Research Network for Metals in Medicine

 

 

Professor Julian Mercer

Position: Head, Centre for Cell & Molecular Biology

Affiliation: School of Biological & Chemical Sciences, Deakin University

Postal Address:
School of Biological and Chemical Sciences
221 Burwood Highway
Burwood Victoria, 3125
AUSTRALIA

Phone: +61 (03) 9251 7329
Email: jmercer@deakin.edu.au
Webpage: http://www.genetics.unimelb.edu.au/Person/JuM.html


Research Profile

My research centres around the molecular analysis of the genetic defects of copper transport. My group has been investigating the genetic basis of the X-linked copper deficiency disorder, Menkes disease. In 1993 in collaboration with Dr Tom Gloverís group (Michigan), we reported the isolation of the gene by positional cloning [Nature Genetics 3: 20-25, 1993]. This breakthrough has opened the way to analysis of the gene structure [Genomics 28: 462-469 (1995)], and investigation of mutations in the mouse models of this disease [Nature Genetics 6: 374-378 (1994)]. In collaboration with Dr Jim Camakarisís group (University of Melbourne) we discovered that the cells become copper resistant by amplification of the Menkes gene due to an enhanced ability to efflux copper, the first clear evidence that the Menkes protein (MNK or ATP7A) is involved in pumping copper out of the cell. Current research involves investigation of the mechanism by which copper affects the intracellular location of the Menkes protein. When cells are exposed to copper the protein relocalises to the plasma membrane thus enabling the efflux of this potentially toxic metal ion. Thus our research is moving into the cell biological mechanisms related to the regulation of protein trafficking, the effect of mutations on this process and the relationship between mutations and disease phenotypes.

We are also investigating the closely related protein which is affected in the genetic copper toxicosis condition, Wilson disease. We are primarily studying a mouse model of this condition, the toxic milk mouse. We have determined the mutation in the mouse homologue of the protein product of the Wilson gene, WND (or ATP7B)and have engineered this mutation in a cDNA construct to study the effect of the mutation on the activity of WND. We are currently using cultured hepatoma cells to investigate the trafficking of WND in a polarized cell. The toxic milk mouse is being used to develop more effective strategies for treatment of Wilson disease, including possible gene therapy, in collaboration with the Gene Therapy unit at the Murdoch Institute (Royal Childrenís Hospital).



Selected Publications

  1. J.F.B. Mercer, J. Livingston, B. Hall, J.A. Paynter, C. Begy, S. Chandrasekharappa, P. Lockhart, A. Grimes, M. Bhave, D. Siemieniak, and T.W. Glover Isolation of a partial candidate gene for Menkes disease by positional cloning. Nature Genetics 3, 20-25 (1993)
  2. M. Theophilos, D.W. Cox and J.F.B Mercer The toxic milk mouse is a murine model of Wilson disease. Human Molecular Genetics 5, 1619-1624 (1996)
  3. M. Petris, J.F.B. Mercer, J.G. Culvenor, P. Lockhart, P.A. Gleeson and J. Camakaris Ligand-regulated transport of the Menkes copper P-type ATPase efflux pump from the Golgi apparatus to the plasma membrane: A novel mechanism of regulated trafficking. EMBO J 15, 6084-6095 (1996)
  4. A. Grimes, C. Hearn, P. Lockhart, D. Newgreen and J.F.B. Mercer Molecular basis of the brindled mouse mutant (Mobr): a murine model of Menkes disease. Human Molecular Genetics 6, 1032-1042 (1997)
  5. D. Strausak, S. La Fontaine, J. Hill, S. D. Firth, P. J. Lockhart and J.F. B. Mercer The Role of GMxCxxC Metal Binding Sites in the Copper-induced Redistribution of the Menkes Protein (MNK or ATP7A). J. Biol. Chem. 274, 11170-11177 (1999).
  6. J.F.B. Mercer The Molecular Basis of Copper transport Diseases. Trends in Molecular Medicine 7, 64-69 (2001)
  7. J.F.B. Mercer, N. Barnes, J. Stevenson, D. Strausak and R. M. Llanos Copper-induced trafficking of the Cu-ATPases: A key mechanism for copper homeostasis. Biometals 16, 175-184 (2003)
  8. D. Strausak, S.D. Firth, M. Howie, A. Schlicksupp, G. Multhaup and J.F.B. Mercer Kinetic analysis of the interaction of the copper chaperone Atox1 with the metal-binding sites of the Menkes protein. J. Biol. Chem. 278, 20821-20827 (2003).
  9. D. Strausak, S.D. Firth, M. Howie, A. Schlicksupp, G. Multhaup and J.F.B. Mercer Kinetic analysis of the interaction of the copper chaperone Atox1 with the metal-binding sites of the Menkes protein. J. Biol. Chem. 278, 20821-20827 (2003).

Facilities

  • Varian GTA100 Atomic absorption spectrometer
  • fluorescent microscope
  • Leica confocal microscope
  • Extensive tissue culture facility
  • phosphoimager
  • various centrifuges including an ultracentrifuge

International Linkages

Prof Marc Solioz, Berne, Switzerland
Prof Diane Cox, University of Alberta Canada
Prof. Arturo Leone, University of Salerno, Italy