Dr. David Rosenblatt and his colleagues, including Tom Hudson, described the genes responsible for two forms of vitamin B₁₂-responsive methylmalonic aciduria.  These genes, MMAA and MMAB, are responsible for the cblA and cblB forms of methylmalonic aciduria. These are severe inherited metabolic diseases that, if untreated, can result in coma and death.

Dr. Guy Rouleau and colleagues identified the ACCPN gene as well as a gene responsible for juvenile myoclonic epilepsy.

Highlights: Teaching

Dr. Mary Ann Thomas is currently in her RIV year of residency and is our Chief Resident in Medical Genetics. She hopes to enter a two-year CCMG training program in cytogenetics beginning in her RV year.  Dr. Chantal Morel is completing her RIII year and will become the Chief Resident in July 2003. Dr. Teresa Rudkin and Dr. Fatma Bastaki are currently in the RII year and Dr. Nicolas Ah Mew and Dr. Fathiya Al-Murshedi are completing their RI year.  For the first time, the new RI in medical genetics beginning in July 2003, will be Phillipe Campeau, who as part of an agreement between Laval and McGill, will do his RI year in Quebec City and transfer to McGill in the RII year.  As her husband has accepted a training position in Orthopedics at the University of Toronto, Dr. Al-Murshedi will transfer to the medical genetics program in Toronto as of July.  We have enjoyed having her in our program and wish her well in Toronto.  Our trainees in graduate programs in the Department of Human Genetics are all thriving in the system. 

Highlights: Clinical

After more than two years, clinical services for medical genetics within the McGill University Health Centre (MUHC) are still in the process of being restructured.  There is a glimmer of hope that the administration of the MUHC is moving to search for a Program Director for medical genetics.  There is even an expectation that some resources will be added to the system.  However, there is still the need to deliver on promises and expectations and take advantage of the excellence in human resources that we have.  Our services in cancer genetics are among the largest in Canada and we have achieved real excellence in this area. A comprehensive clinic for carriers of BRCA mutations has been established and is thriving. The program for the predictive testing for Huntington Disease is a unique resource.

Research Interests and Accomplishments of Individual Members:

Dr. Valerie Désilets is the Director of the prenatal diagnosis program at McGill. She has been involved as a co-investigator on a number of research projects: the study of male-mediated developmental toxicity; the isolation of free fetal DNA in the serum of mothers in an attempt to evaluate mutations in fetuses at risk for fetal cystic fibrosis; the creation of a data bank for prenatal diagnosis; and, the follow-up of newborns with diaphragmatic hernia.

Dr. Ken Dewar relocated from Boston to Montreal during the past year. His laboratory focuses on high-throughput genomic sequencing and sequence analysis to study mammalian evolution and the evolution of gene regulatory sequences. His Computational Biology group, combined with the sequencing core laboratory, has continued to advance projects relating to mammalian evolution. These include participating in a study of human, mouse and zebra fish to elucidate a mutation causing juvenile cystic kidney disease in the mouse, sequencing and analysis of Hox gene clusters in basal vertebrates,  development of an integrated genetic/physical map for the vervet monkey, and development of a genome wide set of pan-mammalian PCR markers.

Dr. Eleanor Elstein focuses her research on genetic modulation in the cardiovascular system. She is pursuing the study of genetic factors modulating the development of  obstructive vasculopathy in cardiac allografts.  She has also looked at the levels of various aminothiols in homocysteine metabolism in heart transplantation.

Dr. Brian Gilfix is investigating the genetic causes of thrombosis. He has received funding from the “Réseau de médicine génétique appliquée” (Fonds de la recherche en santé du Québec) to allow the establishment of techniques and services for the identification of genetic causes of thrombosis among family members.  In addition, he is investigating genetic risk factors for obesity and currently has ongoing a pilot study examining the frequency of several gene polymorphisms related to obesity in a morbidly obese population.

