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Detection of the His1069Gln Mutation in Wilson Disease by Rapid Polymerase Chain Reaction

Theresia Maier-Dobersberger, MD; Peter Ferenci, MD; Claudia Polli; Pauline Balac, PhD; Hans Peter Dienes, MD; Klaus Kaserer, MD; Christian Datz, MD; Wolfgang Vogel, MD; and Alfred Gangl, MD
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From University of Vienna, Vienna, Austria: University of Sheffield, Sheffield, United Kingdom; University of Cologne, Cologne, Germany; General Hospital of Salzburg, Salzburg, Austria; and University of Innsbruck, Innsbruck, Austria. Acknowledgments: The authors thank the members of the families who participated in the study; Drs. Gerhard Granditsch, Bruno Schneewei β, Kurt Erhart, Jozef Holoman, Felix Stockenhuber, Rudolf Stauber, Aniko Somogyi, and Christa Binder for allowing us to examine their patients and providing clinical information; Dr. Edmund Cauza for help in collecting blood samples; and Mr. Cyrus Yeganehfar for technical help. Grant Support: In part by the Medizinisch-wissenschaftlicher Fonds des Burgermeisters der Bundeshauptstadt Wien. Requests for Reprints: Theresia Maier-Dobersberger, MD, Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Vienna, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. Current Author Addresses: Drs. Maier-Dobersberger, Ferenci, and Gangl and Ms. Polli: Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Vienna, Wahringer Gurtel 18-20, A-1090 Vienna, Austria.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1997;127(1):21-26. doi:10.7326/0003-4819-127-1-199707010-00004
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Background: Most known mutations in the gene associated with Wilson disease are rare. Only the His 1069Gln mutation is found often in patients of Northern or Eastern European origin.

Objective: To examine the frequency of the His 1069Gln mutation in Austrian patients with Wilson disease and their families by using a new, rapid polymerase chain reaction (PCR) test.

Design: Cross-sectional study.

Setting: University medical center.

Patients: 83 patients from 72 families and 98 relatives of 11 homozygous index patients.

Measurements: Results of a semi-nested PCR-based assay to detect the His 1069Gln mutation in Wilson disease, clinical symptoms, and liver histologic findings.

Results: 20 patients, including 5 siblings, were homozygous for the His1069Gln mutation. Thirty-three patients, including 4 siblings, were compound heterozygotes. The mutation was not detected in 30 patients, including 2 siblings. Homozygotes were older at onset of symptoms (mean age, 24 ± 6 years) than compound heterozygotes (17 ± 6 years [95% CI, 3.3 to 10.7 years]; P = 0.0135) and patients with other mutations (18 ± 8 years [CI, 1.8 to 10.2 years]; P = 0.117). Homozygotes were more often female (73.3%) than were compound heterozygotes (48% [CI, 0.94% to 2.46%]) and patients with other mutations (50% [CI, 0.91% to 2.37%]) (P = 0.05). Four of 98 asymptomatic relatives of 11 homozygous index patients were also homozygotes. Heterozygosity was confirmed in 46 relatives (19 parents, 11 children, and 16 distant relatives).

Conclusion: The His 1069Gln mutation was detected in 61% of Austrian patients with Wilson disease. Polymerase chain reaction may be useful for diagnosis and screening of family members of homozygous index patients, even if first-degree relatives are not available for examination.


Grahic Jump Location
Figure 1.
Separation of alleles after digestion with the restriction enzyme BsiHKA I.

Lane 1. Healthy control. Lane 2. Patient with unknown mutations in both chromosomes. Lane 3. Heterozygous carrier of the His 1069Gln mutation. Lane 4. Compound heterozygous patient with unknown second mutation. Lane 5. Blank. Lane 6. Patient with Wilson disease who was homozygous for the His1069Gln mutation. The fragments from patients who were homozygous for the His1069Gln mutation were uncut and show a single band. Fragments from heterozygotes or compound heterozygotes (who had the His1069Gln mutation and an unknown mutation with phenotypic disease) were partially digested and show two bands. The fragments from healthy persons or patients with other mutations show a single band that is 21 base pairs shorter. M = Msp I marker.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Correlation of genotype with age at symptom onset.
Grahic Jump Location
Grahic Jump Location
Figure 3.
Pedigree of patient 13.

Filled squares indicate clinically affected men; filled circles indicate clinically affected women; half-filled symbols indicate heterozygous carriers; and symbols filled with diagonal lines indicate persons not examined. * dead relatives of patient 13; † patient 13; ‡ sister of patient 13.

Grahic Jump Location




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