Annual Report 1998/1999
Annual Report 1998/1999
The Hess B. and Diane Finestone Laboratory in Memory of Jacob and Jenny Finestone was established to promote the field of medical genetics at McGill University. Dr. David S. Rosenblatt has been the director of the Laboratory since its inception. The laboratory was established with the help of a million-dollar endowment to McGill and is housed on the fifth floor of the Hershey Pavilion of the Royal Victoria Hospital. Funding from the Finestone Laboratory is used to advance the academic goals of the Division of Medical Genetics in the Department of Medicine of the McGill University Health Centre (MUHC). This report is also available on the Internet (http://www.mcgill.ca/finestone/).
Dr. Tom Hudson has been successful, along with colleagues at McGill and the Centre Hospitalier de lUniversité de Montréal in obtaining a major infrastructure award from CFI and the FRSQ to expand the facilities at the Montreal General Hospital to become the Montreal Genome Centre. This centre was awarded $8.25 million in order to provide technological support to the Montreal community.
Dr. David Rosenblatt and his colleagues in the Medical Research Council of Canada Genetics Group identified additional mutations in patients with inborn errors of vitamin B12 metabolism due to defects in either the enzyme methionine synthase (cblG) or methionine synthase reductase (cblE). This progress was made possible by their previous success in cloning the genes responsible for these diseases. The identification of specific mutations in patients with these diseases allows for the identification of heterozygotes (carriers) within their families.
Genetic counselling and molecular testing for women with a family history of breast cancer has been expanded in both the French Canadian and the Ashkenazi Jewish populations. Lidia Kasprzak, M.Sc., and Karlene Australie, MS, are the devoted genetic counsellors involved with this program and Dr. William Foulkes has provided the clinical expertise. The structure of activity within the Division of Medical Genetics allows for the rapid transfer of clinically relevant laboratory findings by Dr. Patricia Tonin into the clinical laboratory. Maria Galvez has established reliable methods for the detection of common mutations in the BRCA1 and BRCA2 genes in Ashekanzi Jewish and French Canadian women. Dr. Brian Gilfix supervises molecular testing for a1-antitrypsin, hereditary hemochromatosis, apolipoprotein E, cytochrome P450 2D6, Factor V Leiden, and prothrombin 20210G®A. Suzanne Dufrasne, MPS., is the clinical psychologist who has provided stability to the ongoing program in predictive testing for Huntington Disease. She also participated in a multi-centre study that examined the suicide risk for individuals who have undergone such testing.
Dr. Gordon Gowans completed his second year in the clinical training program in Medical Genetics at McGill. He had previously been a Pediatric Resident for three years at Louisiana State University. Dr. Pierre Chappuis, who is a trained oncologist from Switzerland, came to be a research fellow with Dr. Foulkes in the area of hereditary cancer. Rikke Nielsen, a graduate student from the University of Aarthus in Denmark, spent three months in the Laboratory in order to study cobalamin metabolism in cultured kidney cells. As in previous years, independent studies students, summer students, graduate students and postdoctoral fellows were involved in the many ongoing projects of the different investigators.
Honours and Awards:
Dr. William Foulkes was a recipient of The Montreal General Hospital 175th Anniversary Award and Dr. Patricia Tonin was awarded The Stewart Award. Dr. Foulkes received the highest ranking in Quebec in the FRSQ Chercheur Boursier Clinicien II competition.
Dr. Guy Rouleau was appointed to the Graham Boech Chair in Schizophrenia Research at McGill University.
Dr. Thomas Hudson was the recipient of a Canada Top 40 Under 40 award, given out by the Caldwell Partners for his vision, leadership and innovative achievements.
Research Interests and Accomplishments of Individual Members:
Dr. Valerie Desilets was recruited last year by the Department of Obstetrics. She has used comparative genomic hybridization to assess the contribution of placental mosaism to the pathogenesis of intrauterine growth retardation. She has also looked at the risk of chromosomal anomalies in pregnancies with unexplained elevations of maternal serum a-foetoprotein and has completed the largest retrospective evaluation of ultrasound outcome predictors for all trimesters in cases of prenatally diagnosed skeletal displasia. She plans to undertake a major project involving first trimester ultrasound screening for fetal malformations and its acceptability for patients. She will embark on a study to look at first trimester nuchal translucency screening for aneuploidy and fetal cardiac malformation in our population. She will also evaluate the frequency of monozygote twinning in triplet pregnancies resulting from advanced reproductive technology (IVF).
