2009 Vienna - European Society of Human Genetics

Concurrent Sessions
development of the cerebellum and/or the spinal cord, and, in most
cases, by onset before the age of 20 years. Causative genes have
been identified for the most frequent forms of autosomal recessive
ataxia. Nonetheless, genes remain unidentified for about half of the
cases.
A SNP-based genome-wide scan in a consanguineous family with 3
affected siblings allowed us to identify a novel locus for autosomal
recessive ataxia on chromosome 3qter. By direct sequencing of genes
in this family, we have identified a homozygous frameshift mutation
shared by the patients and heterozygous or absent from the 5 healthy
siblings. The patients have an early onset of ataxia before 7 years
associated with delayed motor development, dysarthria, epilepsy with
no relapse observed after treatment since 3 years of age. Two of the
patients present also mental retardation. Nerve conduction studies revealed
no evidence of associated peripheral neuropathy. Bioinformatics
predictions show that the homologs of the mutant gene belong to
a subfamily of genes coding for Plekstrin homology domain. A close
plekstrin homolog may be linked to small GTPase signaling and colocalizes
with late endosomal/lysosomal vesicles in osteoclast-like cells,
suggesting a putative function in vesicular transport in the osteoclasts.
These data suggest that our recessive ataxia gene is involved in membrane
signaling, a function that can now be tested by molecular studies
in order to understand the mechanism of this novel form of recessive
ataxia.
c03.5
tRNA Splicing Endonuclease mutations cause Pontocerebellar
Hypoplasia
Y. Namavar 1 , P. Kasher 1 , B. S. Budde 2 , P. G. Barth 3 , B. Poll-The 3 , K. Fluiter 1 ,
E. Aronica 1 , A. J. Grierson 4 , P. van Tijn 5 , F. van Ruissen 1 , M. Weterman 1 , D.
Zivkovic 5 , P. Nürnberg 2 , F. Baas 1 ;
1 Academic Medical Center, Amsterdam, The Netherlands, 2 Cologne Center
of Genomics and Institute of Genetics, Cologne, Germany, 3 Emma Children’s
Hospital/ Academic Medical Center, Amsterdam, The Netherlands, 4 Academic
Unit of Neurology, University of Sheffield, Sheffield, United Kingdom, 5 Hubrecht
Institute, Utrecht, The Netherlands.
Pontocerebellar hypoplasia (PCH) represents a group of neurodegenerative
autosomal recessive disorders with prenatal onset (PCH1-6).
Children suffer from severe mental and motor impairments due to atrophy
or hypoplasia of the cerebellum, hypoplasia of the ventral pons,
microcephaly and variable neocortical atrophy. The disease is progressive
and usually patients die before they reach adulthood.
We identified a common mutation in TSEN54 (A307S) in the majority
of European PCH2 patients. TSEN54 is one of the four subunits
of the tRNA splicing endonuclease (TSEN34, TSEN2 and TSEN15).
The TSEN complex is responsible for the splicing of intron containing
tRNAs and also plays a role in pre-mRNA 3’end formation. In PCH
patients without the A307S mutation, we identified other missense and
nonsense mutations in TSEN54 , TSEN34 and TSEN2 subunits.
In situ hybridization for TSEN54 using LNA/2OME probes revealed
that TSEN54 is highly expressed in neurons of the pons, cerebellar
dentate and olivary nuclei.
Northern blot analysis of tRNA-Tyrosine from fibroblasts of 3 patients
did not show unspliced products.
The molecular mechanism behind pontocerebellar hypoplasia remains
unclear. In order to study the mechanisms underlying PCH we performed
knock down experiments in zebrafish. Injection of TSEN54 or
TSEN2 morpholino oligonucleotides in zebrafish embryos results in
similar neurodevelopmental phenotypes, most prominently affecting
brain development.
c03.6
Retinal neurone remodelling induced by polyglutamine toxicity
in a scA7 mouse model
Y. Trottier 1 , M. Yefimova 2,1 , N. Messaddeq 1 , C. Jacquard 3,1 , C. Weber 1 , L.
Jonet 4 , J. Jeanny 4 ;
1 Institute of Genetic and Molecular and Cellular Biology, Illkirch, France, 2 Sechenov
institue of evolutionary physiology and biochemistry, Russian Academy
of Sciences, St-Petersburg, Russian Federation, 3 Institute of Neuroscience of
Montpellier, U583, Montpellier, France, 4 Inserm UMRS 872, Centre de recherche
des Cordeliers, Paris, France.
