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

Concurrent Sessions
preliminary results represent the first step to identify novel genes involved
in biological mechanisms important for human cerebral cortex
development and for processes causative of epilepsy.
C36. Activating SOS1 mutations cause Noonan syndrome
M. Tartaglia 1 , L. Pennacchio 2,3 , C. Zhao 4 , K. K. Yadav 4 , V. Fodale 1 , A. Sarkozy
5,6 , B. Pandit 7 , K. Oishi 7 , S. Martinelli 1 , W. Schackwitz 2,3 , A. Ustaszewska 2,3 ,
J. Martin 2,3 , J. Bristow 2,3 , C. Carta 1 , F. Lepri 5,6 , C. Neri 5,6 , I. Vasta 8 , K. Gibson 9 , C.
J. Curry 10 , J. P. Lopez Siguero 11 , M. C. Digilio 12 , G. Zampino 8 , B. Dallapiccola 5,6 ,
D. Bar-Sagi 4 , B. D. Gelb 7 ;
1 Istituto Superiore di Sanità, Rome, Italy, 2 Lawrence Berkeley National Laboratory,
Berkeley, CA, United States, 3 Joint Genome Institute, Walnut Creek, CA,
United States, 4 New York University School of Medicine, New York, NY, United
States, 5 IRCCS-CSS, San Giovanni Rotondo, Italy, 6 Istituto CSS-Mendel,
Rome, Italy, 7 Mount Sinai School of Medicine, New York, NY, United States,
8 Università Cattolica, Rome, Italy, 9 Royal Children’s Hospital, Herston, Australia,
10 Genetic Medicine Central California, Fresno, CA, United States, 11 Hospital
Materno-Infantil, Malaga, Spain, 12 Ospedale “Bambino Gesù”, Rome, Italy.
Noonan syndrome (NS) is a relatively common, genetically heterogeneous
Mendelian trait characterized by short stature, facial dysmorphisms,
congenital heart defects and skeletal anomalies. Accumulating
evidence supports the idea that NS is caused by enhanced RAS-
MAPK signaling. Indeed, gain-of-function mutations in PTPN11, the
gene encoding SHP-2, a protein tyrosine phosphatase that positively
controls RAS signaling, and KRAS have been documented in 50%
of NS cases. Here, we demonstrate that approximately 20% of NS
patients without PTPN11 or KRAS mutation have missense mutations
in SOS1, which encodes a RAS-specific guanine nucleotide exchange
factor (GEF). SOS1 mutations cluster at residues implicated in the
maintenance of SOS1 in its autoinhibited form and expression of two
NS-associated mutants induced enhanced RAS and ERK activation.
The phenotype associated with SOS1 defects is distinctive, although
within NS spectrum, with a high prevalence of ectodermal abnormalities
but generally normal development and linear growth. Our findings
implicate for the first time gain-of-function mutations in a RAS GEF in
inherited disease and define a new mechanism by which upregulation
of the RAS pathway can profoundly change human development.
C37. Mutations in the SPG11 gene, encoding spatacsin, are a
major cause of spastic paraplegia with thin corpus callosum
G. Stevanin1,2 , F. M. Santorelli3 , H. Azzedine1 , P. Coutinho4 , P. Denora1,3 , E.
Martin1 , A. Lossos5 , B. Fontaine6 , A. Filla7 , E. Bertini3 , A. Durr1,2 , A. Brice1,2 ;
1 2 INSERM UMR679 - NEB, Paris, France, APHP- Pitie-Salpetriere Hosptital,
Dpt Genetics Cytogenetics, Paris, France, 3IRCCS-Bambino Gesù Children’s
Hospital, Rome, Italy, 4Hospital S. Sebastiao and UnIGENe, Porto, Portugal,
5 6 Hadassah-Hebrew University Medical Center, Jerusalem, Israel, INSERM
U546, Paris, France, 7Federico II University, Naples, Italy.
Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin
corpus callosum (TCC) is a common and clinically distinct form of familial
spastic paraplegia, linked to the SPG11 locus on chromosome
15 in most families. It clinically manifests as spastic paraplegia usually
beginning during infancy or puberty, preceded by learning difficulties.
Some patients develop a pseudobulbar involvement, with dysarthria,
dysphagia and upper limbs spasticity, associated with bladder dysfunction
and signs of peripheral neuropathy. MRI shows thin corpus
callosum (TCC), with hyperintensities in periventricular white matter,
and cerebral cortical atrophy predominating in the frontal region.
