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Identification of one novel and nine recurrent mutations of the ATP7B gene in 11 children with Wilson disease

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Abstract

Background

Wilson disease (WND), also called hepatolenticular degeneration, is an autosomal recessive genetic disorder in which copper abnormally accumulates in several organs. WND arises from the defective ATP7B gene, which encodes a copper transporting P-type ATPase.

Methods

The molecular defects in 11 unrelated Chinese WND patients aged from 3 to 12 years were investigated. The diagnosis of these patients was based on typical clinical symptoms and laboratory testing results. All 21 exons and exon-intron boundaries of the ATP7B gene were amplified by polymerase chain reaction from the genomic DNA of the patients and then analyzed by direct sequencing. One hundred healthy subjects served as controls to exclude gene polymorphism.

Results

In one novel (c.3605 C>G) and nine recurrent mutations of ATP7B identified, there were eight missense mutations, one splice-site mutation, and one nonsense mutation. The novel c.3605 C>G mutation resulted in the substitution of alanine by glycine at amino acid position 1202 (p.Ala1202Gly). The most frequent ATP7B mutation was c.2333 G>T (p.Arg778Leu), followed by c.2975 C>T (p.Pro992Leu), which accounted for 63.6% of the WND mutated alleles.

Conclusions

The novel c.3605 C>G mutation in. ATP7B is one of the molecular mechanisms of WND.

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References

  1. Cox DW, Roberts E. Wilson Disease. In: Pagon RA, Bird TD, Dolan CR, Stephens K, eds. GeneReviews [Internet]. Seattle (WA): University of Washington; 1993–1999 Oct 22 [updated 2006 Jan 24]

    Google Scholar 

  2. Kenney SM, Cox DW. Sequence variation database for the Wilson disease copper transporter, ATP7B. Hum Mutat 2007;28:1171–1177.

    Article  PubMed  CAS  Google Scholar 

  3. Bartee MY, Lutsenko S. Hepatic copper-transporting ATPase ATP7B: function and inactivation at the molecular and cellular level. BioMetals 2007;20:627–637.

    Article  PubMed  CAS  Google Scholar 

  4. Merle U, Schaefer M, Ferenci P, Stremmel W. Clinical presentation, diagnosis and long-term outcome of Wilson’s disease: a cohort study. Gut 2007;56:115–120.

    Article  PubMed  CAS  Google Scholar 

  5. Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML. Wilson’s disease. Lancet 2007;369:397–408.

    Article  PubMed  CAS  Google Scholar 

  6. Roberts EA, Schilsky ML, American Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of Wilson disease: an update. Hepatology 2008;47:2089–2111.

    Article  PubMed  CAS  Google Scholar 

  7. Li XH, Lu Y, Ling Y, Fu QC, Xu J, Zang GQ, et al. Clinical and molecular characterization of Wilson’s disease in China: identification of 14 novel mutations. BMC Med Genet 2011;12:6.

    Article  PubMed  CAS  Google Scholar 

  8. Caca K, Ferenci P, Kuhn HJ, Polli C, Willgerodt H, Kunath B, et al. High prevalence of the H1069Q mutation in East German patients with Wilson disease: rapid detection of mutations by limited sequencing and phenotype-genotype analysis. J Hepatol 2001;35:575–581.

    Article  PubMed  CAS  Google Scholar 

  9. de Bie P, Muller P, Wijmenga C, Klomp LW. Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes. J Med Genet 2007;44:673–688.

    Article  PubMed  Google Scholar 

  10. Stapelbroek JM, Bollen CW, van Amstel JK, van Erpecum KJ, van Hattum J, van den Berg LH, 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;41:758–763.

    Article  PubMed  CAS  Google Scholar 

  11. Chuang LM, Wu HP, Jang MH, Wang TR, Sue WC, Lin BJ, et al. High frequency of two mutations in codon 778 in exon 8 of the ATP7B gene in Taiwanese families with Wilson disease. J Med Genet 1996;33:521–523.

    Article  PubMed  CAS  Google Scholar 

  12. Kim EK, Yoo OJ, Song KY, Yoo HW, Choi SY, Cho SW, et al. Identification of three novel mutations and a high frequency of the Arg778Leu mutation in Korean patients with Wilson disease. Hum Mutat 1998;11:275–278.

    Article  PubMed  CAS  Google Scholar 

  13. Okada T, Shiono Y, Hayashi H, Satoh H, Sawada T, Suzuki A, et al. Mutational analysis of ATP7B and genotype-phenotype correlation in Japanese with Wilson’s disease. Hum Mutat 2000;15:454–462.

    Article  PubMed  CAS  Google Scholar 

  14. Mak CM, Lam CW, Tam S, Lai CL, Chan LY, Fan ST, et al. Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: identification of 17 novel mutations and its genetic heterogeneity. J Hum Genet 2008;53:55–63.

    Article  PubMed  CAS  Google Scholar 

  15. Gu YH, Kodama H, Du SL, Gu QJ, Sun HJ, Ushijima H. 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 2003;64:479–484.

    Article  PubMed  CAS  Google Scholar 

  16. Wan L, Tsai CH, Tsai Y, Hsu CM, Lee CC, Tsai FJ. Mutation analysis of Taiwanese Wilson disease patients. Biochem Biophys Res Commun 2006;345:734–738.

    Article  PubMed  CAS  Google Scholar 

  17. Ye S, Gong L, Shui QX, Zhou LF. Wilson disease: identification of two novel mutations and clinical correlation in Eastern Chinese patients. World J Gastroenterol 2007;13:5147–5150.

    Article  PubMed  CAS  Google Scholar 

  18. Liu XQ, Zhang YF, Liu TT, Hsiao KJ, Zhang JM, Gu XF, et al. Correlation of ATP7B genotype with phenotype in Chinese patients with Wilson disease. World J Gastroenterol 2004;10:590–593.

    PubMed  CAS  Google Scholar 

  19. Panichareon B, Taweechue K, Thongnoppakhun W, Aksornworanart M, Pithukpakorn M, Yenchitsomanus PT, et al. Six novel ATP7B mutations in Thai patients with Wilson disease. Eur J Med Genet 2011;54:103–107.

    Article  PubMed  Google Scholar 

  20. Schilsky ML, Ala A. Genetic testing for Wilson disease: availability and utility. Curr Gastroenterol Rep 2010;12:57–61.

    Article  PubMed  Google Scholar 

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Correspondence to Qi-Hua Fu.

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Geng, J., Wang, J., Yao, RE. et al. Identification of one novel and nine recurrent mutations of the ATP7B gene in 11 children with Wilson disease. World J Pediatr 9, 158–162 (2013). https://doi.org/10.1007/s12519-012-0388-7

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  • DOI: https://doi.org/10.1007/s12519-012-0388-7

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