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

Concurrent Symposia 10
chromosomal association of the TH1 ifnγ locus and TH2 loci, which
are mutually exclusively expressed by two subtypes of differentiated T
helper cells, precedes differentiation and may act as a checkpoint for T
cell fate determination. Since this primary observation, we have found
several other cases of interchromosomal associations between different
cytokine loci in the naïve T cell precursors. Interestingly, upon TH
cell differentiation, these associations are terminated and replaced by
interactions between expressed loci. Regulatory elements in one locus
appear to play an active role in orchestrating processes across these
chromosomes. The interchromosomal interactions we describe appear
to direct either activatory or silencing roles in gene transcription.
S22. Molecular mechanisms of congenital hyperinsulinism
P. De Lonlay 1,2 , C. Bellanné-Chantelot 3 , I. Giurgea 1 , M. Ribeiro 4 , V. Valayannopoulos
1 , Y. Aigrain 5 , J. Robert 6 , F. Brunelle 7 , J. Rahier 8 , C. Fékété 5 , Y. de
Keyzer 9 , F. Jaubert 10 ;
1 Service de neuropédiatrie et de maladies métaboliques, Hôpital Necker
Enfants-Malades, Paris, France, 2 INSERM-U781, Paris, France, 3 Service de
biologie moléculaire, Hôpital Necker Enfants-Malades, Paris, France, 4 1Service
Hospitalier Frédéric Joliot, Département de Recherche Médicale, Direction des
Sciences du Vivant,, Orsay, France, 5 Service de chirurgie viscérale, Hôpital
Necker Enfants-Malades, Paris, France, 6 Service de diabétologie, Hôpital
Necker Enfants-Malades, Paris, France, 7 Service de radiologie pédiatrique,
Hôpital Necker Enfants-Malades, Paris, France, 8 Service d’anatomopathologie,
Université de Louvain, Louvain, Belgium, 9 INSERM-U781, Hôpital Necker Enfants-Malades,
Paris, France, 10 Service d’anatomopathologie, Hôpital Necker
Enfants-Malades, Paris, France.
Persistent hyperinsulinemic hypoglycemia of infancy (HI) is the most
important cause of hypoglycemia. HI is a heterogeneous disorder
which may be divided into two forms on the basis of the histopathological
lesion, but which are clinically indistinguishable: diffuse (DiHI) and
focal (FoHI).
FoHI is characterized by somatic islet-cell hyperplasia, which is associated
with hemi- or homozygosity of a paternally inherited mutation
of the sulfonylurea-receptor (ABCC8 or SUR1) or the inward rectifying
potassium channel genes (KCNJ11 or Kir6.2) on chromosome 11p15,
and loss of the maternal allele in the hyperplastic islets. The focal lesion
is a sporadic event, as indicated by the somatic molecular abnormality
in the pancreas, the observation of discordant identical twins
and our experience. However, FoHI occurring in consanguineous family
can repeat with a diffuse form.
DiHI is a heterogeneous disorder which can be caused by various defects
in the regulation of insulin secretion by the pancreatic beta-cell.
The same genes can be implicated in neonatal diabetes or MODY.
These include:
i) channelopathies affecting either the SUR1 or the KIR6.2 channel;
Recessive ABCC8 mutations and, more rarely, recessive KCNJ11 mutations,
are responsible for the majority of diffuse and severe neonatal
HI resistant to medical treatment. Dominant ABCC8 mutations are responsible
for less severe HI sensitive to diazoxide;
ii) metabolic HI since anaplerosis appears to play an important role
in the secretion of insulin, including GCK, GDH and probably SCHAD
deficiencies; the two first causes are dominantly inherited or caused
by a de novo mutation;
iii) defects of insulin transcription factors (HNF4A mutations described
in MODY and HI) or insulin receptor, with de novo or dominantly-inherited
mutations, or defect in proinsulin processing.
Syndromic HI (CDG, HI/HA by overactivity of GDH with hyperammonemia,
Sotos, Beckwith-Wiedemann and Kabuki syndromes) is rare in
our recruitment. Symptoms associated to diazoxide-sensitive hypoglycaemia
are mental retardation, diarrhea, liver abnormalities, gigantism,
or malformations. The differential diagnosis is facticious hypoglycemia
secondary to Munchausen by proxy syndrome.