We collected 12 ARHSP-TCC families. All available members were
genotyped using 34 microsatellite markers covering the candidate interval
for SPG11. Linkage analysis and haplotype reconstruction in 10
informative families restricted the SPG11 region to a 3.2-cM homozygous
region. Eighteen genes were analyzed in SPG11 index patients
by direct sequencing, but no disease-causing mutations were found in
17 of them. Ten mutations in 11 of the 12 families were found, however,
in a novel gene (KIAA1840/FLJ21439) expressed ubiquitously
in the nervous system but most prominently in the cerebellum, cerebral
cortex, hippocampus and pineal gland. The mutations were either
nonsense or insertions and deletions leading to frameshifts, suggesting
a loss-of-function mechanism.We have identified the SPG11 gene
that accounts for the majority of the ARHSP-TCC families studied here
(11/12). The identification of the function of the gene will provide insight
into the mechanisms leading to the degeneration of the corticospinal
tract and other brain structures in this frequent form of ARHSP.
C38. OST3 mutation in non-syndromic mental retardation:
expanding the spectrum of congenital disorders of
glycosylation?
F. Molinari 1 , S. Romano 1 , W. Morelle 2 , P. de Lonlay 1 , A. Munnich 1 , L. Colleaux 1 ;
1 INSERM U781, Paris, France, 2 UMR CNRS/USTL 8570, Lille, France.
Congenital disorders of glycosylation (CDG) is a group of inherited
disorders that affect glycoprotein biosynthesis. The Eighteen different
CDG types are characterized by a central nervous system dysfunction
and multi-organ involvement. Group I CDG results in the failure of assembly
or transfer of the N-glycan chain while group II is defined as
defects in the processing of the protein-bound glycan.
Here, we report on a non-syndromic mental retardation (MR) in two sibs
born to first cousin French family. Homozygosity mapping in the two affected
and two healthy children led to the identification of a unique homozygous
region of 8 Mb on 8p23.1-p22. This interval encompassed
the gene TUSC3/OST3 (Ost3 S.cerevisae homologue) encoding a
protein involved in the oligosaccharyltransferase complex which catalyses
the transfer of an oligosaccharide chain on nascent proteins, the
key step of the N-Glycosylation process. Sequencing the OST3 gene
identified a one base-pair insertion in exon 6, 787_788insC. The mutation
co-segregated with the disease and resulted in a premature stop
codon 37 codons downstream of the coding sequence, N263fsX300.
Extensive work-up (Caryotype analysis, liver function, clotting factors,
brain MRI, EEG) was unremarkable with normal isoelectric focusing
and Western blotting assay of serum N-glycoproteins.
Recent studies of glycoprotein fucosylation and polysialic acid modification
of neuronal cell adhesion molecules have shown the critical role
of glycoproteins in synaptic plasticity. However, our results provide the
first demonstration that a defect in N-Glycosylation can result in nonsyndromic
MR providing therefore new insights in the understanding of
the pathophysiological bases of MR.
C39. A defect in the ionotropic glutamate receptor 6 gene
(GLUR6) causes autosomal recessive mental retardation
M. M. Motazacker 1 , B. Rost 2 , T. Hucho 1 , M. Garshasbi 1 , K. Kahrizi 3 , R. Ullmann
1 , F. Behjati 3 , R. Vazifehmand 3 , A. Tzschach 1 , L. R. Jensen 1 , D. Schmitz 4 ,
H. Najmabadi 3 , H. H. Ropers 1 , A. W. Kuss 1 ;
1 Max-Planck-Institute for molecular genetics, Berlin, Germany, 2 Neuroscience
research center (NWFZ), Charité, Berlin, Germany, 3 University of social welfare
and rehabilitation sciences, Tehran, Islamic Republic of Iran, 4 Neuroscience
research center (NWFZ), Charité, Berlin, Germany.
Mental retardation (MR) is among the most common forms of genetic
handicaps. So far, however very little is known about the gene defects
underlying this disorder. Especially the contribution of autosomal recessive
hereditary defects is largely unresolved and to date, only three
genes have been found to be directly associated with non-syndromic
autosomal recessive MR (NS-ARMR).
We have previously identified 8 new genomic loci for NS-ARMR
(MRT6-11) and report here a complex deletion-inversion mutation in
the glutamate receptor 6 gene (GLUR6, GRIK2), a member of the kainate
receptor family. GLUR6 maps to the MRT6 locus, a 10Mb linkage
interval on Chr6q16.3, which we have recently identified in a large consanguineous
Iranian family with moderate to severe non-syndromic
ARMR. As shown by Southern blotting, inverse PCR, array-CGH and
cloning experiments, the sequence changes include a deletion of approximately
120Kb including exons 7 and 8, as well as an inversion of
about 80Kb that encompasses exons 9 to 11. This mutation was not
found in 172 controls, and the integrity of the coding sequence of 7
other potential candidate genes in the interval was verified by direct
sequencing.
Glutamate receptor signalling has previously been implicated in the
pathogenesis of the fragile-X-syndrome and may also play a role in
autism. However, our studies provide the first direct evidence for the
importance of glutamate receptors in human cognition. Moreover, they
have implications for the diagnosis and prevention of NS-ARMR and
may shed new light on the role of ion channels in the human brain.
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