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B.H. Robinson
Professor
Ph.D., Bristol, 1968 |
Hospital for Sick
Children, Research Institute, Room 9146C
416-813-5989
bhr@sickkids.on.ca |
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Inborn Error in Man: Chronic
Childhood Lacticacidemia
Research Synopsis
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Major Research Activities
- Investigation of active site mechanisms in pyruvate
carboxylase and the pyruvate dehydrogenase complex
by site-directed mutagenesis.
- Definition of mtDNA-based diseases, particularly
cardiomyopathies and Leigh disease.
- Analysis of NADH-CoQ reductase deficiency in relation
to the genes of the nuclear-encoded subunits.
- Genetic etiology of cytochrome oxidase deficiency.
- Site and control of oxygen free-radical production
within the mitochondrial respiratory chain.
- Role of oxygen free-radicals in the mechanism
of apoptosis in cardiac failure.
- Role of mitochondria and release of cytochrome
c in the instigation of apoptosis.
Future Research
- Genetic variation in ability to detoxify oxygen-free
radicals, (superoxide dismutase).
- Mitochondrial proliferation mechanisms.
- Therapy for mitochondrial diseases by gene manipulation.
Present Approach
We have a series of cell lines that respond to oxygen
free-radical production by expressing either MnSOD (manganese
superoxide dismutase), the bcl-2 protein or both. These
proteins are located in the mitochondrial matrix and on
the outer mitochondrial membrane respectively, and both
can help the cell in its defence against oxygen free-radicals.
Both are induced in heart under varying conditions of
stress and growing evidence indicates that they are important
cardiac defence mechanisms.
We are using the Differential Display technique to identify
genes activated by the presence of oxygen free-radicals.
In addition we are looking for the site that controls
the onset and rate of free-radical production in response
to cytokines. Thus the inflammatory process may be linked
to cell death through induction of oxygen free-radical
production. This may have implications in heart failure,
viral infections, burns and other injuries.
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Selected Publications
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Castagna, A.E., Addis, J., McInnes, R.R., Clarke, J.T.R., Ashby, P., Blaser, S. and ROBINSON, B.H.: Late Onset Leigh Syndrome and Cerebellar Ataxia Due to a T to C Mutation
at bp 9,185 of Mitochondrial DNA. Am. J. Med. Genet. A. 143(8):808-816, 2007.
Debray,
F.-G., Mitchell, G.A., Allard, P., ROBINSON, B.H., Hanley, J.A. and Lambert, M.:
Diagnostic Accuracy of Blood Lactate-to-Pyruvate Molar Ratio in the Differential
Diagnosis of Congenital Lactic Acidosis. Clin. Chem. 53(5):916-921, 2007.
Debray, F.-G., Lambert, M., Chevalier, I., Robitaille, Y., Decarie, J.-C., Shoubridge,
E.A., ROBINSON, B.H., and Mitchell, G.A.: Long-Term Outcome and Clinical Spectrum of 73
Pediatric Patients with Mitochondrial Diseases. Pediatrics, 119(4):722-733, 2007.
Pettman, R., Hurley, T., Addis, J., ROBINSON, B., Scott, H., and Kronick, J.B.:
Prenatal Diagnosis by Amniocentesis and Chorionic Villus Biopsy of mtDNA Mutation
8993T>G. J. Inherit. Metab. Dis. Online, 2007.
MacKay, N. and ROBINSON, B.H.: Measurement of the Ratio of Lactate to Pyruvate in
Skin Fibroblast Cultures. In: Methods in Cell Biology, Mitochondria. Eds L.A. Pon, E.A.
Schon. Academic Press, New York. 80:173-178, 2007.
Cameron, J.M., Maj, M.C., Levandovskiy, V., MacKay, N., Shelton, G.D. and ROBINSON,
B.H.: Identification of a Canine Model of Pyruvate Dehydrogenase Phosphatase 1
Deficiency. Mol. Genet. Metab. 90(1):15-23, 2007.
Cameron, J.M., Maj, M.C. and ROBINSON, B.H.: Deficiency Disorders of Components of
the PDH Complex: E2, E3 and E3BP Deficiencies. In: Alpha Lipoic Acid: Energy
Production, Antioxidant Activity and Health Effects. Eds. M.S. Patel, L. Packer. CRC
Press, 375-405, 2007.
Debray, F.-G., Lambert, M., Gagne, R., Maranda, B., Laframboise,
R., MacKay, N., ROBINSON, B.H. and Mitchell, G.A.: Pyruvate Dehydrogenase Deficiency
Presenting as Intermittent Isolated Acute Ataxia. Neuropediatrics 39:1-4, 2008.
Roberts, E.A., ROBINSON, B.H. and Yang, S.: Mitochondrial Structure and Function in
the Untreated Jackson Toxic Milk (tx-j) Mouse, a Model for Wilson Disease. Mol. Genet.
Metab. 93(1):54-65, 2008.
Xu, F., Ackerley, C., Maj, M., Addis, J.B.L., Levandovskiy, V., Lee, J., MacKay, N.,
Cameron, J.M. and ROBINSON, B.H.: Disruption of a Mitochondrial RNA-Binding Protein Gene
Results in Decreased Cytochrome b Expression and a Marked Reduction in
Ubiquinol-Cytochrome c Reductase Activity in Mouse Heart Mitochondria. Biochem. J.
416:15-26, 2008.
Tam, E.W.Y., Feigenbaum, A., Addis, J.B.L., Blaser, S., MacKay, N., Al-Dosary, M.,
Taylor, R.W., Ackerley, C., Cameron, J.M. and ROBINSON, B.H.: A Novel Mitochondrial DNA
Mutation in COX1 Leads to Strokes, Seizures and Lactic Acidosis. Accepted for
publication in Neuropediatrics, 40, 1-7. 2009.
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