Truncating Mutations in the Wilson Disease Gene ATP7B Are Associated with Very Low Serum Ceruloplasmin Oxidase Activity and an Early Onset of Wilson Disease

Overview

Journal BMC Gastroenterol

Publisher Biomed Central

Specialty Gastroenterology

Date 2010 Jan 20

PMID 20082719

Citations 35

Authors

Uta Merle

Karl Heinz Weiss

Christoph Eisenbach

Sabine Tuma

Peter Ferenci

Wolfgang Stremmel

Affiliations

Soon will be listed here.

Abstract

Background: Mutations in the gene ATP7B cause Wilson disease, a copper storage disorder with a high phenotypic and genetic heterogeneity. We aimed to evaluate whether 'severe' protein-truncating ATP7B mutations (SMs) are associated with low serum ceruloplasmin oxidase activities and an early age of onset when compared to missense mutations (MMs).

Methods: The clinical phenotype of 59 genetically confirmed WD patients was analyzed retrospectively. Serum ceruloplasmin was measured by its oxidase activity with o-dianisidine dihydrochloride as substrate and immunologically.

Results: Thirty-nine patients had two MMs, 15 had the genotype SM/MM, and 5 patients had two SMs on their ATP7B alleles. Enzymatic and immunologic serum ceruloplasmin levels differed significantly between the three groups (P < 0.001 and P < 0.01, respectively). The lowest levels were measured in patients with two SMs (0.0 U/L; IQR, 0.0-0.0 U/L and 0.02 g/L; IQR, 0.01-0.02 g/L, respectively) and the highest in patients with two MMs (17.8 U/L; IQR, 5.8-35.1 U/L and 0.11 g/L; IQR,0.10-0.17 g/L, respectively). The age of onset was also significantly different between the three patient groups (P < 0.05), with SM/SM patients showing the earliest onset (13 years; IQR, 9-13 years) and patients with two MMs showing the latest onset (22 years; IQR, 14-27 years). By ROC curve analysis a ceruloplasmin oxidase level <or= 5 U/L can predict the presence of at least one SM with a sensitivity of 80% and a specificity of 79.5%.

Conclusions: In our German study cohort truncating ATP7B mutations were associated with lower ceruloplasmin serum oxidase levels and an earlier age of onset when compared to MMs. Measurement of serum ceruloplasmin oxidase might help to predict presence of truncating ATP7B mutations and might facilitate the mutation analysis.

Citing Articles

Spectrum of Pathogenic Variants of the ATP7B Gene and Genotype-Phenotype Correlation in Eastern Eurasian Patient Cohorts with Wilson's Disease.

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Phenotypic and genetic characterization of children with Wilson Disease from Northeast China.

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References

Tanzi R, Petrukhin K, Chernov I, Pellequer J, Wasco W, Ross B . The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet. 1993; 5(4):344-50. DOI: 10.1038/ng1293-344. View

GERMAN 3rd J, Bearn A . Effect of estrogens on copper metabolism in Wilson's disease. J Clin Invest. 1961; 40:445-53. PMC: 290741. DOI: 10.1172/JCI104272. View

Shah A, Chernov I, Zhang H, Ross B, Das K, Lutsenko S . Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses. Am J Hum Genet. 1997; 61(2):317-28. PMC: 1715895. DOI: 10.1086/514864. View

Scott J, Gollan J, Samourian S, Sherlock S . Wilson's disease, presenting as chronic active hepatitis. Gastroenterology. 1978; 74(4):645-51. View

Merle U, Eisenbach C, Weiss K, Tuma S, Stremmel W . Serum ceruloplasmin oxidase activity is a sensitive and highly specific diagnostic marker for Wilson's disease. J Hepatol. 2009; 51(5):925-30. DOI: 10.1016/j.jhep.2009.06.022. View

