2008 Barcelona - European Society of Human Genetics

Cytogenetics
(3 .3%) . This increased frequency of duplications in older donors could
correspond, at least in part, to an excess of acentric fragments in
their spermatozoa . Chromosome 12 was the only autosome with an
increased level (P < .05) of structural aberrations in relation to age .
conclusions: Our results indicate an association between advanced
paternal age and increased risk in offspring for de novo autosomal
unbalanced structural aberrations .
This work received financial support from The Generalitat de Catalunya
(CIRIT, 2005SGR-00495) and The Ministerio de Educación y
Ciencia (SAF2004-06134), Spain
P02.229
A two chromosome inversions 46,XY,inv(4)(p12q21),inv(10)(p11q
21) associated with spermatogenetic failures
E. Shilnikova 1 , I. Fedorova 2,1 , N. Sadik 2 ;
1 Saint-Petersburg State University, Saint-Petersburg, Russian Federation, 2 Ott’s
Institute of Obstetrics and Gynecology, Saint-Petersburg, Russian Federation.
Chromosome aberrations carriers are often affected by reproductive
failures, including spontaneous abortion and newborns with chromosome
abnormalities, due to production of genetically unbalanced
gametes . But such patients do not exhibit any particular phenotypes . A
man from infertile couple was studied to determine the karyotype and
spermatogenesis failures .
Using QFH-banding technique and FISH with DNA probes specific to
chromosome 4 and 10, we detected karyotype with two pericentric inversions:
46,XY,inv(4)(p12q21),inv(10)(p11q21) . There were no chromosome
anomalies in the karyotype of his twin brother (46,XY), their
parents were not available for genetic analysis .
Semen parameters (concentration, motility and morphology) were
analyzed according to WHO criteria . Motile spermatozoa amounted to
25% with other parameters being normal (asthenozoospermia) . Also
Quantitative Karyological Analysis of Immature Sex Cells (QKAISK) in
ejaculate was performed to determine the stage of spermatogenesis
block . Partial block of spermatogenesis after MI division and delay of
karyokinesis was detected . Frequency of diploid and disomic spermatozoa
was identified using multicolour FISH with specific DNA probes
to chromosomes 9 and 10 . Frequency of aberrant chromosome disomy
did not differ from that of normal one and totaled 0,9% . Frequency
of diploid spermatozoa was 0,54% .
This study confirms the necessity of complex cytogenetic somatic cells
and gametes analysis for patients with chromosome aberrations to calculate
the risk of genetically unbalanced offspring more precisely .
Supported by CRDF and RFBR .
P02.230
correlation of Antioxidant Enzyme level with mitochondrial
mutations in North indian infertile men
M. B. Shamsi, S. Venkatesh, R. Kumar, S. Arora, D. Arya, R. Dada;
AIIMS, New Delhi, India.
Oxidative damage to spermatozoa is a well known potential cause of
infertility . The balance between antioxidants and pro-oxidants is essential
. Optimum levels of free radicals (Reactive Oxygen Species)
are important physiological mediators in normal sperm functioning . Antioxidants
as Glutathione Peroxides, Glutathione Reductase (prostatic
origin), Superoxide Dismutase (prostatic and epididymal origin) and
Catalase (multiglandular origin) prevent oxidative stress (OS) . Free
radicals induce mitochondrial DNA damage especially in genes regulating
Oxidative Phosphorylation (OXPHOS) and result in impaired
sperm function and spermatogenesis .
In an ongoing study the correlation between the enzymatic antioxidants,
malonaldehyde (product of lipid peroxidation) in the seminal
plasma and in blood serum was done , the results were further correlated
with semen parameters and mitochondrial DNA integrity . Results
showed significant correlation between SOD in blood serum and
sperm concentration (r=0 .699, and p= 0 .008) . Positive correlation was
observed between the seminal SOD, sperm count and progressive
motility . These results are in accordance with several previous studies
. No correlations could be established between the seminal MDA,
blood serum MDA and semen parameters. In these cases a significant
high number of mitochondrial mutations in the OXPHOS genes were
observed . This may explain for low sperm count and motility defects
in our patients .
