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The molecular bases for variability in the presentation and clinical development of Wilson's disease

16th national competition for scientific and technical research

Rare diseases

Senior Researcher : Ignacio Vicente-Sandoval

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Research Centre or Institution : Centro de Biología Molecular "Severo Ochoa". CSIC-Universidad Autónoma de Madrid


Precise mutations have been described in the COOH domain of the hepatic transporter of Cu++ ATP7B, specifically in the transporter motifs DKXXLLL1456 and DRDEECQYI1465 which remove it from the trans-Golgi network. It was observed that while the D1450R mutation and mutations L1454A and L1455A cause the retention of ATP7B in the plasmatic membrane, mutation L14555 causes it to accumulate in the perinuclear recycling compartment, and that truncation by introducing a stop code in the codon corresponding to R1459 causes it to be retained in yet-to-be-identified post-Golgi vesicles. The aim is to use these mutations to characterise the compartments crossed by ATP7B in its transport from the Golgi to the plasmatic membrane, and also to find out how its delocalisation affects its Cu++ donor function in the Golgi apparatus. Mutation K1451E has also been found to prevent the exit of ATP7B from the compartment in which it is retained in the trans-Golgi network under basic conditions, and this may be of use in studying the mechanism by which it leaves the said compartment and how this is regulated. As part of the characterisation of the peak transport route of ATP7B, its retention is also being studied in the sub-peak compartment and in the tight junctions as a result of the inhibition of the BIG/ARF1 tandem that controls its exit from the Golgi. Research is also under way into how the transport of ATP7B to the biliary canaliculus is regulated by Cu++, and specifically the activating effect of Cu++ on the routes PI3K/PDK/AKT-TBC1D1-RabX/mTORC2 and LKB1/AMPK-TBC1D1/Rab X/mTORC2 is now being examined, together with how it affects this transport.

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