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

Plenary Lectures
Plenary Lectures
PL01. Establishment and hereditary transmission of epigenetic
modifications and pathological developments: the mouse model
F. Cuzin;
Unité 636 de l’Institut de la Santé et, de la Recherche Médicale, Nice, France.
No abstract available as per date of printing. Please check www.eshg.
org for updates in the online database.
PL02. DNA Repair, genome maintenance and human disease
M. Radman;
Faculté de Médecine, Necker, Université Paris 5, Paris, France.
No abstract available as per date of printing. Please check www.eshg.
org for updates in the online database.
PL03. Human neuroimaging - contributions to neurogenetics
R. Frackowiak;
Wellcome Department of Imaging Neuroscience, Institute of Neurology, UCL,
London, United Kingdom.
Voxel based morphometry (VBM) is a new way of analysing structural
MR images. VBM can characterise differences in structural MRI scans
of diseases influenced by genetic variation. In X-linked Kallmann’s syndrome
there is selective hypertrophy of the pyramidal tract in patients
with mirror movements compared to those without. In a dominantly
inherited, dyspraxic, language-impaired family, gene penetrance is
full and associated with abnormal structure and function of the caudate
nucleus and other areas. Atrophy of the caudate in affected family
members is associated with task-related hyperactivity, suggesting
functional compensation. Presently unaffected individuals from families
of Huntington’s patients show caudate atrophy that correlates with
genetic status. Caudate atrophy correlates with clinical score and CAG
codon repeats on chromosome 4. Studies with Turner’s and partial
Turner’s patients have identified focal structural brain abnormalities.
Candidate regions on the X-chromosome have been found that influence
amygdala and orbital frontal cortex development. A structural
amygdala abnormality in patients predicts failure to recognise fear in
photographs of faces; a prediction that is now confirmed. These studies
suggest that imaging is an efficient way of associating candidate
genes with quantitative measures of brain structure and function and
that informative intermediate phenotypes can be described that predict
future disease in asymptomatic at-risk individuals.
PL04. Neurodegeneration in lysosomal storage diseases is
associated with impairment of autophagy
A. Fraldi 1 , C. Settembre 1 , C. Spampanato 1 , R. de Pablo 1 , D. L. Medina 1 , L. Jahreiss
2 , A. Lombardi 1 , C. Venturi 3 , C. Tacchetti 3 , D. C. Rubinsztein 2 , A. Ballabio 1,4 ;
1 Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy, 2 Department
of Medical Genetics, Cambridge Institute for Medical Research, University
of Cambridge, Cambridge, United Kingdom, 3 Department of Experimental
Medicine and §MicroSCoBiO Research Center and IFOM Center of Cell Oncology
and Ultrastructure, University of Genoa, Genoa, Italy, 4 Medical Genetics,
Department of Pediatrics, Federico II University, Naples, Italy.
Autophagy is the mechanism responsible for the turn-over of intracellular
organelles and digestion of protein aggregates which are sequestered
by autophagosomes and degraded upon the fusion of the
autophagosome with the lysosome. Several neurodegenerative disorders,
such as Alzheimer, Parkinson and Huntington diseases are
associated with an impairment of autophagy. We have analyzed the
autophagic pathway in two different murine models of lysosomal storage
disorders (LSDs), Multiple Sulfatase Deficiency (MSD) and Mucopolysaccharidosis
type IIIA (MPS-IIIA). Western blotting, immunofluorescence
and immunohistochemical analyses using anti-LC3 antibodies
demonstrated a significant intracellular accumulation of autophagic
(LC3-positive) vacuoles in MEFs as well as in several brain regions of
both MSD and MPS-IIIA mice. Accumulation of autophagosomes was
also confirmed by ultrastructural analysis. Co-staining of MEFs using
both anti-LC3 and anti-LAMP2 antibodies demonstrated that autophagosomes
do not co-localize with lysosomes, suggesting the presence
of a fusion defect. As a consequence of an impairment of autophagy,
a massive intracellular accumulation of ubiquitin-positive aggregates
and an increased number of mitochondria with altered membrane potential
were detected in the brain of both MSD and MPS-IIIA mice. Interestingly,
the build-up of polyubiquitinated proteins and dysfunctional
mitochondria has been associated with neuronal cell death in neurodegenerative
diseases. Taken together our data indicate that accumulation
of storage material, due to the lysosomal enzyme deficiency,
causes a lysosomal dysfunction which affects the autophagic pathway,
and more specifically the formation of autophagolysosomes. We postulate
that neurodegeneration in LSDs is caused by secondary storage
of toxic protein aggregates due to an impairment of autophagy.
