Annual Report 1996/1997
Annual Report 1996/1997
The goal of the Hess B. and Diane Finestone Laboratory in Memory of Jacob and Jenny Finestone is to promote medical genetics at McGill University. The laboratory was established with the help of a million dollar endowment to McGill and is housed on H5 at the Royal Victoria Hospital (RVH). Dr. David S. Rosenblatt is Director of the laboratory and also is Director of the Divisions of Medical Genetics at both the RVH and Montreal General Hospital (MGH). Funding from the Finestone Laboratory is used to advance the academic mission of the Divisions on both sites. With real progress towards legal merger of the McGill hospitals to form the McGill University Health Centre (MUHC), the goal of a single administrative unit for the Division may soon be achievable. In fact the Divisions at the MGH and RVH have functioned as an integrated entity since their inception. For the first time last year, the annual report was available on the internet:
1996-1997 was once again a year of major achievements in the area of research. Three McGill research laboratories that form part of the Medical Research Council (MRC) Group in medical genetics cloned the gene for methionine synthase. This work involved Dr. Rosenblatt along with Dr. Roy Gravel and Dr. Rima Rozen from the Montreal Children's Hospital (MCH). They also showed that mutations in this gene are responsible for cblG, one of the inborn errors of vitamin B12 metabolism originally described by Dr. Rosenblatt. Because of the central role of methionine synthase in both methionine and homocysteine metabolism, the cloning of this gene will generate many more studies in areas as varied as risk factors for vascular disease, and for birth defects such as neural tube disorders.
Dr. Thomas Hudson returned to McGill from M.I.T. and has been cross appointed in the Division of Medical Genetics at the MGH. Dr. Hudson has been actively involved in the Human Genome Project, and brings a new level of technological possibilities to our research community. There is no research area of gene mapping or mutation detection in which we are now limited by technology.
Dr. William Foulkes, Patricia Tonin, PhD, and Dr. Brian Gilfix have combined to provide expert clinical and laboratory services in the area of hereditary cancer and adult metabolic disease. The clinical service has been able to offer genetic testing for mutations in the two breast cancer susceptibility genes, BRCA1 and BRCA2, to selected patients with a strong family history. Because of the larger number of possible mutations in these two genes, for the moment clinical testing is available mainly to women of Ashkenazi Jewish or of French Canadian origins. This is because of the concentration of a number of common mutations in these populations.
This has been an exceptional year because the recognition of Medical Genetics as a specialty in Quebec. This means that there will be future training positions in Medical Genetics and that McGill can look forward to a continuous source of excellent trainees. It now will be possible to recruit trainees directly from medical school and Medical Genetics will be a five year program leading to specialty recognition.
Dr. Laura Arbour successfully completed her certification by the CCMG and accepted a faculty position at the MCH.
Dr. Gail Graham became the first McGill trainee to complete the Royal College training program in Medical Genetics and to receive her fellowship in Medical Genetics. Dr. Graham has accepted a faculty position at the University of Calgary.
The clinical service provides genetic counselling for adult onset genetic disease. The major areas of service include hereditary cancer (Dr. W. Foulkes, Dr. D. Rosenblatt), predictive testing for Huntington Disease (Dr. D. Rosenblatt, Dr. M. Roy, Dr. E. Andermann) and adult metabolic disease (Dr. B. Gilfix). Affiliated physicians provide service in cardiology (Dr. Elstein) and neurology (Dr. G. Rouleau).
Lidia Kasprzak and Jennifer Ozaki are the genetic counsellors who are responsible for much of the clinical activity of the Divisions at the RVH and MGH. Jennifer is a graduate of the University of Michigan and replaced Corinne Serruya who now is a research assistant with Dr. Tonin. Suzanne Dufrasne is a psychologist who provides excellent care as part of the Huntington predictive testing service. Maria Galvez, Estelle Lamothe, Gang Hu, and Antonia Klitorinos have maintained extremely high standards in the molecular diagnostic laboratory. This is an area with unlimited possibilities for growth.
