Identification and Analysis of Mutations in the Wilson Disease Gene (ATP7B): Population Frequencies, Genotype-Phenotype Correlation, and Functional Analyses

Abstract

Wilson disease (WD) is an autosomal recessive disorder characterized by toxic accumulation of copper in the liver and subsequently in the brain and other organs. On the basis of sequence homology to known genes, the WD gene (ATP7B) appears to be a copper-transporting P-type ATPase. A search for ATP7B mutations in WD patients from five population samples, including 109 North American patients, revealed 27 distinct mutations, 18 of which are novel. A composite of published findings shows missense mutations in all exons-except in exons 1-5, which encode the six copper-binding motifs, and in exon 21, which spans the carboxy-terminus and the poly(A) tail. Over one-half of all WD mutations occur only rarely in any population sample. A splice-site mutation in exon 12 accounts for 3% of the WD mutations in our sample and produces an in-frame, 39-bp insertion in mRNA of patients homozygous, but not heterozygous, for the mutation. The most common WD mutation (His1069Glu) was represented in approximately 38% of all the WD chromosomes from the North American, Russian, and Swedish samples. In several population cohorts, this mutation deviated from Hardy-Weinberg equilibrium, with an overrepresentation of homozygotes. We did not find a significant correlation between His1069Glu homozygosity and several clinical indices, including age of onset, clinical manifestation, ceruloplasmin activity, hepatic copper levels, and the presence of Kayser-Fleischer rings. Finally, lymphoblast cell lines from individuals homozygous for His1069Glu and 4 other mutations all demonstrated significantly decreased copper-stimulated ATPase activity.

Wilson's disease in Southern Brazil: genotype-phenotype correlation and description of two novel mutations in ATP7B gene

“…These findings confirm previous data on correlation of the c.3207C>A mutation and the disease onset 11,17 . On the other hand, we could not detect an association of the c.3207C>A mutation with predominantly neurological manifestations, as described by Caca et al…”

“…As determined for other countries such as India 15 , China 16 , and USA 17 , the regional distribution of the WD mutations is important to be studied since these countries have a highly mixed population with diverse patterns of immigration.…”

“…Other groups also failed to demonstrate this correlation 17,18 . The lack of consensus in the literature regarding this issue could be explained by the observations that clinical manifestations of WD are heterogeneous even in patients carrying the same mutation.…”

“…The lack of consensus in the literature regarding this issue could be explained by the observations that clinical manifestations of WD are heterogeneous even in patients carrying the same mutation. It is, therefore, hypothesized that other additional genetic and/or environmental factors could influence the phenotypes of WD, such as dietary cooper intake, metallothionein inducibility, the individual capacity to handle copper overload, the ApoE genotype, human prion gene polymorphism and mutations in COMMD1 6,17,[19][20][21][22] .…”

Estimate of the frequency of Wilson's disease in the US Caucasian population: a mutation analysis approach

“…There are over 170 mutations characterized in this gene which cripple the gene enough to produce Wilson's disease (Cox & Roberts, 2001). In the US Caucasian population, a His Gln mutation at position 1069 accounts for approximately one-third of the causative mutations, but after that, the frequency of any single mutation is quite small (Thomas et al 1991 ;Tanzi et al 1993 ;Shah et al 1997).…”