PL05. Identification of 3 novel genes that cause X-linked mental
retardation; AP1S2, CUL4B and ZDHHC9.
F. Raymond 1 , P. Tarpey 2 , G. Turner 3 , R. Stevenson 4 , C. Schwartz 4 , J. Gecz 5 , P.
Futreal 2 , M. Stratton 2 , on behalf of the GOLD (Genetics of Learning Disability)
study;
1 Cambridge Institute for Medical Research, Cambridge, United Kingdom,
2 Sanger Institute, Cambridge, United Kingdom, 3 University of Newcastle, Newcastle,
Australia, 4 JC Self Research Institute of Human Genetics, Greenwood,
SC, United States, 5 University of Adelaide, Adelaide, Australia.
Phenotypic variability, genetic heterogeneity and the high number of
disease genes estimated to be involved has made the identification of
causative gene abnormalities in X-linked mental retardation complex.
To identify further novel disease genes we have used a systematic
mutational screen of the X chromosome in 250 families with multiple
affected members with mental retardation.
We report the identification of 3 novel genes that cause X-linked mental
retardation.
AP1S2 encodes the sigma 2 subunit of the adaptor protein 1 complex.
We have identified 3 truncating mutations associated with mental retardation,
hypotonia, delayed walking, absent speech and aggressive
behaviour. The AP1 complex is present in endosomes and the trans-
Golgi network and binds vesicle cargo proteins destined for transport
into different cellular compartments.
CUL4B is an ubiquitin E3 ligase subunit involved in targeting of proteins
for intracellular degradation. We have identified 8 mutations, 5
truncating and 3 conserved missense mutations. Additional clinical
features include macrocephaly, central obesity, hypogonadism, pes
cavus and tremor were observed in some of the affected individuals
but not all.
ZDHHC9 is a palmitoyltransferase that catalyses the post-translational
modification of NRAS and HRAS. The phenotype associated with the
2 truncating and 2 conserved missense mutations found were mental
retardation and a Marfanoid habitus.
This systematic strategy has identified 3 entirely novel disease causing
mechanisms which would not have been predicted by a candidate
gene approach and illustrates that defects in many different cellular
processes may be sufficient to cause a mental retardation phenotype.
PL06. Mutations in LRP2, coding for the multi-ligand receptor
megalin, cause Donnai-Barrow and Faciooculoacousticorenal
(FOAR) syndromes
S. Kantarci 1 , L. Al-Gazali 2 , R. Hill 3 , D. Donnai 4 , G. C. M. Black 4 , E. Bieth 5 , N.
Chassaing 5,6 , D. Lacombe 6 , K. Devriendt 7 , A. Teebi 8 , M. Loscertales 1 , C. Robson
9 , T. Liu 10 , D. T. MacLaughlin 1 , K. M. Noonan 1 , M. K. Russell 1 , C. A. Walsh 3,9 ,
P. K. Donahoe 1 , B. R. Pober 1,9 ;
1 Massachusetts General Hospital, Boston, MA, United States, 2 UAE University,
Al Ain, United Arab Emirates, 3 Beth Israel Deaconess Medical Center,
Boston, MA, United States, 4 University of Manchester and St Mary’s Hospital,
Manchester, United Kingdom, 5 Hopital Purpan, Toulouse, France, 6 Hôpital Pelligrin,
Bordeaux, France, 7 University of Leuven, Leuven, Belgium, 8 Weill Cornell
Medical College in Qatar and Hamad Medical City, Doha, Qatar, 9 Children’s
Hospital, Boston, MA, United States, 10 Brigham and Women’s Hospital, Boston,
MA, United States.
Donnai-Barrow syndrome (DBS) is an autosomal recessive disorder
characterized by hypertelorism, myopia, corpus callosum agenesis,
deafness, omphalocele, and congenital diaphragmatic hernia. There is
phenotypic overlap with Faciooculoacousticorenal syndrome (FOAR).
Genetic mapping using Affymetrix 10K SNP arrays on four DBS children
from one large consanguineous kindred identified a 17 cM region
of homozygosity-by-descent on chromosome 2q23.3-q31.1. This was
refined and confirmed by microsatellite marker analysis in three additional
multiplex DBS families.
Sequencing of candidate genes in six DBS and one FOAR kindreds
revealed homozygous or compound heterozygous mutations in the 79
exon LRP2 gene in all cases. LRP2 encodes megalin, a ~600 kDa