Background: Cytoplasmic chaperones deliver Cu ϩ to P 1B -ATPases for outward transport.
Wilson disease (WD) is an autosomal-recessive disorder caused by mutations in the copper (cu)transporter ATP7B. Thus far, studies of WD mutations have been limited to analysis of ATP7B mutants in the homozygous states. However, the majority of WD patients are compound-heterozygous, and how different mutations on two alleles impact ATP7B properties is unclear. We characterized five mutations identified in Indian WD patients, first by expressing each alone and then by co-expressing two mutants with dissimilar properties. Mutations located in the regulatory domains of ATP7B-A595T, S1362A, and S1426I-do not affect ATP7B targeting to the trans-Golgi network (TGN) but reduce its Cu-transport activity. The S1362A mutation also inhibits Cu-dependent trafficking from the TGN. The G1061E and G1101R mutations, which are located within the ATP-binding domain, cause ATP7B retention in the endoplasmic reticulum, inhibit Cu-transport, and lower ATP7B protein abundance. Co-expression of the A595T and G1061E mutations, which mimics the compoundheterozygous state of some WD patients, revealed an interaction between these mutants that altered their intracellular localization and trafficking under both low and high Cu conditions. These findings highlight the need to study WD variants in both the homozygous and compound-heterozygous states to better understand the genotype-phenotype correlations and incomplete penetrance observed in WD. Copper (Cu) is a redox-active metal that is indispensable for human growth and development. Cu is required for the activity of several enzymes, including cytochrome c oxidase, Cu/Zn-dependent superoxide dismutases, tyrosinase, dopamine-β-hydroxylase, ceruloplasmin, and peptidyl-α-monooxygenase 1. In order to ensure an adequate supply of Cu without toxic accumulation, Cu homeostatic mechanisms are tightly regulated. Either Cu deficiency or overabundance is associated with pathologic changes and disease, such as, Menkes disease or Wilson disease (WD), respectively 2,3. WD is a genetic disorder caused by mutations in the Cu-transporter ATP7B that causes abnormal deposition of Cu in the liver and the brain 4. WD has a spectrum of hepatic and neurological manifestations, along with a broad range of disease onsets 5. The mechanisms behind this variability remain poorly understood. Studies of WD patients identified over 600 ATP7B mutations 6 and revealed the diverse effects of mutations on the functional and cellular properties of the ATP7B protein. Efforts to link different phenotypic presentations of WD to specific ATP7B mutations have not produced strong correlations and have sometimes led to conflicting results 7. High prevalence of compound-heterozygous mutations further complicates the task of genotype-phenotype correlation 8 .
Two single nucleotide polymorphisms in Cu-transporter ATP7B alter protein properties and copper status in humans.
We describe a family with recurrent 11q23-qter deletion Jacobsen syndrome in two affected brothers, with unique mosaic deletion 'rescue' through development of uniparental disomy (UPD) in the mother and one of the brothers. Inheritance studies show that the deleted chromosome is of maternal origin in both boys, and microarray shows a break near the ASAM gene. Parental lymphocyte chromosomes were normal. However, the mother is homozygous in lymphocytes for all loci within the deleted region in her sons, and presumably has UPD for this region. In addition, she is mosaic for the 11q deletion seen in her sons at a level of 20-30% in skin fibroblasts. We hypothesize that one of her #11 chromosomes shows fragility, that breakage at 11q23 occurred with telomeric loss in some cells, but 'rescue' from the deletion occurred in most cells by the development of mitotic UPD. She apparently carries the 11q deletion in her germ line resulting in recurrence of the syndrome. The older son is mosaic for the 11q cell line (70-88%, remainder 46,XY), and segmental UPD11 'rescue' apparently also occurred in his cytogenetically normal cells. This is a novel phenomenon restoring disomy to an individual with a chromosomal deletion.
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