Dr. William Foulkes is a world expert on hereditary cancer syndromes.  His main research highlight for 2002 was the identification of a founder mutation for hereditary colon cancer in the MSH2 gene in the Ashkenazi Jewish population.  This was a large international collaboration, run from the Jewish General Hospital by Dr. Foulkes. Another work of note was the finding that in families with hereditary breast cancer, breast tumors from BRCA1/2 mutation carriers initially respond very well to adjuvant chemotherapy.

Dr. Thomas Hudson and his laboratory moved during the past year to the new McGill building at 740 Dr. Penfield. The genome laboratories (Drs. T. Hudson, K. Dewar, and R. Nadon), merged with the Montreal Proteomics Centre (directed by Dr. J. Bergeron), and the Genome Quebec core facilities (genotyping, sequencing, DNA microarray and proteomics), to create the McGill University and Genome Quebec Innovation Centre. This is the largest genomics and proteomics research centre in Canada. Dr. Hudson directs two large-scale Genome Canada projects entitled "Regulatory Genetics" and "Haplotype Map". The Regulatory Genetics project made considerable advances in a genome survey of allelic imbalances in expressed genes in order to identify genes affected by cis-acting regulatory polymorphisms as well as epigenetic factors. The Haplotype group initiated its task to generate a dense map of the common haplotypes on chromosome 2 and 4p, in collaboration with the International Haplotype Map Consortium that includes the USA, UK, China, Japan and Canada. The Hudson laboratory continued its asthma, diabetes and other complex trait mapping projects. Finally, the Hudson team participated with other McGill, Université de Montréal and Calgary teams in the cloning of four childhood diseases: North American Indian childhood cirrhosis, two forms of vitamin-B12 metabolic diseases (cblA and cblB) (see Rosenblatt) and a form of lactic acidosis prevalent in Northeastern Quebec.

Dr. Kenneth Morgan has major areas of research interest in population genetics, pedigree analysis, and genetic modeling. He leads a Genetic Analysis Group that participates in two Networks of Centres of Excellence programs: the Canadian Genetic Diseases Network (CGDN) and the Mathematics of Information Technology and Complex Systems. His group is involved in the genetic analysis of Mendelian and complex traits in humans, mice and chickens. He is also an investigator in the McGill University and Genome Quebec Innovation Centre, participating in the genotyping core facility, and in mentoring statistical genetic analysis in the regulatory genetics project.

In studies of the Hutterite population, his research group has found that two mutations in two different genes account for all known cases of limb-girdle muscular dystrophy. In addition, they described the clinical variability in Bowen-Conradi syndrome, a rare Mendelian congenital malformation syndrome. They are currently mapping the disease locus, in collaboration with Cheryl Greenberg and Klaus Wrogemann, University of Manitoba; and R. Brian Lowry, Alberta Children’s Hospital.

Studies of susceptibility to salmonella in the mouse suggest that Nramp1 controls the clearance of the bacteria during the late phase of chronic infection. This was unexpected as Nramp1 was known to be involved in the control of the exponential growth of the bacteria during the early phase of acute infection. The results indicate that other loci may be involved in resistance to salmonella infection. By linkage and survival analysis, the results showed that the gene encoding the toll-like receptor 4 plays a role in resistance to salmonella infection in chickens (Collaboration with Danielle Malo, McGill University).

In studies to understand genomic imprinting and other epigenetic phenomena, postdoctoral fellow, J Loredo-Osti and Dr. Morgan collaborated with Carmen Sapienza (Fels Institute for Cancer Research and Molecular Biology, Temple University) and Anna Naumova (McGill University). They found evidence that X-linked loci contribute to variation in genome-wide recombination rates in the mouse. In addition, they found moderate transmission-ratio distortion in a known imprinted region of chromosome 12, but not for other imprinted regions, suggesting that there is a complex relationship between imprinting and transmission-ratio distortion.

