Wilson's Disease Research Today is a free monthly online journal that collates and summarizes the latest research about Wilson's Disease, including details on treatment, causes, symptoms, medication.

ATP7B copper-regulated traffic and association with the tight junctions: copper excretion into the bile.

Hernandez S, Tsuchiya Y, García-Ruiz JP, Lalioti V, Nielsen S, Cassio D, Sandoval IV

Centro de Biología Molecular Severo Ochoa, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Consejo Superior de Investigaciones Científicas, Madrid, Spain.

BACKGROUND & AIMS: The copper transporter ATP7B plays a central role in the elimination of excess copper by the liver into the bile, yet the site of its action remains controversial. The studies reported here examine the correspondence between the site of ATP7B action and distribution and the pathways of copper disposal by the liver. METHODS: Microscopy and cell fractionation studies of polarized Can 10 cells forming long-branched bile canaliculi have been used to study the cellular distribution of ATP7B. Copper excretion into the bile was studied in perfused rat liver. RESULTS: Copper excess provokes a massive download of the ATP7B retained in the trans-Golgi network into the bile canalicular membrane. Furthermore, a stable ATP7B pool is localized to the tight junctions that seal the bile canaliculi. The profile of Cu(64) excretion into the bile by isolated rat livers perfused under one-pass conditions provides evidence of copper excretion by 2 separate mechanisms, transcytosis across the hepatocyte and paracellular transport throughout the tight junctions. CONCLUSIONS: Whereas the ATP7B retained in the trans-Golgi-network is massively translocated to the bile canalicular membrane in response to increased copper levels, a pool of ATP7B associated with the tight junctions remains stable. In situ studies indicate that copper is excreted into the bile by 2 separate pathways. The results are discussed in the frame of the normal and impeded excretion of copper into the bile.

Published 8 April 2008 in Gastroenterology, 134(4): 1215-23.
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Articles on Wilson's Disease published 8 April 2008:

Hepatic cirrhosis, dystonia, polycythaemia and hypermanganesaemia-A new metabolic disorder.   J Inherit Metab Dis.

We report a new constellation of clinical features consisting of hypermanganesaemia, liver cirrhosis, an extrapyramidal motor disorder and polycythaemia in a 12 year-old girl born to consanguineous parents. Blood manganese levels were >3000 nmol/L (normal range <320 nmol/L) and MRI revealed signal abnormalities of the basal ganglia consistent with manganese deposition. An older brother with the same phenotype died at 18 years, suggesting a potentially lethal, autosomal recessive disease. ... [Abstract] [Full-text]

Articles on Wilson's Disease published 31 March 2008:

Delivery of the Cu-transporting ATPase ATP7B to the plasma membrane in Xenopus oocytes.   Biochim Biophys Acta, 1778(4): 896-906.

Cu-transporting ATPase ATP7B (Wilson disease protein) is essential for the maintenance of intracellular copper concentration. In hepatocytes, ATP7B is required for copper excretion, which is thought to occur via a transient delivery of the ATP7B- and copper-containing vesicles to the apical membrane. The currently available experimental systems do not allow analysis of ATP7B at the cell surface. Using epitope insertion, we identified an extracellular loop into which the HA-epitope can be ... [Abstract] [Full-text]

New Mutations in the Wilson Disease Gene, ATP7B: Implications for Molecular Testing.   Genet Test, 12(1): 139-45.

Wilson disease (WND), an autosomal recessive disorder of copper transport with a broad range of genotypic and phenotypic characteristics, results from mutations in the ATP7B gene. ATP7B encodes a copper transporting P-type ATPase involved in the transport of copper into the plasma protein ceruloplasmin, and for excretion of copper from the liver. Defects in ATP7B lead to copper storage in liver, brain and kidney. Mutation analysis was carried out on 300 WND patients of various origins, and new ... [Abstract] [Full-text]

Articles on Wilson's Disease published 17 March 2008:

Sequence variation in the ATP-binding domain of the Wilson disease transporter, ATP7B, affects copper transport in a yeast model system.   Hum Mutat, 29(4): 491-501.

ATP7B is a copper transporting P-type ATPase defective in the autosomal recessive copper storage disorder, Wilson disease (WND). Functional assessment of variants helps to distinguish normal from disease-causing variants and provides information on important amino acid residues. 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. ... [Abstract] [Full-text]

Articles on Wilson's Disease published 11 March 2008:

Frontal-Subcortical Dementias.   Neurologist, 14(2): 100-107.

Frontal-subcortical dementias are a heterogeneous group of disorders that share primary pathology in subcortical structure and a characteristic pattern of neuropsychologic impairment. Their clinical presentation is characterized by memory disorders, an impaired ability to manipulate acquired knowledge, important changes of personality (apathy, inertia, or depression), and slowed thought processes (or bradyphrenia). It also has marked frontal dysfunction. Classic frontal-subcortical dementias ... [Abstract] [Full-text]

Articles on Wilson's Disease published 5 March 2008:

Liver Ischemia and Ischemia-Reperfusion Induces and Trafficks the Multi-specific Metal Transporter Atp7b to Bile Duct Canaliculi: Possible Preferential Transport of Iron into Bile.   Biol Trace Elem Res, 122(1): 26-41.

Both Atp7b (Wilson disease gene) and Atp7a (Menkes disease gene) have been reported to be trafficked by copper. Atp7b is trafficked to the bile duct canaliculi and Atp7a to the plasma membrane. Whether or not liver ischemia or ischemia-reperfusion modulates Atp7b expression and trafficking has not been reported. In this study, we report for the first time that the multi-specific metal transporter Atp7b is significantly induced and trafficked by both liver ischemia alone and liver ... [Abstract] [Full-text]

Articles on Wilson's Disease published 29 February 2008:

Development of cell therapy strategies to overcome copper toxicity in the LEC rat model of Wilson disease.   Regen Med, 3(2): 165-73.

AIMS: Therapeutic replacement of organs with healthy cells requires disease-specific strategies. As copper toxicosis due to ATP7B deficiency in Wilson disease produces significant liver injury, disease-specific study of transplanted cell proliferation will offer insights into cell and gene therapy mechanisms. MATERIALS & METHODS: We used Long-Evans Cinnamon (LEC) rats to demonstrate the effects of liver preconditioning with radiation and ischemia reperfusion, followed by transplantation of ... [Abstract] [Full-text]

Articles on Wilson's Disease published 28 February 2008:

Neurologic complications of liver transplantation in pediatric patients with the hepatic form of Wilson's disease.   J Child Neurol, 23(3): 293-300.

The literature contains very little documentation on neurologic complications in liver transplant recipients for Wilson's disease. We retrospectively reviewed 17 consecutive cases of pediatric liver transplantation for the hepatic form of Wilson's disease to assess the types of neurologic complications that occurred, the incidence of those problems, and associated factors in this patient group. The patients were 12 boys and 5 girls; indications for liver transplantation were fulminant hepatic ... [Abstract] [Full-text]

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