2008 Barcelona - European Society of Human Genetics

Concurrent Symposia
ESHG CONCURRENT SYMPOSIA
s01.1
Dissection of structural variation in common human disease
X. Estivill;
Genes and Disease Program, Center for Genomic Regulation (CRG), Barcelona
National Genotyping Center (CeGen), Public Health and Epidemiology
Network Biomedical Research Center (CIBERESP), Pompeu Fabra University
(UPF), Barcelona, Spain.
CNVs represent a new common source of genetic variability in individuals
(recognized by Science as the breakthrough of 2007), which
might constitute susceptibility factors for the onset, progress and severity
of complex diseases . CNVs could directly affect the dose of
certain genes or modify loci that regulate the expression of relevant
genes, therefore providing important clues for disease and phenotype
variability . We are using and implementing multiple technologies to
further analyze CNVs potentially involved in several complex disorders,
mainly psychiatric diseases, neurodegenerative diseases and
inflammatory disorders. Functional validation of CNVs with respect to
disease needs: a/ verification that the genomic variants are associated
to changes in the expression of a gene product at the mRNA
and protein levels; and b/ characterization of the physiological consequences
associated to changes in the dose of a gene, which might
contribute to specific traits of the disease. We have identified several
genomic regions that contain CNVs that are common in the population
and that could have an enormous impact in disease predisposition .
We have preliminary results on the identification of CNVs for several
neurological, neuropsychiatric and inflammatory disorders, and we are
characterizing such genomic regions and performing genome scans to
uncover the variability landscape of these disorders .
s01.2
Gene copy number variation and common human disease
T. J. Aitman;
Physiological Genomics and Medicine Group, MRC Clinical Sciences Centre
and Imperial College, London, United Kingdom.
Gene copy number variation is now well recognised as a source of
sequence variation in the genome of humans and other mammals .
During positional cloning studies to identify genes for insulin resistance
and autoimmune glomerulonephritis in the rat, we showed that gene
copy number variants, at the Cd36 and Fcgr3 gene loci respectively,
contributed to disease susceptibility in the rat model . In humans, we
went on to show that low copy number of FCGR3B, an orthologue
of rat Fcgr3, was associated with glomerulonephritis in the autoimmune
disease systemic lupus erythematosus (SLE) . More recently we
found that low FCGR3B copy number predisposes to development of
SLE itself and to development of the systemic autoimmune diseases
microscopic polyangiitis and Wegener’s granulomatosis . These studies
provide direct evidence for the importance of heritable variation in
gene copy number in the evolution of genetically complex phenotypes,
including susceptibility to a range of common human diseases .
s01.3
Beta-defensin copy number variation: measurement,
diversification and association with psoriasis
J. A. L. Armour;
Institute of Genetics, Nottingham, United Kingdom.
In the current excitement surrounding the recent discoveries from casecontrol
association studies, it is essential to avoid overenthusiastic interpretation
of error-prone data . Although this is still an important consideration
for SNP typing, it is of particular concern in assessing the role of
copy number variation, for which the development of typing technology
satisfactory for case-control association studies is still in its early stages .
I will address the importance of accuracy (as well as throughput) in measuring
copy number, with reference to our own PRT methods applied to
beta-defensin variation on 8p23 .1 . This copy number variation involves a
cluster of seven defensin genes, presumed to act as antimicrobials, but
which may have a wider spectrum of functions; copy number variation is
commonly over the range between 2 and 7 copies per diploid genome .
The accuracy of the typing methodology has been essential in discovering
an association between beta-defensin copy number and psoriasis,
as well as in revealing an unexpected and highly unusual mechanism
for generating variation in the copy number of these genes .
s02.1
Mutation specific therapy: The CF experience
E. Kerem;
Hadassah University Hospital, Jerusalem, Israel.
CFTR mutations cause defects of CFTR protein production and function
by different molecular mechanisms . The mutations can be classified
according to the mechanisms by which mutations disrupt CFTR
function . This understanding of the different molecular mechanism
of CFTR dysfunction provides the scientific basis for development of
targeted drugs for mutation specific therapy of CF. Class I mutations
are nonsense mutations that result in the presence of premature stop
codon that leads to the production of unstable mRNA or the production
of a short truncated protein that is not functional . Drugs such as
the aminoglycoside antibiotics and PTC124 can suppress premature
termination codons by disrupting translational fidelity and allowing the
incorporation of an amino acid, thus permitting translation to continue
to the normal termination of the transcript . Class II mutations cause
impairment of CFTR processing and folding in the Golgi . As a result
the mutant CFTR is retained in the ER and eventually targeted for degradation
by the quality control mechanisms . Chemical and molecular
chaperons can stabilize protein structure, and allow it to escape from
degradation in the ER and be transported to the cell membrane . Class
III mutations disrupt the function of the regulatory domain . CFTR is
resistant to phosphorylation or ATP binding . CFTR activators can overcome
the affected ATP binding through direct binding to a nucleotide
binding fold . In patients carrying class IV mutations, phosphorylation
of CFTR results in reduced chloride transport . Increases in the overall
cell surface content of these mutants might overcome the relative reduction
in conductance . Activators of CFTR at the plasma membrane
may function by promoting CFTR phosphorylation, by blocking CFTR
dephosphorylation, by interacting directly with CFTR, and/or by modulation
of CFTR protein-protein interactions . Class V mutations affect
the spicing machinery and generate both aberrantly and correctly
spliced transcripts, the level of which vary among different patients
and among different organs of the same patient . Splicing factors that
promote exon inclusion or factors that promote exon skipping can promote
increase of correctly spliced transcripts, depending on the molecular
defect . Inconsistent results were reported regarding the required
level of corrected or mutated CFTR that has to be reached in order to
achieve normal function .
s02.2
synthetic lethal approaches to the development of new
therapies for cancer
A. Ashworth;
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research,
London, United Kingdom.
About one in nine women in the Western world develop cancer of the
breast and at least 5% of these cases are thought to result from a hereditary
predisposition to the disease . Two breast cancer susceptibility
(BRCA) genes have been identified and mutations in these genes account
for most families with four or more cases of breast cancer diagnosed
before the age of 60 . Women who inherit loss-of-function mutations
in either of these genes have an up to 85% risk of breast cancer
by age 70 . As well as breast cancer, carriers of mutations in BRCA1
and BRCA2 are at elevated risk of cancer of the ovary, prostate and
pancreas . The genes are thought to be tumour suppressor genes as
the wild-type allele of the gene is observed to be lost in tumours of
heterozygous carriers. Both BRCA1 and BRCA2 have significant roles
in the maintenance of genome integrity via roles in the repair of DNA
damage via homologous recombination. The specific DNA repair defect
in BRCA-mutant cells provides opportunities for novel therapeutic
approaches based on selective inhibition of functionally interacting
repair pathways, in particular by inhibition of the enzyme PARP . Here
I will describe recent work defining determinants of sensitivity and resistance
to PARP inhibitors, as well as the application of the synthetic
lethal approach to other cancer types .