Dr. Eleanor Elstein has studied the genetic factors modulating the cascade of molecular events resulting in obstructive vasculopathy using cardiac allograph vasculopathy (CAV) as a model. CAV is the most common cause of long term graft failure in heart transplantation. She has shown an association between specific genes of the renin angiotensin system and CAV. She has also shown that polymorphisms of ACE gene influence the responsiveness of the endothelium to different ACE inhibitors.
Mary Fujiwara is a major collaborator on the projects of Ken Morgan, PhD. She provides expertise on the history, demography and genetics of the Hutterite population; genotype data for linkage and genetic epidemiology; analysis of genealogies; linkage analysis; and database management. She participates, directly or indirectly, in all grants and academic programs in which he has participated.
Dr. William Foulkes has a continuing interest in the clinicopathological and survival analysis of patients with hereditary breast cancer. He has also looked at the needs of BRCA mutation carriers and the attitudes of medium and high risk women towards genetic testing. He is also involved in collaborative projects to identify additional susceptibility genes for breast cancer, prostate cancer, and Wilms tumour. Other major areas of his research are the influence of polymorphisms in carcinogen-metabolising genes on the development of head and neck cancer, and the relevance of mutations in P16 for familial pancreatic cancer. He also completed a case-control study on non-medullary thyroid cancer. His text on hereditary cancer which was published last year is a valuable reference for anyone interested in this rapidly evolving clinical area.
Dr. Brian Gilfix completed a project on the utility of apolipoprotein E genotyping in the diagnosis of dementias. Individuals were genotyped for polymorphisms in apolipoprotein E as well as a number of other genes related potentially to dementia. He has completed studies on the changes in drug metabolism that occur in patients with AIDS. This has involved the determination of the metabolism of test drugs in individuals who have been genotyped as to the allelic forms of CYP2D6 and NAT2 present. In the area of risk factors for cardiovascular disease in patients on chronic hemodialysis, Dr. Gilfix has looked at the relationship between polymorphisms in a number of genes in the renin-angiotensin system and the occurrence of cardiovascular disease. He plans to investigate the expression level of a number of candidate genes associated with cardiovascular disease in renal transplant patients who are at high risk of developing such disease.
Dr. Thomas Hudson and Ken Morgan,PhD established a state-of-the-art genotyping facility at the Montreal General Hospital Research Institute in 1996. Dr. Morgan supervises the informatics and computer core which has implemented programs to process the genotype data. Activities of the informatics group include database development, analysis of pedigree and population data, and the analysis of radiation hybrid mapping. In the first two years of operation, twenty-four young scientists have been recruited and trained in these new biotechnologies. Dr. Hudson has been successful, along with colleagues at McGill and the Centre Hospitalier de lUniversité de Montréal in obtaining a major infrastructure award from CFI and the FRSQ to expand the facilities at the Montreal General Hospital to become the Montreal Genome Centre. This centre was awarded $8.25 million in order to provide technological support to the Montreal community. The establishment of cores for large-scale sequencing, high throughput genotyping, DNA chip technologies, and bioinfomatics is crucial for keeping Montreal researchers at the leading edge of genetic research. Dr. Hudsons general area of interest involve common diseases with an important genetic component including asthma, lupus, early-onset heart disease, non-insulin dependent diabetes mellitus and inflammatory bowel disease.
Ken Morgan, PhD provides expertise in population analysis and genetic modelling, collaborating extensively on the analysis of genetic data in the human and the mouse. With the increasing use of genome-based scans as a first step in gene identification, he has developed expertise in all steps of the process from database design to statistical analysis. Areas of active investigation include a spastic ataxia in French Canadians, a muscular dystrophy in the Hutterite population, and Schwachman-Diamond syndrome. He has been involved in the mapping of X-linked loci involved in the skewing of X chromosome inactivation and has studied transmission-ratio distortion on the human X chromosome. In an ongoing collaboration on diabetes insipidus, he has been able to show that both the autosomal recessive and dominant forms of the disease can be caused by mutations in the same gene. A web site has been developed for information on mutations in three genes that cause diabetes insipidus (URL is www.medcon.mcgill.ca/nephros). He is also using a population genetic approach to map susceptibility genes for complex human disease including coronary heart disease and non-insulin dependent diabetes.
