European Human Genetics Conference 2007 June 16 – 19, 2007 ...

Plenary Lectures
transmembrane protein that mediates receptor-mediated endocytosis
for re-uptake of numerous ligands including lipoproteins, sterols, vitamin-binding
proteins, and hormones in the renal proximal tubules and
other sites, and may also play a role in Sonic hedgehog signaling.
The DBS/FOAR phenotypes mirror those of megalin knock out mice
which have perinatal lethality due to respiratory insufficiency, and malformations
of the forebrain and eye (agenesis of the corpus callosum,
holoprosencephaly, microphthalmia). Among surviving mice, low-molecular
weight proteinuria with spillage of retinol binding and vitamin
D-binding proteins has been demonstrated. We confirmed comparable
urinary abnormalities in our patients, which may serve as a valuable
diagnostic marker.
We suggest that malformations of DBS/FOAR result from mutations in
LRP2 and absence of functional megalin leading to embryonic failure
to uptake and deliver key lipophilic compounds required for normal development.
This identifies pathways important in neural and diaphragmatic
development and suggests potential targets for therapy.
PL07. RAB23 mutations in Carpenter syndrome imply an
unexpected role for Hedgehog signaling in cranial suture
development and obesity
D. Jenkins1 , D. Seelow2 , F. S. Jeehee3 , C. A. Perlyn4 , L. G. Alonso5 , D. F.
Bueno6 , D. Donnai7 , D. Josifiova8 , I. M. J. Mathijssen9 , J. E. V. Morton10 , K.
Orstavik11 , E. Sweeney12 , S. A. Wall13 , J. L. Marsh14 , P. Nurnberg2 , M. Passos-
Bueno15 , A. O. M. Wilkie1 ;
1 2 Weatherall Institute of Molecular Medicine, Oxford, United Kingdom, Cologne
Center for Genomics and Institute for Genetics, Cologne, Germany, 3Centro de Estudos de Genomca Humano, Sao Paulo, Brazil, 4Washington University
School of Medicine, St Louis, MO, United States, 5Universidade Federal de Sao
Paulo, Sao Paulo, Brazil, 6Universidade de Campinas, Sao Paulo, Brazil, 7Uni versity of Manchester, Manchester, United Kingdom, 8Guy’s Hospital, London,
United Kingdom, 9Erasmus Medical Center, Rotterdam, The Netherlands, 10Bir mingham Women’s Hospital, Birmingham, United Kingdom, 11Rikshospitalet- Radiumhospitalet Medical Centre, Oslo, Norway, 12Liverpool Women’s Hospital,
Liverpool, United Kingdom, 13John Radcliffe Hospital, Oxford, United Kingdom,
14 15 St John’s Mercy Medical Center, St Louis, MO, United States, Universidade
de Sao Paulo, Sao Paulo, Brazil.
Carpenter syndrome is a pleiotropic disorder with autosomal recessive
inheritance, the cardinal features of which include craniosynostosis,
polysyndactyly, obesity and cardiac defects. Using homozygosity
mapping, we found linkage to chromosome 6p12.1-q12 and, in 15
independent families, identified five different mutations (4 truncating, 1
missense) in RAB23, which encodes a member of the RAB GTPase
family of vesicle transport proteins and acts as a negative regulator
of Hedgehog (HH) signaling. In 10 patients the disease was caused
by homozygosity for the same nonsense mutation, L145X, which resides
on a common haplotype, indicative of a founder effect in patients
of northern European descent. Surprisingly, nonsense mutations of
Rab23 in open brain mice cause recessive embryonic lethality with
neural tube defects, suggesting a species difference in the requirement
for RAB23 during early development. The discovery of RAB23
mutations in Carpenter syndrome implicates HH signaling in cranial
suture biogenesis, an unexpected finding given that craniosynostosis
is not usually associated with mutation of other HH pathway components,
and provides a new molecular target for studies of obesity.
PL08. Y chromosome detection by Real Time PCR and
pyrophosphorolysis-activated polymerization using free fetal
DNA isolated from maternal plasma.
H. B. Schlecht 1 , E. M. J. Boon 2 , P. Martin 3 , G. Daniels 3 , R. H. A. M. Vossen 4 , J.
T. den Dunnen 4 , B. Bakker 2 , R. Elles 1 ;
1 National Genetics Reference Laboratory, Manchester, United Kingdom,
2 Leiden University Medical Centre, Leiden, The Netherlands, 3 International
Blood Group Reference Centre, Bristol, United Kingdom, 4 Leiden Genome
Technology Centre, Leiden, The Netherlands.
