Annual
Report 2002/2003
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 Director of the laboratory since its inception. Dr. Rosenblatt is currently Chair of the
Department of Human Genetics at McGill and his mandate has been renewed for a
five-year term beginning in June 2005. The laboratory was established with the
help of an endowment to McGill University and funding 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). As such, this report also
serves as the Annual Report of the Division of Medical Genetics of the
Department of Medicine of the MUHC. It is available on the Internet (http://www.mcgill.ca/finestone). Since the University Division in Medicine
also has included the Division at the Jewish General Hospital, this report also
encompasses parts of that activity.
Within the past few years, major advances have occurred with the
creation of the Department of Medical Genetics at the Jewish General Hospital.
Highlights: Research
Dr. Thomas
Hudson and his laboratory continued its asthma, diabetes and other complex
trait mapping projects. Work in
2004-2005 led to the discovery of links between vitamin D related genes and
asthma, and a detailed map of transplantation antigens and their role in
multiple sclerosis (soon to be published in Nature Genetics).
Dr. Patricia Tonin was awarded the 2004 Merck Frosst Award for
Excellence in Research, by the Department of Medicine, McGill University
Highlights: Teaching
A notable and
very sad event last year was the untimely death of Jamie C. Tirone, a Ph.D.
student with Dr. Rosenblatt. He will be
greatly missed.
Dr. Mary Ann Thomas completed her final year of Medical Genetics
residency and her first year in the cytogenetics program of the CCMG. Dr.
Chantal Morel has completed her RV year in Medical Genetics. Both Dr. Thomas and Dr. Morel successfully
completed the examination of the Royal College
and CMQ in Medical Genetics. Dr. Teresa
Rudkin and Dr. Fatma Bastaki completed their RIV year, with Dr. Rudkin serving
as Chief Residents. Dr. Nicolas Ah Mew
completed his RIII year and will serve in the upcoming year as Chief
Resident. Dr. Philippe Campeau, as part
of an agreement between Laval and McGill, completed his RII year in Quebec
City. Dr. Rudkin
will be the Chief Resident in the coming yea.
Dr. Maha Al-Awadi and Dr. Khalid Al-Thihli completed their RI year in
the Medical Genetics residency. Our
trainees in graduate programs in the Department of Human Genetics are all doing
well and are listed in the annual report of the Department of Human Genetics.
Highlights: Clinical
After more than
four years, clinical services for medical genetics within the McGill University
Health Centre (MUHC) are still in the process of being restructured. The administration of the MUHC has started to
put together a committee to search for a Program Director for medical genetics.
We
have been successful in recruiting Marc Tischkowitz, M.B., Ph.D. from the United
Kingdom. He is fully trained clinically in the area of
medical genetics and also has a special interest in cancer genetics. He will be primarily based at the Jewish
General Hospital where he will be the first full time medical geneticist since
the retirement of Dr. Leonard Pinsky, the founding Chair of the Department of
Human Genetics. Dr. Tischkowitz will
also be the first full time medical geneticist in the newly created Department
of Medical Genetics at the Jewish General Hospital. He will hold a hospital appointment in the
Division of Medical Genetics at the MUHC and will hold university appointments
in the Departments of Oncology and Medicine, as well as in the Program in
Cancer Genetics of the Departments of Human Genetics and Oncology, led by Dr.
William Foulkes. The recruitment of Dr.
Tischkowitz adds to our existing strengths in both the basic and clinical areas
of cancer genetics and general medical genetics. He is expected to begin work in the fall of 2005.
Research Interests and Accomplishments of Individual
Members:
Dr.
Ken Dewar and his laboratory have
entered the 2nd year of a 4 yr NIH project to develop SNP-based genetic mapping
tools for the vervet monkey. Of note,
their analysis of using rhesus and human genome data to predict SNP locations
in vervet sequence was the focal points of presentations given at the Cold Spring Harbor international genome biology meeting.
A complementary project to compute a physical map for the vervet monkey
genome is under evaluation by Genome Canada, with a co-funding grant also submitted to the
NIH. As a comparative mammalian genomics
bioinformatics exercise, they developed and published a strategy to develop
dolphin genetic markers with associated positional location as inferred from
human and cow genome assemblies. As part
of a larger Regulatory Genetics project, they have identified a novel level of
genomic organization (long-range conserved genomic spacing) and are preparing a
manuscript summarizing their results.
Dr.
Eleanor Elstein continues her
interest in caridovascular genetics, with particular emphasis on genetic
factors modulating the development of obstructive vasculopathy in cardiac
allographs, and on the levels of aminothiols in heart transplantation.
Dr.
Brian Gilfix follows a cohort of
patients with homocystinuria in the adult genetics clininc. He is using this opportunity to explore new
treatments for this disease and to investigate the effect of elevated
homocysteine on other risk factors for cardiovascular disease. He also is developing and implementing assays
based on hybridization probes to replace molecular diagnostic assays based on
restriction length polymorphisms. The
benefit of this is decreased net cost and faster turn around times.
Dr.
William Foulkes’ main research
accomplishment this year was the publication of several papers further
describing the clinico-pathological features of hereditary breast cancer. In particular, he has helped to define the
basal pehnotype of BRCA1-related breast cancer.
He co-ordinated the publication
of the largest allelic association study of prostate cancer to date. Finally, with Dr. Steven Narod, he co-authored a 10-year anniversary review
of BRCA1/2.
T.
Mary Fujiwara studies the
distribution and maintenance of genetic variability, including deleterious
alleles in well-defined populations, in particular, the Hutterite population of
North America-an inbred population isolate. She also collaborates with Dr. Daniel Bichet
on a world-wide collection of families with nephrogenic diabetes
insipidus. They have shown locus heterogeneity,
a wide spectrum of mutations, and mutation-dependent mode of inheritance.