The University Division of Medical Genetics in the Department of Medicine at McGill has activities at the RVH, MGH and Jewish General (JGH) Hospitals. The hospital division at the JGH is directed by Dr. Leonard Pinsky who is also Chairman of the University Department of Human Genetics. The Department of Human Genetics takes an active role in co-ordinating, not only the academic activities in medical genetics, but also the clinical activities at the McGill hospitals. Dr. Rosenblatt is Program Director at McGill for training in Medical Genetics recognized by the Royal College of Physicians and Surgeons of Canada (RC), the Canadian College of Medical Geneticists (CCMG) and the Collège des Médecins du Québec (CMQ).
Dr. Foulkes has begun to offer a clinic at the JGH in the area of hereditary cancer. Along with Nora Wong, a genetic counsellor, and Dr. Pinsky, this activity is provided in co-operation with the oncologists at the JGH as part of a Cancer Prevention Service. The Division of Medical Genetics is responsible for this clinic.
Honours and Awards:
Dr. David Rosenblatt was elected correspondant étranger of l'Académie Nationale des Médecines of France. This lifetime honour is limited to 100 people worldwide and there are only three other Canadians in l'Académie. He is also past president of the Society of Inherited Metabolic Disease (USA).
Dr. Guy Rouleau is an MRC Scholar and Dr. Patricia Tonin is an MRC/CRS Scholar. Dr. William Foulkes and Dr. David Watkins have received awards from the MGH Research Institute. Dr. Foulkes was also awarded Chercheur Boursier Clinicien of the FRSQ for next year once he meets the non-academic requirements of the FRSQ.
Specific Accomplishments Submitted by Individual Members:
Dr. Eleanor Elstein: "Over the past year my laboratory has focused on the determination of genetic polymorphisms and their association with the atherosclerotic process and cardiac allograft vasculopathy in particular. We have studied the significance of polymorphisms in genes of the renin angiotensin system as well as in genes coding for vasoactive peptides. We have also investigated the association of homocysteine mutations and the atherosclerotic process in heart transplantation."
Dr. William Foulkes: "In 1996 I was active in the areas of the genetics of head and neck cancer, double primary cancers and melanoma. I collaborated with members of the Division and with international groups on the genetics of breast and ovarian cancer, and provided a Canadian perspective on genetic testing for breast cancer gene mutations. I spent considerable time editing a book for Cambridge University Press on inherited susceptibility to cancer, which will be published in 1998. I also continued my collaborative work on ovarian cancer with scientists in the UK. I employed a medical student who started a case-control study of thyroid cancer, which is nearing completion. I also employed a McGill student on a winter bursary to work on reproductive factors in endometrial cancer."
Dr. Brian Gilfix: "We have completed a project at St. Anne's Veterans Hospital (with Dr. L. Briones) on the utility of APOE genotyping in the diagnosis of dementias. This has involved genotyping 194 individuals for polymorphisms in apolipoprotein E and angiotensin-converting enzyme. A manuscript on this work has been published and another is in preparation. The same subjects are now being genotyped for a polymorphism in CYP2D6 in collaboration with Dr. J. Nalbantoglu (Montreal Neurological Institute). In collaboration with Dr. I. Wainer (Montreal General Hospital), we have recently submitted two publications on the changes in drug metabolism that occur in AIDS patients. The metabolic profile of these patients was performed at MGH, while the identification of the allelic forms of CYP2D6 and NAT2 carried by these patients was performed at RVH. We have received 3 year funding ($75 000) to examine the relationship between polymorphisms in a number of genes of the renin-angiotensin system and the occurrence of cardiovascular disease in chronic hemodialysis patients. We are currently assembling the patient population."
Dr. Thomas Hudson: "I have led the effort at the Whitehead Institute to generate dense STS and transcript maps of the human genome using Yeast Artificial Chromosome and Radiation Hybrid Strategies. My interests in human genetic disease focus on the dissection of complex traits using linkage disequilibrium mapping in founder populations of Canada. Ongoing disease projects at the Montreal General Hospital Research Institute include the search for genes predisposing to lupus, inflammatory bowel disease, coronary artery disease, and asthma.
As leader of the Human Mapping Group at the Whitehead Institute Genome Center, I have contributed to the human genome projects effort to build maps of the human genome (Hudson et al., Science, 270: 1945-1954 and http://www.genome.wi.mit.edu). The genome maps built by my group contain close to 25,000 markers. This is a widely used resource.
