DR. ROY A. GRAVEL

B.Sc., M.Sc. (McGill), M.Phil., Ph.D. (Yale) Professor, Department  Biochemistry & Molecular Biology with a Cross Appointment in the Faculty of Kinesiology.

Affiliations: Member - Neuroscience Research Group.

Research Interests:

Vitamin B12 is an essential nutrient in humans, but it must be metabolized through many steps in order for it to function as a cofactor in cells. At least eight genetically distinct diseases are known that affect newborns or young children in which the metabolism of the vitamin is blocked. Our goal has been to identify the genes and biochemical steps involved in vitamin B12 metabolism and to develop tools for the diagnosis, prevention and treatment of B12 disorders. Our current studies include genetic and biochemical investigations of several genes involved in vitamin B12 metabolism in order to determine the function of these genes and how mutations result in failed utlization of the vitamin. We are also investigating mouse models of a defect in one of the vitamin B12 genes in order to determine the involvement of this gene in metabolism and in the risk of birth defects. Our experiments are leading to an explanation for how low nutrient folate/B12 intake in mothers increases the risk of having babies with spina bifida. We are also opening a new area of vitamin B12 research using the nematode, C. elegans (microscopic worm), and D. discoideum (a slime mold) as models in the effort to identify the remaining genes and metabolic steps in B12 metabolism. We are making use of these organisms because, in both cases, their genomes have been sequenced and their DNA sequences reveal the presence of human-like vitamin B12 pathway genes. Because these organisms have similar metabolism and cellular structures as human cells, we anticipate that B12 genes found in these organisms will lead us to similar genes in humans. The opportunity to probe the genomes of lower organisms as tools for understanding human biology is an important legacy of genome science.

In a second area of research, Tay-Sachs and Sandhoff diseases are devastating neurodegenerative diseases which can be fatal in early childhood or cause debilitating, chronic disease in milder forms. Unlike humans, mouse models of Tay-Sachs disease, with a complete knockout of the affected gene (Hexa), have only a mild disease similar to the chronic human disease. This is due to the presence of a sialidase-dependent alternative metabolism which partially avoids the metabolic block caused by the Hexa defect.  Humans have a similar sialidase bypass but it is of very low activity and inadequate to protect agains disease in Tay-Sachs patients. Our goal is to chemically induce the sialidase bypass in humans, resulting in a sparing of disease in affected patients. Our studies focus on human cell culture studies to characterize the elements of the bypass pathway and to evaluate the impact of inducing agents. We use mouse models to investigate the mechanism of disease and the behavior of the bypass pathway in the nervous system.

Personnel:

View Pub Med for Recent publications & abstract

Recent Publications: 

•  Zhang J, Wu X, Padovani D, Schubert HL, Gravel RA. (2009, Nov) Ligand-binding by catalytically inactive mutants of the cblB complemenattion group defective in human ATP:cob(I)alamin adenosyltransferase. Mol Genet Metab 98:278-284.
•  Froese DS, Zhang J, Healy S, Gravel RA. (2009, Dec) Mechanism of vitamin B₁₂-responsiveness in cblC methylmalonic aciduria with homocystinuria. Mol Genet Metab, 98:338-343
•  Healy S, Perez-Cadahia B, Jia D, McDonald M, Davie JR, Gravel RA (2009, Nov) Biotin is not a natural histone modification. Biochim Biophys Acta, 1789:719-733
•  Froese DS, Healy S, McDonald M, Kochan G, Oppermann U, Niesen FH, Gravel RA. (2010, May) Thermolability of mutant MMACHC protein in the vitamin B₁₂-responsive cblC disorder. Mol Genet Metab 100:29-36
•  Healy S, McDonald MK, Wu X, Yue WW, Kochan G, Oppermann U, Gravel RA (2010, June) Structural impact of human and Escherichia coli biotin carboxyl carrier proteins on biotin attachment. Biochemistry 49:4687-4694
• Lerner-Ellis JP, Tirone JC, Pawelek PD, Dore C, Atkinson JL, Watkins D, Morel CF, Fujiwara TM, Moras E, Hosack AR, Dunbar GV, Antonicka H, Forgetta V, Dobson CM, Leclerc D, Gravel RA, Shoubridge EA, Coulton JW, Lepage P, Rommens JM, Morgan K, Rosenblatt DS (2006) Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. Nat Genet 38:93-100 (Erratum: Nat Genet 38:957, 2006)
• Zhang J, Dobson CM, Wu X, Lerner-Ellis J, Rosenblatt DS, Gravel RA (2006) Impact of cblB mutations on the function of ATP:cob(I)alamin adenosyltransferase in disorders of Vitamin B12 metabolism. Molec Genet Metab 87:315-322
• Lerner-Ellis JP, Gradinger AB, Watkins D, Tirone JC, Villeneuve A, Dobson M, Montpetit A, Lepage P, Gravel RA, Rosenblatt DS. (2006) Mutation and biochemical analysis of patients belonging to the cblB complementation class of vitamin B12-dependent methylmalonic aciduria. Molec Genet Metab, 87:219-225
• Dobson CM, Gradinger A, Longo N, Wu X, Leclerc D, Lerner-Ellis J, Lemieux M, Belair C, Watkins D, Rosenblatt DS, Gravel RA. (2006) Homozygous nonsense mutation in the MCEE gene and siRNA suppression of methylmalonyl-CoA epimerase expression: A novel cause of mild methylmalonic aciduria. Mol Genet Metab 88:327-333
• Yamada K, Gravel RA, Toraya T, Matthews RG. (2006) Human methionine synthase reductase is a molecular chaperone for human methionine synthase. Proc Natl Acad Sci, USA 103:9476-9481
• Bifsha P, Landry K, Ashmarina L, Durand S, Seyrantepe V, Trudel S, Quiniou C, Chemtob S, Xu Y, Gravel RA, Sladek R, Pshezhetsky AV. Altered gene expression in cells from patients with lysosomal storage disorders suggests impairment of the ubiquitin pathway. Cell Death Differ Epub, Aug 4, 2006

Contact Information:

The University of Calgary,
250 Heritage Medical Research Building,
3330 Hospital Drive NW, Calgary, Alberta
Canada T2N 4N1.
Phone: (403) 220-3063
Fax: (403) 210-8115
E-mail: rgravel [at] ucalgary [dot] ca.