2008 Barcelona - European Society of Human Genetics

Cytogenetics
P02.106
Aneuploidy of chromosome 21 in the Alzheimer’s disease brain
Y. B. Yurov 1,2 , I. Y. Iourov 1,2 , S. G. Vorsanova 1,2 , T. Liehr 3 ;
1 National Research Center of Mental Health, RAMS, Moscow, Russian Federation,
2 Institute of Pediatrics and Children Surgery, Rosmedtechnologii, Moscow,
Russian Federation, 3 Institute of Human Genetics and Anthropology, Jena,
Germany.
Apart from single gene mutations, Alzheimer’s disease (AD) is suggested
to be associated with mosaic aneuploidy of chromosome 21 .
This hypothesis has been repeatedly supported by studies of AD blood
lymphocytes and skin fibroblasts. However, the diseased brain has
not been directly studied . We have performed molecular cytogenetic
studies by interphase chromosome 21-specific multicolour banding on
cells of AD brain samples derived from the cerebral cortex, hippocampus
and cerebellum . The analysis was performed through evaluation
of about 14000 intephase nuclei . Control samples exhibited mean rate
of aneuploid cells to be about 0 .7% (all brain areas) . The average rate
of aneuploidy achieved 4% in the AD hippocampus, 3 .5% _ in the AD
cerebral cortex, and 0 .9% _ in the AD cerebellum . Aneuploidy manifested
more frequently as chromosome 21 monosomy, but the proportion
of cells with additional chromosome 21 was also significant. The
monosomy-to-trisomy ratio was about 2:1. AD brain exhibited significant
increase of chromosome 21 aneuploidy in the hippocampus and
cerebral cortex . Interestingly, these two areas are known to be more
affected by neurodegenerative processes featuring AD . Together, this
suggests a correlation between molecular cytogenetic and neuropathology
data . We hypothesize that increased aneuploidy rates in the
AD hippocampus and cerebral cortex are the results of mitotic errors
during adult neurogenesis. Our data shows that specific areas of the
senecent brain can be selectively affected by acquired aneuploidy . Aneuploidization
of specific brain areas is, therefore, a genetic process
that is likely involved in the pathogenesis of AD .
P02.107
Evaluation of micronuclei and nondisjunction frequencies in
workers exposed to internal plutonium by cytokinesis-blocked
binucleated cells assay
S. A. Vasilyev, V. A. Timoshevskiy, I. N. Lebedev;
Scientific Research Institute of Medical Genetics, Tomsk, Russian Federation.
Damage or dysfunction of any component of mitotic segregation complex
by mutagens can lead to mistakes in chromosome number . One
of the most reliable methods of aneugenic influence detection is FISHanalysis
of cytokinesis-blocked binucleated cells . Detection of micronuclei
in these investigations is an indicator of clastogenic effects . We
have tested abilities of this approach on a group of Siberian Chemical
Plant (SCP) workers exposed to internal plutonium . We have formed
groups of exposed individuals - SCP workers with incorporated plutonium
(10-276 nCi) - 70 individuals, and control set - people living in
Seversk and not exposed of nuclear-chemical agents - 50 individuals .
In preliminary analysis we have demonstrated that missegregation frequencies
for chromosomes 7 and 12 was 0 .2% for each chromosome
in cells of 27 SCP workers, and 0 .1% and 0 .075% in 8 individuals
from control group, respectively. Significantly increased frequency of
nondisjunction in exposed group was noted for chromosome 12 only
(p=0 .03) . However, tendency to increase of missegregation of chromosome
7 (p=0.06) was observed. Significant differences in frequencies
of micronuclei in exposed and control groups (0 .77 and 0 .74 %, respectively)
were not found . Since we have carried out only a preliminary
study of abnormal chromosome number frequency it is early to
make conclusion about aneugenic influence of incorporated plutonium.
However, we can suggest that this approach is sufficiently informative
and sensitive for frequency detection of abnormalities which lead to
genomic mutations . Subsequent analysis of segregation abnormalities
provides some clues to the quantitative features of aneuploidy induction
by internal plutonium .