Dr. David Rosenblatt and his laboratory completed a study on mutation analysis among patients with hyperhomocysteinemia due to methionine synthase deficiency (cblG). In collaboration with the laboratory of Dr. Roy Gravel of the University of Calgary, they cloned the genes for two forms of vitamin B12-responsive methylmalonic aciduria. This allows for carrier detection and more rapid molecular diagnosis in this serious cause of organic acidosis. The cloning of the MMAA gene responsible for the cblA form of the disease was published in the Proceedings of the National Academy of Science (USA). The cloning of the MMAB gene responsible for the cblB form of the disease was published in Human Molecular Genetics. There was considerable attention to the cloning of these disorders in the popular press. In addition, Dr. Rosenblatt and his group published the first mutation in glutamate formiminotransferase, the second most common inborn error of folate metabolism. The MUHC clinical laboratory remains the world referral centre for patients with suspected inherited disorders in the metabolism of the vitamin folate and vitamin B12.

Dr. Guy Rouleau is an expert in neurogenetics and has varied research interests in this area: 1) defining the role of neurofilaments in amyotrophic lateral sclerosis disease, and working on mechanism of SOD1 pathogenesis; 2) collection of a cohort of schizophrenia patients characterized by their response to neuroleptics and severity of the disease; 3) identification of a possible expanded CAG repeat containing protein gene in this disease, and association studies showing a possible role for a number of different genes in schizophrenia; 4) collection of a cohort of lithium-responsive bipolar affective disorder patients with the identification of phospholipase C?1 as possibly involved in the pathogenesis of this disease, as well as the identification of a novel susceptibility loci using a genome scan; 5) characterizing the French Canadian founder effect in three different genetic diseases. The work on OPMD is particularly detailed with a combination of history, genealogies and molecular studies; 6) creation of new methods for analyzing this founder effect (ex GEMS count). 7) important contributions to the fine mapping, gene isolation, genotype/phenotype correlation of numerous diseases, as well as studies of the pathogenesis of CAG repeat containing diseases; 8) showing that frame shifting occurs during translation or transcription of long CAG tracts, suggesting a possible new mechanism for development of disease; 9) mapping and identifying the ACCPN gene; 10) mapping and identifying a gene for juvenile myoclonic epilepsy.

Dr. Patricia Tonin and her laboratory have two principal areas of research. 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. These two areas are described below:

The molecular study of human epithelial ovarian cancer: The 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 tumors of epithelial origin. Dr. Tonin and colleagues have shown deletions in low grade, early stage tumors 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 a CIHR-funded project, are to refine the localization and then clone the putative chromosome 3p and 17q tumour suppressor genes. Previously, Dr. Tonin's team published a deletion map of chromosome 3p deletions observed in a large series of epithelial ovarian tumors. In addition they are applying a candidate gene approach and have excluded known candidates, such as TGF-ß-RII. This past year they described a chromosome 3 transcriptome based on the comparison of expression profiles of ovarian cancer cell lines with normal surface epithelial cells using high throughput oligonucleotide expression microarrays. In this study they were able to establish the sensitivity of detection and show that subtle changes in gene copy number are detectable by microarray analysis. They attempted to characterize the putative TSG on chromosome 3p implicated in ovarian tumourigenesis. To do this, they established the relationship between chromosome losses frequently associated with specific regions of the human genome (BRCA2 and 13q, TP53 and 17p, BRCA1 and 17q, and Xp11), with that of 3p regions, lost in ovarian cancer. They established chromosome 3p loss occurs independently from TP53 mutagenesis.

Breast cancer susceptibility genes: BRCA1 and BRCA2: Hereditary breast cancer accounts for approximately 5% to 10% of all breast cancers and a large majority of hereditary cancer families are attributed to germline mutations in BRCA1 and BRCA2 which confer an increased susceptibility to both breast and ovarian cancer. Dr. Tonin's team is continuing to further define the spectrum of mutations in the BRCA1 and BRCA2 cancer susceptibility genes in the French Canadian population of Quebec. In collaboration with Dr. Will Foulkes, response to neoadjuvant chemotherapy in BRCA1/2-related breast cancers was investigated; and a correlation between the structure of hair and breast cancer or BRCA1/2 mutations was investigated.

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