S23. Title not available as per date of printing
J. M. Houghton;
Department of Medicine, GI Division (JH), Department of Cancer Biology,
Worcester, MA, United States.
No abstract available as per date of printing. Please check www.eshg.
org for updates in the online database.
S24. Stem cell renewal and the Nanog gene
A. Smith;
Wellcome Trust Centre for Stem Cell Research, Department of Biochemistry,
School of the Biological Sciences, Cambridge, United Kingdom.
No abstract available as per date of printing. Please check www.eshg.
org for updates in the online database.
S25. The role of Pax5 in B-cell commitment and
lymphomagenesis
C. Cobaleda1 , W. Jochum2 , M. Busslinger1 ;
1Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria,
2Department of Pathology, University Hospital, Zurich, Switzerland.
Lineage commitment and differentiation to a mature cell type are considered
to be unidirectional and irreversible processes under physiological
conditions. Mature B lymphocytes critically depend on the
transcription factor Pax5 for their differentiation and function. Here we
show that conditional Pax5 deletion allowed mature B cells from peripheral
lymphoid organs to dedifferentiate in vivo back to early uncommitted
progenitors in the bone marrow, which rescued T-lymphopoiesis
in the thymus of T cell-deficient mice. These B cell-derived T-lymphocytes
carried not only immunoglobulin heavy- and light-chain gene
rearrangements, but also participated as functional T cells in immune
reactions. Notably, mice lacking Pax5 in mature B cells also developed
aggressive lymphomas, which were identified by their gene expression
profile as progenitor cell tumours. Hence, the complete loss of Pax5
in late B cells could initiate lymphoma development and uncovered
an extraordinary plasticity of mature peripheral B cells despite their
advanced differentiation stage.
S26. Copy number variation in the human genome
S. W. Scherer;
Hospital for Sick Children, Toronto, ON, Canada.
The advent of genome-scanning technology and comparative DNA
analysis has uncovered a significant extent of structural variation in the
human genome. Structural variants can include microscopic and more
commonly submicroscopic deletions, duplications, insertions, and
large-scale copy number variants - collectively termed copy number
variants (CNVs) or polymorphisms - as well as, inversions and translocations.
CNVs are the most prevalent form of structural variation and
they can comprise millions of nucleotides of heterogeneity within every
genome, having an important contribution to human diversity and disease
susceptibility. We have been applying numerous experimental
and data mining approaches to catalogue the complete complement of
CNVs in worldwide populations, as well as to characterize the genomic
features and affects of CNVs. Our collective data, integrated with all
other available information, is released in the ‘Database of Genomic
Variants’ (http://projects.tcag.ca/variation/), which we are continually
curating and upgrading. The database serves as a resource to assist
numerous clinical research studies. Our latest data assessing CNV
content for involvement in disease will also be presented.
S27. Destabilization of the NFAT Signaling Pathway in Down
Syndrome
I. A. Graef 1 , G. R. Crabtree 2 , A. Polleri 1 , U. Francke 3 ;
1 Dept.of Pathology, Stanford, CA, United States, 2 Dept.of Developmental Biology
& Pathology, HHMI, Stanford, CA, United States, 3 Dept.of Genetics, Stanford,
CA, United States.
Trisomy 21 results in Down Syndrome (DS), but little is known about
how a 1.5-fold increase in gene dosage produces the pleiotropic phenotypes
of DS. Studies of patients with partial trisomy 21 have defined
a DS critical region (DSCR) on chromosome 21q. We have recently
shown that increased dosage of two genes, found within the DSCR,
cooperatively reduces the activity of the calcineurin/NFAT signaling
pathway, which is a critical regulator of vertebrate development (1,2).
At the centromeric border of the DSCR is DSCR1, a member of a
family of closely related inhibitors of the protein phosphatase calcineurin.
DSCR1 is blocks the calcineurin dependent nuclear localization of
the NFATc proteins in response to Ca 2+ influx. DYRK1a is telomeric to
DSCR1 and encodes a nuclear kinase that blocks NFAT signaling by
rapid nuclear export of NFATc proteins. We found that mice harbouring
mutations of the four genes encoding NFATc transcription factors,
individually and in combinations, exhibit many of the characteristics of
DS. Transgenic expression of DYRK1a and DSCR1 produces features