2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
show any statistically significant association in LOAD group. On the
other hand, we didn’t find any association between APOA1 -75bp G/A
polymorphism and the EOAD group (χ 2 =0,084, df = 2, p = 0,959) . In
opposition to Vollbachet al . (2005) our results show that variants of
APOA1 don’t influence the onset and the risk for Italian AD sample.
P06.018
Paraoxonase gene polymorphism association with ALs in the
French, Quebec and swedish populations
P. N. Valdmanis 1,2 , E. Kabashi 2 , J. Bouchard 3 , F. Salachas 4 , V. Meininger 4 , P.
Andersen 5 , W. Camu 6 , N. Dupre 3,2 , G. A. Rouleau 2 ;
1 McGill University, Montreal, QC, Canada, 2 Center of Excellence in Neuromics,
University of Montreal, CHUM-Notre-Dame Hospital, Montreal, QC, Canada,
3 Department of Neurological Sciences, CHAUQ Enfant-Jesus, Quebec City,
QC, Canada, 4 Fédération des maladies du système nerveux, Hôpital de la
Salpêtrière, Paris, France, 5 Department of Neurology, Umeå University hospital,
Umea, Sweden, 6 Unité de Neurologie Comportementale et Dégénérative Molecular
Unit, Institute of Biology, Montpellier, France.
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative
disease that results in the loss of upper and lower motor neurons .
The disease is 90-95% sporadic in nature which suggests that multiple
subtle genetic effects may lead to the development of ALS . One primary
threat to motor neurons is oxidative stress . As such, an association
has been observed between paraoxonase (PON) gene variants and
ALS susceptibility . The PON cluster consists of three adjacent genes
on chromosome 7q21.3 that aid in the detoxification of organophosphate
insecticide and prevent the oxidation of lipoproteins . We sought
to examine the frequency of coding and intronic PON polymorphisms
in a set of 1197 ALS case and 1076 control samples from France, Sweden,
and the founder French Canadian population of Quebec . Twenty
SNPs that span the three paraoxonase genes were selected for Taqman
genotype analysis . While individual SNPs were not considered
associated on their own, a haplotype of SNPs at the C-terminal portion
of PON2 that includes the PON2 C311S amino acid change was significant
in the French (p-value 0 .0075) and Quebec (p-value 0 .026) populations
as well as all three populations combined (p-value 1 .69x10 -6 ) .
Thus, we have identified two populations where susceptibility to ALS
is significantly associated with variants in the PON gene cluster. The
functional consequence of the variants identified with respect to motor
neuron degeneration will provide insight into the role of these genes in
susceptibility to ALS .
P06.019
Identification of TDP-43 variants in amyotrophic lateral sclerosis
(ALs) patients
E. Kabashi, P. N. Valdmanis, P. Dion, G. A. Rouleau;
Centre de Recherche de l’Universite de Montreal, Montreal, QC, Canada.
Recently, TDP-43 was identified as a major component of ubiquitinated
aggregates in amyotrophic lateral sclerosis (ALS) and frontotemporal
dementia (FTD) . We have screened 200 ALS patients, 120 sporadic
(SALS) and 80 familial (FALS) cases and we have identified several
missense variants in the TDP-43 gene . None of these variants were
present in 360 unaffected controls . We are currently aiming to determine
the causative effect of TDP-43 mutations in ALS pathogenesis
and motor neuron degeneration . We will sequence further ALS cases
for mutations, perform functional assays to determine what could be
the gain or loss of function of TDP-43 and test whether this leads to selective
vulnerability of motor neurons . Finally, we are generating three
in vivo models, including transgenic mice, which will determine whether
mutations in TDP-43 induce a motor neuron disorder and motor
neuron pathology in other species . This project will contribute greatly
to our understanding of ALS pathophysiology and the functional role
that TDP-43 plays in this disease .
P06.020
Analysis of assosiation of Apo E gene with placental
insufficiency at habitual non-carrying of pregnancy
N. Mamedalieva, G. Svyatova, T. Nurbayeva;
Scientific Center of Obstetric, Ginecology and Perinatology, Almaty, Kazakhstan.
Both non-carrying of pregnancy and placental insufficiency are the basis
of many kinds of heavy obstetrical pathology which causes unfavorable
outcome for the fetus .