The analysis of antioxidant levels in seminal plasma and blood and
their impact on the semen parameters corroborated with mitochondrial
mutations and DNA integrity would help to provide a deep insight into
the understanding of the OS induced infertility and thus in better management
of such cases .
P02.231
cFtR gene mutations and tt-polymorphism in infertile men of
Russia
T. M. Sorokina, L. F. Kurilo, S. A. Kazakova, A. A. Stepanova, V. B. Chernykh;
Research Centre for Medical Genetics of RAMS, Moscow, Russian Federation.
Cystic fibrosis conductance transmembrane regulator (CFTR) gene
mutations are common genetic cause of male infertility. Cystic fibrosis,
congenital bilateral and unilateral absence of the vas deferens (CBAVD
and CUAVD syndromes) lead to azoospermia or severe oligozoospermia
. Also CFTR mutations are associated with reduced sperm quality
in men who do not present CF phenotype .
We investigated a cohort of 568 men from Russian infertile couples .
Fourteen common CFTR mutations (del21kb, ΔF508, ΔI507, 1677del-
TA, 2143delT, 2184insA, 394delTT, 3821delT, L138ins, G542X,
W1282X, N1303K, R334W, 3849+10kbC>T) and TT-polymorphism in
the intron 8 (IVS8T) have been analyzed .
CFTR mutations were found in 25 out of 568 (4 .4%) patients . Following
mutations have been revealed: ΔF508 (n=9), del21kb (n=5), W1282X
(n=5), 2143delT (n=2), 2184insA (n=1), G542X (n=1), R334W (n=1),
1677delTA (n=1) . The 5T allele frequency was 10 .6% in examined patients
. This allelic variant has been revealed in the heterozygous (n=52
cases), in the homozygous (n=3 cases) and in the compound heterozygote
state with common CFTR mutation (n=5 cases) . The combined
frequency of CFTR mutations and 5T allele was 7 .6% in infertile men
cohort .
All patients with CFTR mut/5T and 5T/5T genotypes had a diagnosis of
azoospermia or severe oligozoospermia . Two azoospermic men with
CFTR mutations had extragenital features of cystic fibrosis (chronic
bronchitis or a chronic pancreatitis) . In one severe oligozoospermic
patient with CFTR mutation the CUAVD syndrome associated with renal
abnormalities has been diagnosed .
P02.232
modelling reduced male fertility in mice
E. Bolcun-Filas, R. Speed, M. Taggart, H. J. Cooke;
MRC Human Genetics Unit, Edinburgh, United Kingdom.
Human fertility is highly variable and a substantial part of that variation
is genetic . The phenotype is hard to measure and involves input from
two individuals making whole genome association studies difficult if
not impossible to design robustly . Candidate gene approaches based
on a knowledge of the underlying processes of gametogenesis have
had only limited success. This is a reflection both of the large number
of genes thought to be required, particularly for sperm production, and
the likelihood that the majority of mutations are recessive requiring
rare homozygosity for a mutation at any one locus to produce a phenotype
.
Recognising this we have asked if compound heterozygosity at genes
encoding proteins required for meiosis can be a factor . SYCE1 and
SYCE2 are proteins of the meiotic Synaptonemal Complex . We have
shown that SYCE2 is essential for male and female fertility in mice
and here we show that this is also true for SYCE1 . Heterozygous null
animals are fertile in the case of both genes . Mice heterozygous for
both null alleles have a ten fold elevation in XY asynapsis and also an
increase in unpaired autosomes . Lack of pairing is predicted to result
in cell death and a consequent reduction in sperm count . We observe
a reduction in sperm count of up to 40% showing that compound hemizygosity
in genes involved in the same pathway can have a significant
impact .
P02.233
Gene expression profiling of normal and pathological testis by
microarray analysis
V. Gatta1 , F. Raicu1 , A. Scioletti1 , A. Ferlin2 , G. Palka1 , C. Foresta2 , L. Stuppia1 ;
1 2 G. D’Annunzio University Foundation, Chieti, Italy, University of Padova, Padova,
Italy.
Microdeletions of the AZFa, AZFb and AZFc loci on Yq are detected in
about 10% of infertile males . Despite the large amount of data collected
in the last years, the biological mechanisms leading to the disruption