The discovery of cell-free fetal DNA in the maternal blood plasma has
potential for the development of non-invasive prenatal diagnosis of fetal
sex and genetic traits. Current fetal genetic testing relies mainly on
invasive testing by chorionic villus sampling or amniocentesis, which
carry a significant risk of fetal loss (1-2%). Detection of Y chromosomal
sequence of fetal origin is highly advantageous for early fetal
sex determination where there is a risk of X-linked genetic disorders
or conditions such as congenital adrenal hyperplasia. Highly sensitive
and specific techniques are required to accurately detect the very low
levels of cell free fetal DNA in the maternal plasma. This study is to
validate the use of Real Time PCR, a widely used technique that can
detect very low levels of Y chromosomal sequence, and to assess the
use of a highly sensitive PCR technique, pyrophosphorolysis-activated
polymerisation (PAP), for fetal sex determination. Both techniques detected
Y chromosome sequence at very low levels with high specificity
and sensitivity. Furthermore, the PAP technique was shown to be more
robust than the Real Time PCR as none of the samples tested failed to
meet the acceptance criteria. Combining the two techniques for male
fetal sex detection from maternal blood plasma increases the sensitivity
and specificity in this series. This study shows that the PAP assay
can be used for Y chromosome detection using ffDNA. Furthermore,
by using PAP in combination with Real Time PCR more reliable early
non invasive prenatal sexing can be performed.
PL09. Neurodegenerative dementias
C. Van Broeckhoven;
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics,
VIB; Laboratory of Neurogenetics, Institute Born-Bunge; and University of Antwerp,
Antwerpen, Antwerpen, Belgium.
The neurodegenerative dementias are characterized by different clinical
and pathological phenotypes and are diagnosed according to specified
criteria. In brain the pathology shows different neurodegenerative
profiles due to the deposition of defined proteins in defined areas that
are characteristic for the disease e.g. tau within neurons in tauopathies.
Neurodegenerative dementias are known to have a genetic aetiology
though multifactorial in nature meaning that both genetic and
environmental factors contribute to the expression of the disease.
Since almost 20 years molecular and epidemiological geneticists are
aiming at identifying the genetic variations that underlie the disease
process. Initial results were obtained in families in which the disease
was apparently only genetically since the disease was transmitted as
an autosomal dominant trait. As in most multifactorial diseases, also in
all dementia subtypes rare families with a monogenic trait have been
identified. In these families causal genes were identified that when
mutated produced a 100% risk for the carrier of the mutated gene.
The proteins involved are being studied in detail and have resulted in
important biological hypothesis that are currently being pursued for the
development of suitable and more effective treatments e.g. the amyloid
cascade in Alzheimer’s dementia. For the majority of patients where
the disease is multifactorial, not many susceptibility genes have been
identified i.e. genes that carry a genetic variation that predisposes to
disease in conjunction with environmental factors. One reason is that
each one of these genetic variants contributes a small fraction of the
risk and that not yet the right instruments are available for finding these
small effects contributed by several distinct genes. Nevertheless, the
current knowledge of genetics and biology of neurodegeneration in
dementias indicates that there is substantial crosstalk between the different
pathways that lead to disease substantiating the complexity of
brain and disease.
PL10. Selective reduction of cerebellar iron accumulation in
Friedreich’s Ataxia obtained by a moderate defriprone chelation
treatment
A. Munnich 1 , N. Boddaert 2 , Z. I. Cabantchik 3 ;
1 Med. Genetics Clinic and Research Unit INSERM 393, Pediatric Radiology
Unit, Paris, France, 2 Hôpital Necker-Enfants Malades and Université Paris V
René Descartes, Paris, France, 3 Dept of Biol. Chemistry and Charles E. Smith
Psychobiology Laboratory, A. Silberman Institute of Life Sciences, Hebrew
University of Jerusalem, Safra Campus-Givat Ram, Jerusalem, Israel.
Background. Friedreich’s ataxia (FA) is caused by a deficiency in
frataxin needed for mitochondrial Fe-S cluster (ISC) formation and
heme protein synthesis. The resulting dysfunctional respiratory chain
activity and ensuing oxidative damage are accompanied and possibly
associated with mitochondrial iron accumulation. Previous attempts to
overcome the above deficiencies have led to the successful application
of the CoQ 10 analog Idebenone for reducing cardiac complications.
Failure of Idebenone to slow-down neurodegeneration has led to us to
consider the removal of regionally accumulated iron as a possible adjunct
therapy in FA. The rationale used in this work rested on the concept
that oxidative damage is generally caused by iron accumulated
in chemically labile (redox-active and chelatable) forms, but also that