Dr. Rosenblatt and his colleagues in the Medical Research Council of Canada Genetics Group identified additional mutations in patients with inborn errors of vitamin B12 metabolism due to defects in either the enzyme methionine synthase (cblG) or methionine synthase reductase (cblE). This progress was made possible by their previous success in cloning the genes responsible for these diseases. The identification of specific mutations in patients with these diseases allows for the identification of heterozygotes (carriers) within their families. His diagnostic laboratory for the inborn errors of folate and cobalamin metabolism is the major international reference centre for patients with persistent elevation of either homocysteine or methylmalonic acid, receiving one to two new patients weekly. Nora Matiaszuk and David Watkins, PhD, have been instrumental in maintaining this resource. In collaboration with Joe Nadeau, PhD, at Case Western Reserve University, Dr. Rosenblatt and Angela Hosack have been studying homocysteine metabolism is a series of mouse strains with susceptibility to heart disease or birth defects. A pattern that suggests a link between folate metabolism and the sonic hedgehog pathway has been observed. With Rima Rozen of the MRC Genetics Group and with colleagues in Nancy, France, Dr. Rosenblatt has been involved in the study of the effect of common polymorphisms in folate enzymes in populations with either heart disease or neural tube defects.
Dr. Guy Rouleau has maintained an internationally renowned research group whose major themes include the cloning of genes responsible for nervous system dysfunction. Two major themes are being addressed. The first are a number of hereditary neurodegenerative disorders where he performs linkage analysis followed by chromosomally based cloning of the defective gene and mutation analysis. Diseases that are under investigation include amyotrophic lateral sclerosis, spastic paraplegia, spinocerebellar ataxia, epilepsy, oculopharyngeal muscular dystrophy, manic depressive illness and schizophrenia. The second theme included predispositions to central nervous system cancer in an attempt to define the molecular evens underlying carcinogenesis in the central nervous system. Approaches include linkage analysis, reverse genetics, physical mapping of human chromosomes, cDNA cloning and characterization, mutation analysis and cell biology. Dr. Rouleau is a Medical Research Council of Canada Scholar.
Patricia Tonin, PhD has focussed on the identification of genes implicated in breast cancer, ovarian cancer, and in endometriosis. She has collaborated on both international teams that led to the identification of the cancer susceptibility genes, BRCA1 and BRCA1. Germline mutations in either of these genes confer an elevated risk of breast and ovarian cancer. Since the discovery of these genes, research has focussed on establishing the spectrum of mutations. She has shown recurrent BRCA1 and BRCA2 mutations in two specific populations: Ashkenazi Jewish and French Canadian. As mentioned above, advances in Dr. Tonins laboratory are rapidly transferred to the clinical service which can provide appropriate genetic counselling and molecular testing. Current studies focus on the contribution of the known genes to breast and ovarian cancer in the Quebec population and thus they have the potential to identify novel susceptibility genes. Genes implicated in ovarian cancer are being investigated by two approaches: characterization of genes which map to regions deleted or amplified in the ovarian cancer as determined by allelotyping ovarian tumours and analysis of the expression of genes using high throughput technology. Genes which map to minimal regions of loss are further identified by established genetic mapping and cloning strategies. The genetic basis of endometriosis is being investigated by first assessing the prevalence of this disease and family history in women experiencing infertility. Future studies include developing genetic models to identify genes implicated in endometriosis.
Dr. Tonin has used an in vitro assay model based on the establishment of primary cultures derived from human epithelial ovarian tumours to delineate the cellular and molecular events that are important in ovarian carcinogenesis. A targeted approach based on the localization of interesting gene candidates to regions shown to be deleted or amplified in ovarian cancer has been used to characterize their role in ovarian cancer. Another approach that she is exploring is the establishment of expression profiles for genes that are differentially expressed during neoplastic progression. This process has been revolutionized by the development of high through-put genome-wide studies that permit the quantisation of large sets of transcripts simultaneously. This technology is currently being applied to the ovarian cancer model in order to establish molecular pathways of carcinogenesis. This approach also has the potential to identify markers of ovarian cancer that can be used in the identification, stratification or prognosis of this disease. These collaborative projects with Dr. Hudson are made possible because of the presence of the Genome Centre.
David Watkins, PhD has an ongoing interest in the molecular basis of the methionine dependence of some tumour lines. He also studies the extent and nature of somatic cell complementation among cells lines from patients with cobalamin-dependent methylmalonic aciduria. In collaboration with Eric Shoubridge, PhD and Dr. Rosenblatt, he is undertaking studies to clone genes from a number of inborn errors of cobalamin metabolism using chromosome transfer.
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(c)1999 pmn for Finestone Labloratory