Commenced in January 2007
Paper Count: 31532
Mutation Analysis of the ATP7B Gene in 43 Vietnamese Wilson’s Disease Patients
Abstract:Wilson’s disease (WD) is an autosomal recessive disorder of the copper metabolism, which is caused by a mutation in the copper-transporting P-type ATPase (ATP7B). The mechanism of this disease is the failure of hepatic excretion of copper to bile, and leads to copper deposits in the liver and other organs. The ATP7B gene is located on the long arm of chromosome 13 (13q14.3). This study aimed to investigate the gene mutation in the Vietnamese patients with WD, and make a presymptomatic diagnosis for their familial members. Forty-three WD patients and their 65 siblings were identified as having ATP7B gene mutations. Genomic DNA was extracted from peripheral blood samples; 21 exons and exon-intron boundaries of the ATP7B gene were analyzed by direct sequencing. We recognized four mutations ([R723=; H724Tfs*34], V1042Cfs*79, D1027H, and IVS6+3A>G) in the sum of 20 detectable mutations, accounting for 87.2% of the total. Mutation S105* was determined to have a high rate (32.6%) in this study. The hotspot regions of ATP7B were found at exons 2, 16, and 8, and intron 14, in 39.6 %, 11.6 %, 9.3%, and 7 % of patients, respectively. Among nine homozygote/compound heterozygote siblings of the patients with WD, three individuals were determined as asymptomatic by screening mutations of the probands. They would begin treatment after diagnosis. In conclusion, 20 different mutations were detected in 43 WD patients. Of this number, four novel mutations were explored, including [R723=; H724Tfs*34], V1042Cfs*79, D1027H, and IVS6+3A>G. The mutation S105* is the most prevalent and has been considered as a biomarker that can be used in a rapid detection assay for diagnosis of WD patients. Exons 2, 8, and 16, and intron 14 should be screened initially for WD patients in Vietnam. Based on risk profile for WD, genetic testing for presymptomatic patients is also useful in diagnosis and treatment.
Digital Object Identifier (DOI): doi.org/10.5281/zenodo.1128893Procedia APA BibTeX Chicago EndNote Harvard JSON MLA RIS XML ISO 690 PDF Downloads 1232
 A. Ala, A. P. Walker, K. Ashkan, J. S. Dooley, M. L. Schilsky, “Wilson’s disease”, Lancet, vol. 369, no. 9559, pp. 397-408, Feb. 2007.
 R. F. Pfeiffer, “Wilson’s disease”, Semin Neuro, vol. 27, no. 2, pp. 123-132, May 2007.
 D. Huster, A. Kühne, A. Bhattacharjee, L. Raines, V. Jantsch, J. Noe, W. Schirrmeister, I. Sommerer, O. Sabri, F. Berr, J. Mössner, B. Stieger, K. Caca, S. Lutsenko, “Diverse functional properties of Wilson disease ATP7B variants”, Gastroenterology, vol. 142, no. 4, pp. 947-956, Apr. 2012, Epub Jan. 2012.
 S. M. Kenney, D. W. Cox, “Sequence variation database for the Wilson disease copper transporter, ATP7B”, Hum Mutat, vol. 28, no. 12, pp. 1171-1177, Dec. 2007.
 E. A. Roberts, M. L Schilsky, “A practice guideline on Wilson disease”, Hepatology, vol. 37, no. 6, pp. 1475-1492, Jun. 2003.
 J. K. Seo, “Wilson disease: an update” (Article in Korean), Korean J Hepatol, vol. 12, no. 3, pp. 333-363, Sep. 2016.
 D. Kuppala, J. Deng, G. J. Brewer, M. Wang, J. Borjigin, “Wilson disease mutation in the American population: Identification of five novel mutations in ATP7B”, The open Hepatology Journal, vol. 1, pp. 1-4, 2009.
 European Association for the study of the liver, “EASL Clinical practice guidelines: Wilson’s disease, J Hepatology, vol. 56, no. 3, pp. 671-685, Mar. 2012.
 S. Vrabelova, O. Letocha, M. Borsky, L. Kozak, “Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease”, Mol Genet Metab, vol. 86, no. 1-2, pp. 277-285, Sep.-Oct. 2005.
 P. Ferenci, “Regional distribution of mutations of the ATP7B gene in patients with Wilson disease: impact on genetic testing”, Hum Genet, Vol. 120, no. 2, pp. 151-159, Sep. 2006, Epub Jun. 2006.
 M. L. Schilsky, “Wilson disease: Current status and the future” Biochimie, vol. 91, no. 10, pp. 1278-1281, Oct. 2009.
 Y. Kusuda, K. Hamaguchi, T. Mori, R. Shin, M. Seike, T. Sakata, “Novel mutations of the ATP7B gene in Japanese patients with Wilson disease”, J Hum Genet, vol. 45, no. 2, pp. 86-91, 2000.