P02.108
cytogenetic effects of doxazosina a alpha-blocker
antihypertensive drug: sister chromatid exchanges and
micronuclei frequencies before and after pharmacological
treatment
I. Arrieta Saez 1 , O. Peñagarikano 2 , M. Télez 1 , M. Barasoain 1 , I. Huerta 1 , J.
Ramírez 1 , B. Criado 3 , P. Flores 4 , A. González 5 ;
1 Dpto Genetica, Antropología Fisica y Fisiologia animal Facultad de Ciencia y
Tecnología, Bilbao, Spain, 2 Emory University School of Medicine, Atlanta, GA,
United States, 3 High School Da Maia, CESPU, Porto, Portugal, 4 Dpto de enfermería,
Escuela de Enfermería, Bilbao, Spain, 5 Dpto Medicina Interna, Facultad
de Medicina, Bilbao, Spain.
Arterial hypertension is a health problem representing one of the most
frequent diagnoses in the population at large in terms of prevalence
and incidente . Drug treatment of hypertension may last for decades .
Long-term treatment require documentation of long-term safety and
efficacy, including sensitive indices of genotoxic damage.
In our previous works Sister Chromatid Exchange (SCE) and Micronuclei
(MN) assays were aplied to asses the genotoxicity of atenolol a
beta-blocker antihypertensive drug and nimodipine a calcium antagonist
antihypertensive in culture peripheral lymphocytes of treated patientes
and control individuals . The results showed no genotoxic effect
of nimodipine, however a statistical significant increase in the frequency
of MN was detected in patients treated with atenolol . Aplication of
FISH with an alphoid stellite probe revealed also a statistical significant
higher percentage of centromere positive MN .
We report here our data from a study of the genotoxic potential of
Doxazosina The pharmacological aplication of the antihypertensive
Doxazosina is due to their ability to blocker alpha receptors . This antihypertensive
was tested for its ability to induced SCE and MN in cultured
human peripheral blood lymphocytes of patients before and after
pharmacological treatment, so that the patient is control himself .
The results of the study revealed that the frequency of SCE did not
show significant differences. However a statistical significant increase
in the frecuency of centromere positive MN was detected, thus indicating
more frequent envolvement of aneuploidy phenomena in the origin
of Doxazosina-induce MN .
P02.109
chromosome instability in the ataxia telangiectasia cerebellum
I. Y. Iourov 1,2 , S. G. Vorsanova 1,2 , T. Liehr 3 , A. D. Kolotii 2 , Y. B. Yurov 1 ;
1 National Research Center of Mental Health, RAMS, Moscow, Russian Federation,
2 Institute of Pediatrics and Children Surgery, Rosmedtechnologii, Moscow,
Russian Federation, 3 Institute of Human Genetics and Anthropology, Jena,
Germany.
Ataxia-telangiectasia (AT) is a chromosome instability (CIN) syndrome
associated with progressive neuronal degeneration affecting exclusively
the cerebellum . Molecular basis of cerebellar neurodegeneration
in AT is unknown, but hypothesized to be closely linked to the loss
of genome integrity in the cerebellar neural cells manifesting as CIN .
Here, we monitored CIN in the AT brain by interphase chromosomespecific
multicolour banding allowing analysis of interphase chromosomes
in their integrity . We found stable 2-4-fold increase of stochastic
aneuploidy involving whole chromosomes 7 and 14 in the cerebellum
of the AT brain as to controls . Additionally, dramatic 5-40-fold increase
of CIN involving chromosome 14 (aneuploidy (including supernumerary
rearranged chromosomes) and non-random chromosome breaks)
as to other brain areas has been revealed . The latter was found to
progress with the age of patients . Paradoxically, the longevity of AT
patients was in direct proportion to CIN levels in the cerebellum . We
hypothesize that aneuploidization and acquired CIN may result from
autoactivation of aberrant processes triggered in response to progressive
neuronal degeneration . Newly generated neural cells, being genetically
abnormal, nevertheless, partially substitute the loss of cells
in the cerebellum and play an ameliorative role in stabilization of the
diseased brain homeostasis . We suggest CIN in the AT cerebellum
to be involved in processes that mediate either neurodegeneration
or endogenous neuroprotection . The way CIN is progressed, can be,
therefore, proposed as definitive for the course of neurodegeneration
and for cerebellar dysfunction in AT patients .