2008 Barcelona - European Society of Human Genetics

Concurrent Symposia
s08.3
chromosome rearrangements and fusion genes in breast and
other epithelial cancers
P. Edwards;
Department of Pathology, University of Cambridge, Hutchison-MRC Research
Centre, Cambridge, United Kingdom.
Chromosome translocations that form fusion transcripts or activate
genes by promoter insertion are central to leukaemias, lymphomas,
and sarcomas, but for various reasons have been neglected in the
common epithelial cancers . It is now clear that at least some of the
abundant chromosome rearrangements in the common cancers create
fusion genes (reviewed by Mitelman et al, Nature Reviews Cancer
2007;7:233) . Tomlins et al . (Science 2005;310:644) have shown
that most prostate cancers have fusions of ETS transcription factors
and Soda et al (Nature 2007;448:561) reported an EML4-ALK fusion
present in around 7% of NSCLC lung cancers . We have undertaken
a comprehensive analysis of chromosome rearrangements in breast
cancer cell lines, mapping all rearrangements to 1Mb resolution or better
(Howarth et al, Oncogene 2008, PMID18084325) . We used ‘array
painting’, in which chromosomes are isolated using a cell sorter (flow
cytometer) and then hybridised to DNA microarrays to determine what
parts of the genome are present in each chromosome . We found that
many more translocations were balanced than expected: a total of nine
reciprocal translocations in three cell lines completely analysed, with
several other translocations balanced for at least one of the participating
chromosomes . Many of the mapped breakpoints were in the kind
of genes one would expect oncogenic translocations to target, and to
date three in-frame fusion transcripts have been verified. It may be
that gene fusions caused by chromosome rearrangement will prove to
be as significant in common epithelial cancers as in leukaemias and
sarcomas .
s09.1
Intracelluar Traficking and Neurodegeneration - The SCA1/
ataxin-1 story
H. T. Orr;
Institute of Human Genetics, The University of Minnesota, Minneapolis, MN,
United States.
Spinocerebellar Ataxia type 1 (SCA1) is one of nine inherited disorders
caused by a polyglutamine expansion in the affected protein . In SCA1
this expansion is in the ataxin-1 (ATXN1) protein . Nuclear localization
of ATXN1 is implicated in the pathology of SCA1 . Previous worked
showed that toxicity of mutant ATXN1 is due to soluble protein and its
interacting proteins . Thus, polyglutamine-expanded mutant ATXN1 is
able to interact with several other nuclear proteins and incorporate into
native complexes similar to wild type protein. We identified partners
of ATXN1 that interact with it in a manner dependent on two criteria
necessary for toxicity: polyglutamine expansion and phosphorylation
at serine 776 . Polyglutamine expansion as well as phosphorylation of
serine 776 in ATXN1 favors the formation of a particular protein complex
containing a putative regulator of RNA splicing RBM17 . We further
found that changing the serine at position 776 to an aspartic acid
(a substitution that can mimic phosphorylation) renders a wild type allele
of ataxin-1 with 30 glutamines pathogenic in vivo . Mice expressing
ataxin-1 30Q-D776 have a phenotype very similar to that seen in mice
expressing ataxin-1 82Q-S776. These findings demonstrate the glutamine
expansion in ATXN1 enhance protein/protein interactions that
are normally regulated by its phosphorylation at serine at position 776
and that polyglutamine-induced misregulation of S776 phosphorylation
and subsequent alterations in nuclear trafficking underlie SCA1
pathogenesis .
s09.2
Polyneuropathies and axonal trafficking
K. A. Nave;
Department of Neurogenetics, Max Planck Institute of Experimental Medicine,
Goettingen, GERMANY.
s09.3
‚Neurotic Yeast‘ and the molecular Basis of Parkinson‘s Disease
T. F. Outeiro;
Instituto de Medicina Molecular, Cell and Molecular Neuroscience Unit, Lisboa,
Portugal.
Aging is the major known risk factor for Alzheimer’s disease (AD) and
Parkinson’s disease (PD), but genetic deffects have been associated
with familial cases . Huntington’s disease (HD) is a purely genetic neurodegenerative
disorder, where mutations in the IT15 gene, encoding
for the protein huntingtin, determine the development of the disease .
A common hallmark to many neurodegenerative diseases is the presence
of proteinacious inclusions inside neuronal populations, which
are selectivelly affected in each disorder. Lewy bodies, made of αsynuclein
in PD, and huntingtin inclusions, in HD, are but a few examples
of protein aggregates deposited inside neurons . Whether inclusions
are themselves toxic or actually cytoprotective is still under
current debate, but it is widely accepted that protein misfolding and
oligomerization are central molecular events in these diseases .
Molecular genetic approaches using different model organisms, from
yeast to mammalian cell culture and mouse models, coupled with advanced
microscopy techniques resulted in a detailed characterization
of the pathways and events involved in cytotoxicity .
Using the budding yeast Saccharomyces cereviseae as a ‘living test
tube’ we were able to unveil fundamental aspects of α-synuclein biology
. Powerful yeast genetic screens enabled us to identify several
molecular pathways as playing central roles in the toxicity induced by
α-synuclein. Genes involved in intracellular trafficking, lipid metabolism,
and oxidative stress, were among the most highly represented
categories . With this knowledge at hand, we are applying a variety of
tools to unravel the molecular basis of neurological disorders associated
with protein misfolding, with the goal of developing novel avenues
for therapeutic intervention .
s10.1
in utero stem cell transplantation: where are we now?
T. H. Bui;
The Karolinska Institute, Department of Molecular Medicine, Clinical Genetics
Unit, Karolinska University Hospital, Stockholm, Sweden.
In the last 35 years, extensive progress has been made in the prenatal
diagnosis of genetic disorders . In contrast, success in fetal therapeutic
interventions has been more limited .
One of the basic tenets of immunology is learned self tolerance: the
ability, at the cellular and molecular levels, to recognise “self” and to
eliminate that which is “foreign” must be “learned” during fetal life .
This paradigm has served to support the concept of in utero transplantation
(IUT), a promising approach with the potential to effectively
treat fetuses with a variety of genetic defects . The rationale is to take
advantage of normal events during haematopoietic and immunological
ontogeny to facilitate allogeneic stem cell engraftment at an early
stage of pregnancy, before permanent damage has occurred to the
fetus . Clinical success has been realised, so far, in only fetuses with
severe combined immunodeficiency syndromes. More recently, research
has focused on mesenchymal stem cells (MSCs) . Like adult
bone marrow-derived MSCs, fetal liver-derived MSCs appear to be
non-immunogenic both in vitro and in vivo . Both adult and fetal MSCs
retain multilineage potential to form e .g . cartilage, bone, adipose and
muscular tissues on induction. The first cases of IUTs using fetal MSCs
for fetuses with severe osteogenesis imperfecta have been performed
in our Centre .
Lessons learned from animal studies and clinical cases have contributed
in defining new strategies to possibly overcome barriers to engraftment
or tolerance in the fetus . The experience gained in IUTs is likely
to benefit also the new experimental field of intrauterine gene therapy.
Clearly, ethical issues relating to these new frontiers of medicine need
also to be addressed .