The aim of this research is to study features of distribution of alleles
of Apo E Gene at pregnant women of Kazakh population with clinical
placental insufficiency and habitual non-carrying of pregnancy in
anamnesis .
Materials and Methods of Research . By the method of PDRF analysis
on the basis of PCR-mediated and site-directed mutagenesis,
an analysis of frequencies of alleles of Apo E Gene was held at 12
pregnant Kazakh women with diagnosed placental insufficiency and
habitual non-carrying of pregnancy in anamnesis . Examples of DNA,
taken from 32 sound non-related pregnant Kazakh women with physiologically
going pregnancy, were used as control examples .
Results . The analysis of frequency of detecting polymorphism of Apo E
Gene made known that favorable genotype E2E3 was really detected
more frequently at patients of the control group (75%) than at those
of the basic group (50%) . Frequency of genotypes E3E3 and E3E4
was 33 .3% and 8 .3% in the researched pathology group against 6 .25
and 0% in the sound group . The revealed data are in accordance with
data taken from publications, and they are proof of its possible genetic
relation with unfavorable allele E3E4 of Apo E Gene at development of
placental insufficiency during habitual non-carrying of pregnancy.
The further research of molecular-and-genetic markers will allow us to
get more objective information about the nature and mechanisms for
rise of placental insufficiency.
P06.021
A second candidate gene causing aniridia? : preliminary results
F. Bayrakli 1 , D. Ceyhan 2 , Y. Bayri 3 , I. Guney 4 , T. Cankaya 5 , K. Bilguvar 3 , S.
Bayrakli 6 , M. Gunel 3 ;
1 Marmara University, Department of Neurosurgery, Istanbul, Turkey, 2 Van Military
Hospital, Department of Ophthalmology, Van, Turkey, 3 Yale University, Department
of Neurosurgery, New Haven, CT, United States, 4 Marmara University,
Department of Medical Genetics, Istanbul, Turkey, 5 Istanbul Surgery Hospital,
Division of Genetics, Istanbul, Turkey, 6 Istanbul University, Department of Family
Practice, Istanbul, Turkey.
Aniridia can range from a readily visible, almost complete absence of
the iris, through enlargement and irregularity of the pupil mimicking a
coloboma, to small slit-like defects in the anterior layer seen only on
transillumination with a slit-lamp .
Approximately one third of all cases of aniridia are sporadic and these
are often found to have cytogenetically detectable deletions involving
11p13, besides balanced chromosomal translocations and single chromosomal
breaks .
Aniridia can also be caused due to six different categories of PAX6
mutations including nonsense, splicing, frame-shifting insertions or
deletions, in-frame insertions or deletions, missense, and run-on mutations
.
We found a large kindred with aniridia that have 10 live affected patients
with autosomal dominant trait . While ophthalmological examinations
of the affected patients revealed total aniridia, cranial magnetic
resonance imaging studies showed no abnormalities in brain tissue .
Karyotype analysis (550 bands) revealed normal male (46, XY) and
sequencing of translated and untranslated exons of PAX6 gene were
revealed no causative mutation. Chromosome 11 specific array-CGH
for micro unbalanced translocation, deletion or amplification detection
in or around the PAX6 gene is underway .
This preliminary results suggest that there can be another causative
gene for aniridia . Whole genome linkage analysis is the next step to
identify responsible chromosomal locus .
P06.022
APO E epsilon genetic polymorphism and foot ulceration
severity in peripheral vascular complications of type 2 diabetes
mellitus
V. V. Petrova 1 , M. A. Bogdanova 2 , A. N. Voitovich 2 , Y. A. Spesivcev 2 , V. I. Larionova
2 ;
1 St. Petersburg State University, Saint-Petersburg, Russian Federation, 2 St.
Petersburg State Pediatric Medical Academy, Saint-Petersburg, Russian Federation.
Peripheral vascular disease (PVD) includes inflammatory process that
leads to cell damage and impaired regeneration within a vessel wall
resulting in the formation of foot ulcers . PVD is a common and severe
complication of type 2 diabetes mellitus . Many investigations show that
polymorphisms in apolipoproteins genes can be associated with PVD .