Spinocerebellar ataxia type 7 (SCA7) belongs to a group of nine inherited
neurodegenerative disorders caused by polyglutamine (polyQ)
expansion in unrelated disease proteins. PolyQ expansion confers to
mutant proteins a toxic gain of function, which compromises neuronal
function and survival. However, the molecular and cellular mechanisms
underlying polyQ expansion toxicity remain unclear.
SCA7 is unique among polyQ diseases to cause retinal degeneration
and blindness. To get insight into the mechanisms of polyQ toxicity, we
are studying the SCA7 retinopathy in the R7E transgenic mice, which
express the polyQ expanded ataxin-7 under the rhodopsin promoter.
Initial studies showed that R7E retinopathy was characterized by a
progressive reduction of photoreceptor segments and of electroretinograph
(ERG) activities, however, without extensive loss of photoreceptors.
That differed R7E retinopathy from other retinal degenerations in
mammalian (inherited or light-induced), in which degenerative outer
segment disappearance is typically followed by photoreceptor death.
We now describe the morphological deconstruction of R7E photoreceptor
cells, which is reminiscent of the structural reorganization that
assures the survival of photoreceptors in some retinal detachment
paradigms. Moreover, a subset of R7E photoreceptors migrate out of
outer nuclear layer, die by non-apoptotic cell death and thereby cause
a continuous loss of photoreceptor cells along the pathology. Remarkably,
some photoreceptors expressing mutant ataxin-7 undergo cell
division and likely contribute to maintain the photoreceptor cell population
until late disease stage.
In conclusion, in response to ataxin-7 toxicity photoreceptors undergo
a wide range of cell fate, including adaptative deconstruction, lethal
migration and proliferative cell renewal.
c04.1
spondylocheiro dysplastic form of the Ehlers-Danlos syndrome
- A novel recessive entity caused by mutations in the zinc
transporter gene sLc39A13
C. Giunta 1 , C. Bürer-Chambaz 1 , N. H. Elçioglu 2 , B. Albrecht 3 , G. Eich 4 , A. R.
Janecke 5 , M. Kraenzlin 6 , H. Yeowell 7 , M. Weis 8 , D. R. Eyre 8 , B. Steinmann 1 ;
1 Division of Metabolism, Univ. Children’s Hospital, Zurich, Switzerland, 2 Department
of Pediatric Genetics, Marmara University Hospital, Istanbul, Turkey,
3 Institute of Human Genetics, University Duisburg-Essen, Essen, Germany,
4 Pediatric Radiology, Kantonspital Aarau, Aarau, Switzerland, 5 Division of Clinical
Genetics, Medical University, Innsbruck, Austria, 6 Division of Endocrinology
and Diabetes, University Hospital, Basel, Switzerland, 7 Division of Dermatology,
Duke University Medical Center, Durham, NC, United States, 8 Department of
Orthopaedics, University of Washington, Seattle, WA, United States.
We present clinical, radiological, biochemical and genetic findings on
six patients from two consanguineous families who show EDS-like features
and radiological findings of a mild skeletal dysplasia. The EDSlike
findings comprise hyperelastic, thin, and bruisable skin; hypermobility
of the small joints with a tendency to contractures; protuberant
eyes with bluish sclerae; hands with finely wrinkled palms, atrophy of
the thenar muscles and tapering fingers. The skeletal dysplasia comprises
platyspondyly with moderate short stature, osteopenia, and
widened metaphyses. Patients have an increased ratio of total urinary
pyridinolines, lysyl pyridinoline/hydroxylysyl pyridinoline (LP/HP), of ~
1 as opposed to ~ 6 in EDS VI or ~ 0.2 in controls. Lysyl and prolyl
residues of collagens were underhydroxylated despite normal lysyl hydroxylase
and prolyl 4-hydroxylase activities; underhydroxylation was
a generalized process as shown by mass spectrometry of the α1(I)-
and α2(I)-chain derived peptides of collagen type I and involved at
least collagen types I and II. A genome-wide SNP-scan and sequence
analyses identified in all patients a homozygous c.483_491del9 mutation
in SLC39A13 that encodes for a membrane-bound zinc transporter
SLC39A13. We hypothesize that an increased Zn++ content inside the
endoplasmic reticulum competes with Fe++, a cofactor which is necessary
for hydroxylation of lysyl and prolyl residues, and thus explains
the biochemical findings. These data suggest a novel entity which we
have designated “spondylocheiro dysplastic form of EDS (SCD-EDS)”
to indicate a generalized skeletal dysplasia involving mainly the spine
(spondylo) and striking clinical abnormalities of the hands (cheiro) in
addition to the EDS-like features.