 Y. H. Gu, H. Kodama, S. L. Du, Q. J. Gu, H. J. Sun, H. Ushijima, “Mutation spectrum and polymorphisms in ATP7B identified on direct sequencing of all exons in Chinese Han and Hui ethnic patients with Wilson’s disease”, Clin Genet, vol. 64, no. 6, pp. 479-4684, Dec. 2003.
 S. Park, J. Y. Park, G. H. Kim, J. H. Choi, K. M. Kim, J. B. Kim, H. W. Yoo, “Identification of novel ATP7B gene mutation and their functional roles in Korean patients with Wilson disease”, Hum Mutat, vol. 28, no. 11, pp. 1108-1113, Nov. 2007.
 X. H. Li, Y. Lu, Y. Ling, Q. C. Fu, J. Xu, G. Q. Zang, F. Zhou, D-M. Y, Y. Han, D. H. Zhang, Q. M. Gong, Z. M. Lu, X. F. Kong, J. S. Wang, X. X. Zhang, “Clinical and molecular characterization of Wilson’s disease in China: identification 04 14 novel mutations”, BMC Med Genet, vol. 12, no. 6, Jan 2011.
 Y. Fan, L. Yu, Y. Jiang, Y. Xu, R. Yang, Y. Han, Y. Cui, M. Ren, S. Zhao, “Identification of a mutation hotspot in exon 8 Wilson disease gene by cycle sequencing”, Chin Med J (Engl), vol. 113, no. 2, pp. 172-174, Feb. 2000.
 L. Wan, C. H. Tsai, Y. Tsai, C. M. Hsu, C. C. Lee, F. J. Tsai, “Mutation analysis of Taiwanese Wilson disease patients”, Biochem Biophys Res Commun, vol. 345, no. 2, pp. 734-738, Jun. 2006.
 G. Firneisz, P. L. Lakatos, F. Szalay, C. Polli, T. T. Glant, P. Ferenci, “Common mutations of ATP7B in Wilson disease patients from Hungary”, Am J Med Genet, vol. 108, no. 1, pp. 23-28, Feb. 2002.
 Y. N. Zong, X. D. Kong, “Analysis and application of ATP7B gene mutations in 35 patients with hepatolenticular degeneration”, Genet Mol Res, vol. 14, no. 4, pp. 18764-18770, Dec. 2015.
 I. Maleki, R. M. Zali, N. H. Abadi, “Novel mutation of ATP7B gene in Iranian patients with Wilson’s disease”, Res Mol Med, vol. 1, no. 1, pp. 44-47, 2013.
 L. H. Wang, Y. Q. Huang, X. Shang, Q. X. Su, F. Xiong, Q. Y. Yu, H. P. Lin, Z. S. Wei, M. F. Hong, X. M. Xu, “Mutation analysis of 73 southern Chinese Wilson’s disease patients: identification of 10 novel mutations and its clinical correlation”, J Hum Genet, vol. 59, no. 9, pp. 660-665, Sep. 2011, Epub Jul. 201l.
 L. M. Luoma, T. M. Deeb, G. Macintyre, D. W. Cox, “Functional analysis of mutations in the ATP loop of the Wilson disease copper transporter, ATP7B”, Hum Mutat, vol. 31, no. 5, pp. 569-577, May 2010.
 T. Okada, Y. Shiono, H. Hayashi, H. Satoh, T. Sawada, A. Suzuki, Y. Takeda, M. Yano, K. Michitaka, M. Onji, H. Mabuchi, “Mutational analysis of ATP7B and genotype-phenotype correlation in Japanese with Wilson disease”, Human Mutation, vol. 15, pp. 454-462, 2000.
 Y. Zhang, Y. W-Z, “Wilson’s disease in Asia”, Neurology Asia, vol. 1, no. 2, pp. 103-109, 2011.
 J. Manoochehri, R. D Masoumi, H. Faraji, S. Mohammadi, H. Dastsooz, T. Moradi, E. Rezaei, K. H. Sadeghi, M. Fardaei, “Family screening for a novel ATP7B gene mutation, c.2335T>G, in the South of Iran”, Iran J Ped Hematol Oncol, vol. 4, no. 1, pp. 26-31, 2014, Epub Feb 2014.
 M. Patil, K. A. Sheth, A. C. Krishnamurthy, H. Devarbhavi, “A Review and Current Perspective on Wilson Disease”, J Clin Exp Hepatol, vol. 3, no. 4, pp. 321–336, Dec 2013.