title: 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.
abstract: Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism. The clinical phenotype of the disease is varied. It is proposed that this variation may be a result of differential functional disruption of ATPase7B (ATP7B) resulting from mutations in the gene ATP7B. We aimed to assess the relationship between specific mutational defects in ATP7B and divergence in the phenotypic expression of WD. One hundred and forty-two patients with clinically, biochemically and genetically diagnosed WD were included in the study. The phenotypic expression of WD was compared between patients with different types of mutations in ATP7B, detected by direct sequencing of exons 1-21 of the gene. Twenty-six mutations were identified in ATP7B; eleven of them were mutations predicted to result in the absence of a full-length normal protein [frameshift/nonsense mutations; classified as 'severe' mutations (SMs)], 14 were missense mutations (MMs) and one was a splice site mutation. Patients with one or two SMs on their alleles had lower serum copper and ceruloplasmin and were younger when the first symptoms of the disease appeared, compared with individuals with two MMs. The effect of SMs on the WD phenotype was dose-dependent. It is concluded that mutations within ATP7B are very heterogeneous. Frameshift and nonsense mutations are associated with a severe phenotype of WD.
authors.affiliation: Institute of Psychiatry and Neurology, Second Department of Neurology, Warsaw, Poland. gromadz@ipin.edu.pl
authors.forename: G
authors.initials: G
authors.lastname: Gromadzka
authors.forename: H H-J
authors.initials: HH
authors.lastname: Schmidt
authors.forename: J
authors.initials: J
authors.lastname: Genschel
authors.forename: B
authors.initials: B
authors.lastname: Bochow
authors.forename: M
authors.initials: M
authors.lastname: Rodo
authors.forename: B
authors.initials: B
authors.lastname: Tarnacka
authors.forename: T
authors.initials: T
authors.lastname: Litwin
authors.forename: G
authors.initials: G
authors.lastname: Chabik
authors.forename: A
authors.initials: A
authors.lastname: Członkowska
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000367:Age Factors; D027682:Cation Transport Proteins / Q000235:genetics*; D002570:Ceruloplasmin / Q000378:metabolism; D018389:Codon, Nonsense / Q000235:genetics*; D003300:Copper / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D005838:Genotype; D006527:Hepatolenticular Degeneration / Q000235:genetics*; D006801:Humans; D008297:Male; D010641:Phenotype; D017422:Sequence Analysis, DNA
chemical_list: D027682:Cation Transport Proteins; D018389:Codon, Nonsense; D003300:Copper; D002570:Ceruloplasmin; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases