2017, vol. 292, no. 44, pp. 18 16918 177.

8. Hatori, Y. and Lutsenko, S., The role of copper chaperone atox1 in coupling redox homeostasis to intracellular copper distribution, Antioxidants (Basel), 2016, vol. 5, no. 3, p. 25.

9. Polishchuk, R.S. and Polishchuk, E.V., From and to the Golgi: defining the Wilson disease protein road map, FEBS Lett., 2019, vol. 593, pp. 234150.

10. Chang, I.J. and Si, H.H., The genetics of Wilson disease, Handb. Clin. Neurol., 2017, vol. 142, pp. 1934.

11. Khosravifarsani, M., Shabestani, A. M., Pouramir, M., and Zabihi, E., Effects of Fenton reaction on human serum albumin: an in vitro study, Electron. Physician, 2016 vol. 8, no. 9, pp. 29702976.

12. Zhong, H.-J., Sun, H.-H., Xue, L.-F., McGowan, E.M., and Chen, Y., Differential hepatic features presenting in Wilson disease-associated cirrhosis and hepatitis B-associated cirrhosis, World J. Gastroenterol., 2019, vol. 25, no. 3, pp. 378387.

13. Lorincz, M.T., Wilson disease and related copper disorders, Handb. Clin. Neurol., 2018, vol. 147, pp. 279292.

14. Weiss, K.H. and Stremmel, W., Clinical considerations for an effective medical therapy in Wilsons disease, Ann. N.Y. Acad. Sci., 2014, vol. 1315, pp. 8185.

15. Li, W.J., Chen, C., You, Z.F., Yang, R.M., and Wang, X.P., Current drug managements of Wilsons disease: from West to East, Curr. Neuropharmacol., 2016, vol. 14, no. 4, pp. 322325.

16. Purchase, R., The treatment of Wilsons disease, a rare genetic disorder of copper metabolism, Sci. Progr., 2013, vol. 96, pp. 1932.

17. Tanner, S., Clinical and Translational Perspectives on Wilson disease, ScienceDirect, 2019, pp. 111.

18. Makukh, H., Zastavna, D., and Tyrkus, S.I., UA Patent no. 32 044, 2008, Bull. no. 8.

19. Polakova H., Katrincsakova B., Minarik G., Ferakova E., Ficek A., Baldovic M., et al., Detection of His1069Gln mutation in Wilson disease by bidirectional PCR amplification of specific alleles (BI-PASA) test, Gen. Physiol. Biophys., 2007, vol. 26, pp. 9196.

20. Bucossi, S., Mariani, S., Ventriglia, M., Polimanti, R., Gennarelli, M., and Bonvicini, C., Association between the c. 2495 A > G ATP7B polymorphism and sporadic Alzheimers disease, Int. J. Alzheimers Dis., 2011, vol. 2011, ID 973692.

21. Sauna, Z.E. and Kimchi-Sarfaty, C., Synonymous Mutations as a Cause of Human Genetic Disease, eLS, Wiley, 2013.

22. Haiboniuk, I., Spectrum and frequency of mutations in gene ATP7B in different populations and ethnic groups, Bull. LNU, 2019, vol. 80, pp. 311.

23. Gomes, A. and Dedoussis, G.V., Geographic distribution of ATP7B mutations in Wilson disease, Ann. Hum. Biol., 2016, vol. 43, pp. 18.

Copyright© ICBGE 2002-2023 Coded & Designed by Volodymyr Duplij Modified 03.12.23