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Determination of the frequencies of ten allelic variants of the Wilson disease gene (ATP7B), in pooled DNA samples
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. (Molecular Medicine)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. (Molecular Medicine)
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2000 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 8, no 12, 933-938 p.Article in journal (Refereed) Published
Abstract [en]

Wilson disease is an autosomal recessive disorder characterised by toxic accumulation of copper in liver, brain and other organs. The disorder is caused by mutations in the ATP7B gene, encoding a copper transporting P-type ATPase. Based on the number of known patients with this diagnosis in Sweden, the prevalence can be estimated to 1 in 250 000 to 300 000, whereas the prevalence of Wilson disease has been estimated to be 1 in 30 000 in other populations. We estimated the prevalence of Wilson disease by determining the Swedish population frequencies of two mutant alleles, making up approximately half the mutations in Swedish Wilson patients, in a large number of DNA samples. In addition we determined the allele frequencies of eight common single-nucleotide polymorphisms (SNPs) in the ATP7B gene. For the analyses we devised two strategies for analysing pooled DNA samples using the quantitative minisequencing method. The two procedures allowed sensitive identification of rare mutant alleles present as a mixture with an excess of the normal allele, as well as accurate estimation of the frequencies of the common SNPs in a large pooled DNA sample.

Place, publisher, year, edition, pages
2000. Vol. 8, no 12, 933-938 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95656PubMedID: 11175281OAI: oai:DiVA.org:uu-95656DiVA: diva2:169959
Available from: 2007-04-05 Created: 2007-04-05 Last updated: 2012-04-13Bibliographically approved
In thesis
1. Genetical and Clinical Studies in Wilson's Disease
Open this publication in new window or tab >>Genetical and Clinical Studies in Wilson's Disease
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Wilson’s disease is a rare inborn error of metabolism caused by a defect in ATP7B, a protein necessary for proper copper excretion into bile. It is characterised by copper accumulation with hepatic and central nervous system dysfunction.

We investigated 24 Swedish families with Wilson’s disease by sequencing the entire coding sequence using a new technique called manifold sequencing. Disease causing mutations were found in 44 out of 48 alleles.

From data obtained in the first study, the two most common mutations (C3207A and C2930T) were sought in 2640 anonymous DNA samples from a Swedish population, using a pooling strategy and solid-phase minisequencing. Four C3207A and one C2930T were found. From the number of C3207A, a prevalence of Wilson’s disease in Sweden of about 1 in 110,000 could be estimated.

Four groups with three patients each had four different genotypes concerning mutations in ATP7B. The patients’ psychopathological symptoms were investigated, using the Karolinska Scales of Personality rating (KSP) and Comprehensive Psychopathological Rating Scale (CPRS). A trend towards lower CPRS scores was seen in the groups with mutations known to render ATP7B completely without activity.

Using 61Cu liver PET in patients homozygous for mutations in ATP7B, heterozygotes, normal individuals and two patients with alcoholic liver cirrhosis, significantly slower uptake was seen in the homozygotes as compared to the heterozygotes and normal individuals. The patients with cirrhosis had values in between. This implies that 61Cu liver PET might be used as an additional rapid and little invasive diagnostic tool in Wilson’s disease.

In a retrospectively studied cohort consisting of 363 patients followed in Sweden and the UK, nine cases of aggressive intra-abdominal malignancies were seen, which is more than expected. Caution should be taken in the follow-up of Wilson’s disease patients.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 46 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 246
Keyword
Internal medicine, copper radioisotopes, DNA sequence analyses, genotype, hepatolenticular degeneration, neoplasms, phenotype, positron-emission tomography, psychopathology, Invärtesmedicin
Identifiers
urn:nbn:se:uu:diva-7779 (URN)978-91-554-6845-3 (ISBN)
Public defence
2007-04-26, Robergsalen, Entrance 40, Akademiska sjukhuset, Uppsala, 09:15
Opponent
Supervisors
Available from: 2007-04-05 Created: 2007-04-05Bibliographically approved

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PubMedhttp://www.nature.com/ejhg/journal/v8/n12/abs/5200566a.html

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Syvänen, Ann-Christine

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