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.

Clinical presentation and mutations in Danish patients with Wilson disease

“…Merle et al 11 found that patients with two severe truncating mutations had an onset at 13 years with an interquartile range of 9-13 years, whereas patients with two missense mutations had an onset at 22 years with an interquartile range of 14-27 years. Similar results were published by Gromadzka et al, 38 who reported that in the presence of two severe truncating mutations the age of onset was 14 ± 7 years, while in the presence of two missense mutations the age of onset was 29 ± 9 years. They reported an intermediate age of onset in the presence of one missense mutation and one severe truncating mutation (25±9 years).…”

“…They reported an intermediate age of onset in the presence of one missense mutation and one severe truncating mutation (25±9 years). 38 Interestingly, we found that the p.Q1351X mutation in our material could be classified as moderate with late onset, although it leads to a termination of the protein. Truncating mutations associated with relatively late onset has also been described with p.C271X (age of onset 17-19 years) 39 and p.S932X (age of onset 24 years).…”

Identification of a novel Wilson disease gene mutation frequent in Upper Austria: a genetic and clinical study

“…19 Patients carrying the R816S(c.2448G4T) mutation had about the same mean age at presentation than p.H1069Q(c.3207C4A) homozygotes (hepatic: 16.3 years; neurological: 23.6 years), with a higher frequency of hepatic presentation. In contrast, patients with truncating 20 or frameshift mutations 21 are associated with early onset of hepatic disease. Thus, like p.H1069Q(c.3207C4A), the R816S(c.2448G4T) mutation might be considered as a 'mild' mutation, although the number of patients is too low to draw firm conclusions.…”

Re-evaluation of the diagnostic criteria for Wilson disease in children with mild liver disease

“…[20][21][22][23] Furthermore, as reported elsewhere, ceruloplasmin serum levels are also influenced by the ATP7B genotype. 24,25 As for basal daily urinary copper excretion, on the basis of our results, the diagnosis of WD should be considered when this test produces a value > 40 lg/ 24 hours. This cutoff value has also been recently stressed by AASLD guidelines, 2 although its diagnostic Male 60 Neg 121 25 24 1666 ND -NRH ND 2 2 NRH Male 156 Neg 100 23 7 104 ND -NRH ND 0 0 NRH Male 192 Neg 90 22 20 1165 ND -NRH ND 2 2 The WD scores were calculated under the assumption of urinary copper ULNs of **40 and †100 lg/24 hours.…”