The Wilson disease gene, a copper transporting ATPase (Atp7b), is responsible for the sequestration of Cu into secretory vesicles, and this function is exhibited by the orthologous Ccc2p in the yeast.
Of particular interest was the observation that the patient's older sister, who carried the same ATP7B genotype and laboratory evidence for biochemical WD but was clinically asymptomatic, lacked the PRNP variant allele.
Taken together, our experiments revealed an unexpected role for TM1/TM2 in copper-regulated trafficking of ATP7B and defined a unique class of WD mutants that are transport-competent but trafficking-defective.
The authors conclude that patients can carry a heterozygous mutation of the ATP7B gene that is associated with hypoceruloplasminaemia and display no overt clinical hepatic and/or central nervous system manifestations of WD.
The aim of this study was to screen and detect mutations of the ATP7B gene in unrelated Turkish Wilson disease patients (n = 46) and control group (n = 52).
The most frequent ATP7B mutation was c.2333 G>T (p.Arg778Leu), followed by c.2975 C>T (p.Pro992Leu), which accounted for 63.6% of the WND mutated alleles.
We determined the genetic prevalence of Wilson's disease in the United Kingdom by sequencing the entire coding region and adjacent splice sites of ATP7B in 1000 control subjects.
The exons 8 and 14 of ATP7B gene were analyzed in 65 unrelated Wilson disease patients by Denaturing High Performance Liquid Chromatography, and samples with abnormal peak profile were selected for direct DNA sequencing.
We analyzed 28 variants of ATP7B from patients with Wilson disease that affected different functional domains; the gene products were expressed using the baculovirus expression system in Sf9 cells.
Detection of new mutations in the ATP7B gene in new populations increases our capability of molecular analysis that is essential for early diagnosis and treatment of WD.
To understand further the mechanisms regulating the intracellular dynamics of ATP7B, using multiple functional assays, we characterized the protein phenotypes of 10 engineered and Wilson disease-associated mutations in the ATP7B COOH terminus in polarized hepatic cells and fibroblasts.
We conclude that the structural stability of the N-domain rather than the loss of ATP binding plays a defining role in the ability of ATP7B to reach the trans-Golgi network, thus contributing to phenotypic variability in WD.
The presenting phenotype strongly affects the clinical outcome of WD, and is related to the ATP7B mutation type and location, providing an evidence for genotype-phenotype correlations in WD.
Furthermore, N41S, which is part of the signal we identified, is the first and only Wilson disease-causing missense mutation in residues 1-63 of ATP7B.
A total of 11 missense variants of ATP7B, originally identified in WND patients, were examined for their capacity to functionally complement a yeast mutant strain in which the yeast gene ortholog, CCC2, was disrupted.