Nicastro E, Loudianos G, Zancan L, DAntiga L, Maggiore G, Marcellini M . Genotype-phenotype correlation in Italian children with Wilson's disease. J Hepatol. 2009; 50(3):555-61. DOI: 10.1016/j.jhep.2008.09.020. View

Kojimahara N, Nakabayashi H, Shikata T, Esumi M . Defective copper binding to apo-ceruloplasmin in a rat model and patients with Wilson's disease. Liver. 1995; 15(3):135-42. DOI: 10.1111/j.1600-0676.1995.tb00660.x. View

Stapelbroek J, Bollen C, Ploos van Amstel J, van Erpecum K, van Hattum J, van den Berg L . The H1069Q mutation in ATP7B is associated with late and neurologic presentation in Wilson disease: results of a meta-analysis. J Hepatol. 2004; 41(5):758-63. DOI: 10.1016/j.jhep.2004.07.017. View

Palsson R, Jonasson J, Kristjansson M, Bodvarsson A, Goldin R, Cox D . Genotype-phenotype interactions in Wilson's disease: insight from an Icelandic mutation. Eur J Gastroenterol Hepatol. 2001; 13(4):433-6. DOI: 10.1097/00042737-200104000-00023. View

10.

Caca K, Ferenci P, Kuhn H, POLLI C, Willgerodt H, Kunath B . 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(5):575-81. DOI: 10.1016/s0168-8278(01)00219-7. View

11.

Panagiotakaki E, Tzetis M, Manolaki N, Loudianos G, Papatheodorou A, Manesis E . Genotype-phenotype correlations for a wide spectrum of mutations in the Wilson disease gene (ATP7B). Am J Med Genet A. 2004; 131(2):168-73. DOI: 10.1002/ajmg.a.30345. View

12.

Okada T, Shiono Y, Hayashi H, Satoh H, Sawada T, Suzuki A . Mutational analysis of ATP7B and genotype-phenotype correlation in Japanese with Wilson's disease. Hum Mutat. 2000; 15(5):454-62. DOI: 10.1002/(SICI)1098-1004(200005)15:5<454::AID-HUMU7>3.0.CO;2-J. View

13.

Gromadzka G, Schmidt H, Genschel J, Bochow B, Rodo M, Tarnacka B . Frameshift and nonsense mutations in the gene for ATPase7B are associated with severe impairment of copper metabolism and with an early clinical manifestation of Wilson's disease. Clin Genet. 2005; 68(6):524-32. DOI: 10.1111/j.1399-0004.2005.00528.x. View

14.

Scheinberg I . Wilson's disease. J Rheumatol Suppl. 1981; 7:90-3. View

15.

Bull P, Thomas G, Rommens J, FORBES J, Cox D . The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet. 1993; 5(4):327-37. DOI: 10.1038/ng1293-327. View

16.

Roberts E, Schilsky M . A practice guideline on Wilson disease. Hepatology. 2003; 37(6):1475-92. DOI: 10.1053/jhep.2003.50252. View

17.

Saenko E, Skorobagatko O, Iaropolov A . [Immunoenzyme determination of the total level of ceruloplasmin in the serum from patients with hepatocerebral dystrophy]. Biokhimiia. 1991; 56(9):1640-6. View

18.

Schosinsky K, Lehmann H, BEELER M . Measurement of ceruloplasmin from its oxidase activity in serum by use of o-dianisidine dihydrochloride. Clin Chem. 1974; 20(12):1556-63. View

19.

Firneisz G, Lakatos P, Szalay F, Polli C, Glant T, Ferenci P . Common mutations of ATP7B in Wilson disease patients from Hungary. Am J Med Genet. 2002; 108(1):23-8. DOI: 10.1002/ajmg.10220. View

20.

Ferenci P, Czlonkowska A, Merle U, Ferenc S, Gromadzka G, Yurdaydin C . Late-onset Wilson's disease. Gastroenterology. 2007; 132(4):1294-8. DOI: 10.1053/j.gastro.2007.02.057. View