Dr.
Thomas Hudson directs the rapidly
expanding McGill University and Genome Quebec Innovation Centre, which is the largest genomics and
proteomics centre in Canada. The high
throughput core facilities in genotyping, sequencing, DNA chip and proteomics
supported over 300 Canadian projects.
Dr. Hudson directs two large-scale Genome Canada projects entitled
"Regulatory Genetics" and "Haplotype Map: The Regulatory
Genetics project made considerable advances in identifying genetic factors that
affect the level of gene expression. The
Haplotype group generated a dense map of the common haplotype of chromosome 2
and 4p, in collaboration with the International Haplotype Map Consortium that
includes the USA, UK, China, Japan and Canada. This map is accessed over 10,000 times per week by
genetics labs around the world. The Hudson laboratory continued its asthma, diabetes and other
complex trait mapping projects. Work in
2004-2005 led to the discovery of links between vitamin D related genes and
asthma, and a detailed map of transplantation antigens and their role in
multiple sclerosis.
Dr.
Kenneth Morgan has research
interests in the areas of population genetics, pedigree analysis, and genetic
modelling. He lead 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 and mice. 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.
Collaborations with researchers in Calgary and Winnipeg of Mendelian diseases in the Hutterite
population included identifying a mutation in the FKRP gene that causes
limb-girdle muscular dystrophy, demonstrating genetic heterogeneity as they
previously identified a mutation in the TRIM32 gene. Two autosomal recessive syndromes were
mapped: Bowen-Conradi syndrome, a rare congenital malformation syndrome, and
disequilibrium syndrome, a cerebellar hypoplasia [In collaboration with Dr. Alexey
Pshezhetsky, Hôpital Ste-Justine, they used homozygosity mapping to map a locus
for mucopolysaccharidosis IIIC (Sanfilippo syndrome)
In a continuing collaboration with Dr.
Danielle Malo on the genetic architecture of host response to Salmonella
persistence in mice, significant interactions have been detected.
Postdoctoral fellow, Dr. Loredo-Osti
developed methodology for segregation analysis of a quantitative trait in
sibships to find evidence for a major gene for urine calcium excretion in
families ascertained for kidney stones, a collaboration with Alain Bonnardeaux,
Hôpital Maisonneuve-Rosemont.
Dr.
David Rosenblatt and his laboratory
continue to be the major international referral source for the diagnosis of
patients with inherited disorders of folate and vitamin B12. They are involved
in studying the molecular bases of these diseases. Dr. Lisa Worgan, a medical geneticist from Australia working with Dr. Rosenblatt completed an analysis of
mutations in the MUT gene among 160 patients with classical methylmalonic
aciduria (MMA). This is a rare autosomal recessive disease that is usually
diagnosed in infants in the first few weeks or months of life, because of
severe metabolic acidosis. They
identified one hundred and sixteen different mutations, of which sixty-eight
were new. Several mutations showed a
high frequency in specific ethnic groups.
In particular, a novel mutation, R108C, was identified in sixteen of
twenty-seven patients of self-identified Hispanic origin and SNP genotyping
data demonstrated that the Hispanic patients who carry this mutation share a
common haplotype. This information has
been transmitted to the physicians who had referred these patients to our
laboratory over several decades. Knowledge
of the mutations that are responsible for MMA can help in both the detection of
carriers and in prenatal diagnosis. Dr.
Chantal Morel, a fifth year medical genetics resident at McGill, published the
laboratory’s experience with prenatal diagnosis in eleven at-risk
families for severe methylenetetrahydrofolate reductase (MTHFR)
deficiency. This showed that in
appropriate families, linkage analysis is a practical approach for the prenatal
diagnosis of this disease. This is important because in many families, the
mutations responsible for the disease have not yet been detected.
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.
A. The
Molecular study of Human Epithelial Ovarian 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. Dr. Tonin has shown deletions
in low grade, early stage tumours and therefore has 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 projects, are to refine the localization and then clone the
putative chromosome 3p and 17q tumour suppressor genes. Previously, she published
a deletion map of chromosome 3p deletions observed in a large series of
epithelial ovarian tumours. In addition she is applying a candidate gene
approach and have excluded known candidates, such as TGF-ß-RII. Shedescribed a
chromosome 3 transcriptome based on the comparison of expression profiles of
ovarian cancer cell lines with normal surface epithelial cells using high
through put oligonucleotide expression microarrays. In this study she was able
to establish the sensitivity of detection and show that subtle changes in gene
copy number are detectable by microarray analysis. In an effort to characterize
the putative TSG on chromosome 3p implicated in ovarian tumourigensis, she
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), and that of 3p
regions lost in ovarian cancer. She established chromosome 3p loss occurs
independently from TP53 mutagenesis.
Most recently she reported a comprehensive analysis addressing the
fidelity of expression microarrays, such as Affymetrix GeneChips,
showing that rigorous investigation of target sequences representing genes on
these microarrays should be pursued prior to engaging in experiments of target
genes.
B. Breast
Cancer Susceptibility Genes: BRCA1 and BRCA2
Hereditary breast cancer accounts for
approximately 5% to 10% of all breast cancers and 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
and her laboratory are continuing to further define the spectrum of mutations
in the BRCA1 and BRCA2 cancer susceptibility genes in the French Canadian
population of Quebec. Most recently they reported a new recurrent BRCA2
mutation in the French Canadian population at risk for hereditary breast and
ovarian cancer. This latest discovery has redefined mutation screening
protocols and improved genetic testing, and consequently genetic counseling,
for this population.
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