I have been part of an international effort to build a transcript map of the human genome. To date, my group alone has mapped over 10,000 human genes. See Schuler et al., Science, 540-546 and http://www.ncbi.nlm.nih.gov/ SCIENCE96. This is a widely used resource.
I have supervised a large team of engineers, biologists, computer scientists for a project to build high throughput PCR systems. The robot built by this team, called the "Genomatron", performs from 150,000 to 300,000 PCR reactions per day. This effort was largely responsible for the success at building STS maps at the Whitehead Institute. Since 1996, I have collaborated with scientists at the Whitehead Institute and Affymetrix on the use of DNA chips for genomic applications.
I have been a participant in several disease gene mapping projects including those for myotonic dystrophy, prostate cancer, hemochromatosis, Schneiders corneal dystrophy, schizophrenia, eosinophilia, Machado-Joseph disease, SCA 2, Ataxie cérébelleuse de Charlevoix-Saguenay, inflammatory bowel disorder, mesothelioma, cat eye syndrome, bipolar affective disorder, and melanoma. In most cases, my contribution was/is the genetic/physical mapping steps.
I have developed a method called RED that is used to identify expansions of trinucleotide repeats in the genome. I have mapped over 300 CAG repeats on the human genome. This resource is used by genetic scientists to look for new disease genes suspected to carry this type of mutation."
Ken Morgan, PhD: "My major research areas are population genetics, pedigree analysis, and genetic modelling. I have collaborated extensively on the analysis of genetic data in the human and mouse. During the past year, Carmen Sapienza (Temple University, Philadelphia) and I collaborated on the study of transmission ratio distortion in the mouse and heritability of chromosome inactivation skewing in humans. I collaborated on mapping two autosomal recessive Mendelian disorders, a spastic ataxia (with Andrea Richter and Serge Melançon, Hôpital Sainte-Justine) and a muscular dystrophy (with Cheryl Greenberg and Klaus Wrogemann, University of Manitoba). A new initiative was developed in collaboration with Thomas Hudson for a comprehensive program for the genetic analysis of complex traits and common diseases in Canadian populations. There are three components: (1) development of a clinical core focusing on families from the Saguenay-Lac St. Jean region of Quebec; (2) implementation of a high-throughput, automated genotyping facility; development of new genotyping technology; and (3) development of an informatics core facility. I am responsible for the informatics core facility for genetic analysis."
Dr. David Rosenblatt: "With colleagues at Baylor, Yale and the University of Michigan, we have defined the molecular basis for dysfunction of some mutant forms of methylmalonyl CoA mutase using deductions from the structure of homologous regions of methionine synthase. At the same time, with Charles Adjalla, we have shown that the mutation G717V is seen in black patients of American and African background. With Fred Ledley, I have written a definitive review on mut mutations as of January 1997. With Rima Rozen of the MRC group, we have defined the first 15 mutations in severe MTHFR deficiency and have shown that in many patients with severe deficiency, the thermolability of residual enzyme activity is due to the presence in cis with the severe mutation, of the common A->V polymorphism shown to be the cause of thermolability in the general population. With colleagues at Yale University we have completed a study on the outcome of cblC disease and have shown that the morbidity and mortality of this disorder are great, particularly in cases diagnosed during the first year of life. With Dr. E.H. Pezacka and Dr. F. Watanabe, we have shown that cobalamin reductase activities are reduced in fibroblasts from cblC patients. As mentioned in the highlights above, in collaboration with Roy Gravel and Rima Rozen of the MRC group, we have delineated the first mutations in methionine synthase responsible for cblG disease. With Ruma Banerjee of the University of Nebraska, we have shown that reducing activity can be separated from apoenzyme methionine synthase activity and that in an anaerobic NADPH assay cblG and cblE cell extracts complement one another. This data confirms my original findings in somatic cells that cblE represents and altered reducing activity whereas cblG represents defects in the methionine synthase enzyme itself. With Joe Nadeau (Cleveland) we have begun to look at the variability in total homocysteine levels among strains of mice. The goal of this study is to determine the number of genes involved in the control of homocysteine metabolism in the mouse. With Rima Rozen and Benedicte Christensen, we have shown that there is a relationship between the A->V polymorphism of MTHFR and increased total homocysteine levels in coronary heart disease patients. With Dr. Watanabe we have shown that a mitochondrial aquocobalamin reductase is deficient in fibroblasts from a cblA patient".
