2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
individuals without a family history with onset before age 45 years .
A variety of deletional and point mutations has been described in
PARK2 gene as well as a few coding polymorphism being a possible
risk factors for sporadic and familial PD . The role of this polymorphisms
is still unclear and published results contradictory .
We present the analysis of the frequency of the four coding polymorphism
detected in the group of EO-PD sporadic patients of Polish origin
(Ex4 S167N, Ex10 V380L, Ex 11 D394N and R402C) in comparison
with the group of control subject .
Presented results are preliminary as the groups are not big enough to
be conclusive (70 EO-PD patients, 100 control subjects) but they indicate
no difference in frequency of analysed polymorphisms in both of
them . We can conclude there is no association of any of polymorphism
under consideration with sporadic EO-PD form .
P06.092
Genetic association of single sNPs and a LD-Haplotype at
PsORs6 in patients with early onset psoriasis and evidence for
epistasis with PsORs1 risk locus
U. D. Hüffmeier 1 , J. Lascorz 1 , T. Becker 2 , A. Ekici 1 , S. Endele 1 , C. Thiel 1 , F.
Schürmeier-Horst 3 , R. Mössner 4 , K. Reich 5 , W. Kurrat 6 , T. F. Wienker 2 , H.
Traupe 3 , A. Reis 1 ;
1 University of Erlangen, Erlangen, Germany, 2 University of Bonn, Bonn, Germany,
3 University of Münster, Münster, Germany, 4 University of Göttingen, Göttingen,
Germany, 5 Dermatologikum Hamburg, Hamburg, Germany, 6 Asklepios
Klinik, Westerland/ Sylt, Germany.
Psoriasis is a genetically complex, chronic inflammatory skin disease.
We have previously performed a genome wide linkage study in a set of
psoriasis families and have identified a susceptibility locus on chromosome
19p13 (PSORS6) . In a follow-up linkage disequilibrium (LD) study
in an independent family based cohort, we found evidence for association
to two newly discovered microsatellites at this locus (D19SPS20:
P < 2 .7*10 -2 , D19SPS21: P < 5 .3*10 -5 ) . An association scan in 300
trios, based on the LD structure of the region, revealed association to
several single SNPs in one LD block. When we stratified this cohort for
carrying the PSORS1 risk allele at the HLA-C locus on chromosome
6p, evidence for association became much stronger at single SNP
and haplotype levels (p-values between 2 .0*10 -4 and 9 .0*10 -4 ) . In a
population based replication study of 1,114 psoriasis patients and 937
control individuals, evidence for association was observed again after
stratification to the PSORS1 risk allele. In both study groups, logistic
regression showed evidence for interaction between the risk alleles at
PSORS1 and PSORS6 . The associated LD block did not comprise any
known genes . Interestingly, an adjacent gene, MUC16, coding for a
large glycosylated protein expressed in epithelia, could be shown to be
also expressed in tissues relevant for pathogenesis of psoriasis such
as skin and thymus. In summary, we confirmed and refined the susceptibility
locus at PSORS6 which seems to be restricted to patients
with early onset psoriasis carrying the PSORS1 risk allele .
P06.093
Parkin, DJ- and PINK mutations in Dutch patients with earlyonset
Parkinson’s disease
M. G. Macedo1 , D. Verbaan2 , Y. Fang1 , B. Anar1 , A. Uras1 , J. L. Groen1 , P.
Rizzu1 , J. J. van Hilten2 , P. Heutink1 ;
1 2 VU University Medical Center, Amsterdam, The Netherlands, Leiden University
Medical Center, Leiden, The Netherlands.
Objectives Recessively inherited early-onset Parkinson’s disease
(EOPD) has been associated with mutations in the Parkin, DJ-1 and
PINK1 genes . In order to assess the genetic contribution of all known
recessive genes in EOPD in the Dutch population we investigated
the prevalence and nature of mutations in the PROPARK (PROfiling
PARKinson’s disease) patient cohort . methods A total of 186 unrelated
Dutch EOPD patients (mean age at onset: 41 .1 ± 6 .6 years, 130
sporadic, 56 familial) with an age at onset (AAO) ≤ 50 years were studied
. The genetic screening was performed by direct sequencing and
dosage analysis of the three genes . Results Mutations were found in
9% (16/186) of the patients however PD may be explained in only six
(3%) patients who carried homozygous or heterozygous compound
mutations in Parkin (n=5) or DJ-1 (n=1) . No homozygous or compound
heterozygous mutations were detected in PINK1 gene . In addition, 6
(3%), 3 (2%) and 2 (1%) patients carried a single heterozygous mutation
in Parkin, DJ-1 and PINK1 genes, respectively . Interestingly, two
novel mutations were found in one patient in heterozygous state but
not in 700 ethnically matched control chromosomes . conclusions
Parkin was the most frequently mutated gene in EOPD, followed by
DJ-1 and PINK1 . The low overall mutation frequency observed indicates
that caution has to be taken with the extrapolation of mutation
frequencies found in other studies and populations and suggests that
other genes and risk factors for PD remain to be discovered .
