Diane W. Cox

Genes involved in transport of copper; inherited liver disease; serpin gene cluster on chromosome 14; brain development genes on chr.14, schizophrenia

Heavy metals are important environmental pollutants, and our studies will lead to an increased knowledge of heavy metal transport in humans, as well as other organisms. Our focus is currently on copper. In 1993, we cloned the gene for Wilson disease, a disorder in which copper transport from the body is impaired. This results in damage to the liver and brain. We have identified a number of specific mutations in the gene in order to identify those amino acids important for gene function. Our functional assays in yeast and in cultured cells identify which amino acids are critical for the transport function and for intracellular trafficking of the protein. We are examining the interactions of similar heavy metals on copper transport. We are also studying the control of gene expression, expression during development, and animal models. Bedlington copper toxicosis has led to study of the MURR1 gene. We currently have a project under way to identify genetic modifiers that influence clinical variability in Wilson disease.

Alpha1-antitrypsin (AAT) deficiency is associated with liver disease and obstructive lung disease. We are studying the organization, function and genetic variation of the serine protease inhibitor (serpin) cluster on human chr.14, which includes AAT and newly identified genes. We currently have a project under way to identify genetic modifiers that influence clinical variability in AAT deficiency.

Long-standing interest in gene mapping on chr.14 has led to studies of genes involved in brain/facial defects, particularly holoprosencephaly. Candidate genes are being studied in zebra fish and mouse models. Recently, we discovered a gene, NPAS3, involved in schizophrenia. How many patients will be found to have mutations in this gene? We hope to find out. We also study rings and deletions, particularly the cause of seizures in some of these patients.

Patients are needed for our WND schizophrenia AAT deficiency projects, chr.14 ring and deletion studies; and diane.cox@ualberta.ca

Resources:
Wilson Disease Database


Information on Wilson disease


Mutation and Haplotyp Analysis for Wilson Disease


TAGC: The Applied Genomics Centre

Positions Available
Postdoctoral fellow position. A position is available for a recent (< 3 years) PhD graduate in the laboratory of Diane W. Cox, Department of Medical Genetics. The project involves using yeast, other model organisms and mammalian cells to study the role of selected copper transport proteins, including interactions with other proteins and cellular localization. Structure function relations are examined through the use of mutant proteins.
Graduate student position. A position is available for a graduate student seeking an MSc degree. Candidates should have a BSc in genetics, Biochemistry, Cell Biology, or a related discipline. The position is available immediately. The project involves the use of yeast as a model system, to study effects of various mutations in the gene ATP7B, as found in patients with Wilson disease.
Positions are sometimes available for BioSci499 and summer projects

Wilson Disease
Bull P, Thomas GR, Forbes J., Rommens, JM. and Cox DW. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes disease gene. Nature Genet. 5:327-337, 1993.

Thomas GR, Forbes JR, Roberts EA., Walshe JM. and Cox DW. The Wilson disease gene: spectrum of mutations and their consequences. Nature Genet. 9:210-217, 1995.

Forbes JR and Cox DW.. Functional characterization of missense mutations in ATP7B: Wilson disease mutation or normal variant?. Am. J. Hum. Genet. 63: 6 1663-74. 1998.

Forbes JR and Cox DW. Copper-dependent trafficking of Wilson disease mutant ATP7B proteins. Hum. Mol. Genet. 9:1927-1935, 2000.

Coronado V, Nanji MS, Cox DW. The Jackson toxic milk mouse as a model for copper loading. Mamm. Genome 12: 793-795, 2001

Moore DP, Cox DW. Expression in mouse kidney of membrane copper transporters Atp7a and Atp7b. Nephron 92:629-634, 2002.

Coronado VA., Damaraju, D, Kohijoki, R., Cox, D W. New haplotypes in the Bedlington terrier indicate complexity in copper toxicosis. Mamm. Genome 14:483-491, 2003.

Hsi G, Cullen LM, Glerum D. Functional assessment of the carboxy terminus of the Wilson disease copper transporting ATPase, ATP7B Genomics 83: 473-481, 2004.

Hsi G and Cox DW. A comparison of mutation spectra of Menkes diseae and Wilson disease Hum.Mut. 114: 165-172, 2004.

Macintyre, G., Gutfreund, K., Martin, W., Camicioli, R., Cox, D.W. Value of an enzymatic assay for the determination of serum ceruloplasmin assay. J. Lab. Clin. Med. 144: 294-301, 2004.

Cox DW, Prat L, Walshe JM, Heathcote J, Gaffney D. Twenty-four new mutations in Wilson disease patients of predominantly European origin. Hum. Mutation 26:280-286, 2005.

Coronado VA, Bonneville JA, Nazer H, Roberts EA, Cox DW. COMMD1 (MURRI) as a candidate in patients with copper storage disease of undefined etiology Clin. Genet 68;548-51, 2005

Chromosome 14
Kamnasaran D, O'Brien P, Ferguson-Smith MA, Cox DW. Comparative mapping of human chromosome region 14q11.2-q13 with mouse syntenic chromosomes Mamm. Genome 11:993-999,2000.

Kamnasaran D, O'Brien P., Schuffenhauer S., Quarrell O., Lupski J.R., Grammatico P., Ferguson-Smith M, Cox DW. Defining the breakpoints of proximal chromosome 14q rearrangements in nine patients, using flow sorted chromosomes. Am.J.Med.Genet 102: 173-83, 2001.

Kamnasaran D, Muir WJ., Ferguson-Smith MA, Cox DW. Disruption of the neuronal PAS3 gene in a family affected with schizophrenia J. Med. Genet. 40: 325-332, 2003.

Kamnasaran, D.,Chen, C-P, Devriendt, K.,Mehta, L.,Cox, D. W. Defining a holoprosencephaly locus on human chromosome 14q13 Genomics In press 2005.

Schlade-Bartusiak K, Costa T, Summers AM, Nowaczyk MJM, Cox DW. FISH-mapping of telomeric 14q32 deletions: search for the cause of seizures AM. J. Med. Genet. A. 138:218-228, 2005

Book Chapters:
Cox, D.W. 1-antitrypsin deficiency. In: The Metabolic and Molecular Bases of Inherited Disease, vol. III. 8th edition, C.R. Scriver, A.L. Beaudet, W.S. Sly, D. Valle (eds.), McGraw-Hill, New York, pp 5559-5586,2001.

Cox, D. W. and Roberts, E. A. Wilson Disease. In: Sleisenger and Fordtrans Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. Vol 2, 7th edition. M. Feldman, B. Scharschmidt and M.H. Sleisenger (eds.), Philadelphia: W. B. Saunders, 67: 1269-77, 2002.

Other sites of interest and recent awards:
June 1999 Mentor of the Month

2001: Woman of the year: U. Alberta Academic Women's Association
2002: Queen's Golden Jubilee Medal
2004: Fellow, The Royal Society of Canada

Wilson Disease Database

Information on Wilson disease