Guy A. Rouleau: "My laboratory has been attempting to characterize human genes which, when mutant, lead to nervous system dysfunction. Two major themes are currently being addressed. The first are a number of hereditary neurodegenerative disorders, where we perform linkage analysis followed by chromosomally based cloning of the defective gene and mutation analysis. We are currently investigating amyotrophic lateral sclerosis, spastic paraplegia, spinocerebellar ataxia, epilepsy, oculopharnygeal muscular dystrophy, manic depressive illness and schizophrenia. The second theme includes inherited predispositions to central nervous system cancer. The most important disorder is neurofibromatosis type 2 which we have recently cloned. We are attempting to define the molecular events underlying carcinogenesis in the CNS. Our approach involves linkage analysis, reverse genetics, somatic cell genetics, physical mapping of human chromosomes, cDNA cloning and characterization, mutation analysis and cell biology."
Patricia Tonin, PhD: "There are two principal areas of research conducted in my lab. The first involves the identification of genetic factors that are implicated in the development and/or progression of human epithelial ovarian cancer. The second involves the study of genetic factors that predispose to hereditary forms of breast cancer.
Our knowledge of the molecular events associated with the development and progression of epithelial ovarian cancer has been limited by the lack of a suitable model system. Also, since the disease is often diagnosed at a late stage when numerous complex chromosomal changes have already taken place, the early molecular events remain largely unknown. Deletions of chromosome 3p and 17q (distinct from the BRCA1 locus) are frequent events in ovarian tumours of epithelial origin. We have shown deletions in low grade, early stage tumours and therefore have hypothesized that these chromosomal regions harbour tumour suppressor genes whose function is lost early in the development and/or progression of ovarian cancer. The goals of an NCIC and MRC funded project, is to refine the localization and then clone the putative chromosome 3p and 17q tumour suppressor genes. This past year we have devoted the majority of the effort towards the first phase of the project which entails the use of highly polymorphic markers and PCR technology to determine the precise boundaries of the regions deleted on chromosomes 3 and 17 in a panel of greater than 100 tumour (matched control) samples. We have now initiated the second phase of the project which involves the characterization of candidate genes which map to these regions. In parallel we have used the approach of differential display technology to identify genes which encode transcripts that are differentially expressed to characterize the pattern of expression in various subtypes of epithelial ovarian cancer. The eventual goal of this particular project will be to identify "molecular markers" of ovarian cancer to improve methods of early detection and prognosis.
Hereditary breast cancer accounts for approximately 5% to 10% of all breast cancers. With the identification of two predisposing susceptibility genes, BRCA1 and BRCA2, studies are now in progress focus on: (1) the continued identification of recurrent mutations in specific populations which will lead to improved strategies for mutation detection (French-Canadian population, for example); (2) correlation of carrier status and various host (reproductive, etc.) and environmental factors (contraceptive pill, use smoking, for example); and (3) identification of other susceptibility genes (BRCAX?); and (4) correlating carrier status and various prognostic indicators (estrogen and progesterone, e.g.) to better understand the biology of BRCA1 and BRCA2".
David Watkins, PhD: "Propionate and methylTHF incorporation were investigated in a panel of 14 methionine dependent cell lines derived from various types of human tumor. The abnormal cobalamin metabolism previously described in the human melanoma cell line MeWoLC1 was not observed in any other member of the panel. Thus defective cobalamin metabolism does not appear to be a frequent cause of methionine dependence in transformed cell lines. The nature of the defect in cobalamin metabolism in MeWoLC1 was investigated using somatic cell complementation analysis. The defect in this cell line complemented the defect in fibroblasts from patients with inborn errors of cobalamin metabolism, with the exception of cblC fibroblasts. these results suggest that inactivation of the cblC gene accounts for methionine dependence in this cell line".
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