P06.094
DNER, a neuronal transmembrane protein is dispensable for
gross cellular morphology and sensory nerve fiber excitability
U. Brandt-Bohne 1,2 , D. R. Keene 3 , B. Erdmann 4 , G. Lewin 4 , M. Koch 2 ;
1 Center for Genomic Regulation, Barcelona, Spain, 2 Institute for Biochemistry II
University Clinics Cologne, Cologne, Germany, 3 Shriners Hospital for Children
Research Center, Portland, OR, United States, 4 Max Delbrueck Center for
Molecular Medicine, Berlin-Buch, Germany.
DNER is the first transmembrane protein expressed in the brain containing
only multiple epidermal growth factor (EGF) - like repeats in its
extracellular domain . DNER further contains a signal peptide, a serine
rich stretch, a transmembrane domain and a cytoplasmatic C-terminus
. Since its close relation to Notch and Delta it has been named
Delta/Notch-like-related receptor . Structural homology to other EGFbearing
proteins involved in extracellular signalling events and in neuronal
development, point out a possible involvement of DNER in such
processes .
The extracellular domain of DNER was cloned and recombinant protein
was used for polyclonal antibody production . Recombinant and
full length protein is larger than the theoretical calculated mass and
glycosidase digestion indicate that DNER is glycosylated . Distribution
analysis by semi quantitative RT-PCR show that almost no mRNA was
present in non-neuronal tissues . In mouse embryos, DNER mRNA is
detectable at day 9 .5 of gestation in the neural tube, dorsal root ganglia,
ear placode, anterior and posterior zones of the developing forelimb,
and in different cell types of the retina . The distribution of DNER
protein is also mainly restricted to neuronal tissues and can also be
detected in peripheral ganglia and nerves . A knock-out targeting vector
was generated and the homozygote animals are being analyzed .
In the homozygote knock out animals no DNER protein was detected .
Surprisingly, the mice are viable and show no obvious phenotype . The
gross cellular morphology appears unchanged and further analysis of
the peripheral nerve functions, reveal no effects in excitability of specific
A-fibers.
P06.095
Polymorphisms in ESR and ESR genes are associated with
susceptibility to endometriosis
M. Lamp 1 , M. Peters 1 , H. Karro 1,2 , Ü. Kadastik 2 , E. Reinmaa 3 , K. Haller 1,3 , A.
Metspalu 3 , A. Salumets 1,3 ;
1 Department of Obstetrics and Gynaecology, University of Tartu, Tartu, Estonia,
2 Tartu University Hospital’s Women’s Clinic, Tartu, Estonia, 3 Department of
Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Tartu,
Estonia.
Introduction. Endometriosis is defined as the presence of endometrial-like
tissue outside the uterus . It affects about 5-10% of women of
reproductive age and causes dysmenorrhoea, abdominal pain, dyspareunia
and infertility . Endometriosis is considered to be an estrogen-dependent
disease with a genetic background . The aim of this
study was to evaluate possible associations between endometriosis
and polymorphisms in the estrogen receptor α (ESR1) and β (ESR2)
genes .
Materials and methods . 123 women (age: 18-44 years) with surgically
confirmed endometriosis were enrolled in the study. 200 fertile women
(at least two children; age: 30-50 years) from general population were
used as controls. The 397 T/C polymorphism in the first intron of the
ESR1 gene was determined by PCR-RFLP analysis, using the restriction
endonuclease PvuII. The number of CA repeats in the fifth intron
of the ESR2 gene was detected with fragment analysis .
Results . The distribution of ESR1 TT/TC/CC genotypes was
17 .9/54 .5/27 .6% among patients and 30 .0/51 .0/19 .0% in the control
group (p=0.028; χ 2 -test) . The T/C allele frequencies were 45 .1/54 .9%
and 55 .5/44 .5%, respectively (p=0 .008) . The number of CA repeats in
the ESR2 gene ranged from 14 to 26 . The ESR2 alleles were classified
as short and long, with ≤21 and >21 repeats, respectively. Endome-
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