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PubMed2004

Safety issues in assisted reproduction technology: should ICSI patients have genetic testing before treatment? A practical proposition to help patient information.

ICSI is a highly efficient treatment of male factor infertility and therefore increasingly used to treat infertile men successfully. However, when used to treat patients with a genetic cause for their infertility, there may be an increased risk for the offspring. Chromosome aberrations, Y chromosome microdeletions and CFTR (cystic fibrosis transmembrane conductance regulator) mutations alone may explain up to 25% of azoospermia and severe oligozoospermia. These genetic defects could be identified before treatment, in which case informed decisions could be made by the couple to be treated concerning the treatment, prenatal testing or preimplantation genetic diagnosis. Therefore, we propose that men with very low sperm counts (<5 x 10(6)/ml) considering ICSI should always be informed of the possibility of genetic testing. The information should include a precise statement of the implications of the results for the patient, his family and his offspring, and reassurance that a decision to test or not to test, or the subsequent test results will not be used as a reason for withholding treatment. Testing should always remain voluntary, and the couples themselves should decide whether or not they choose to be tested. If an abnormality is identified, patients should be referred to specialist genetic counselling.

Chromosome Aberrations↗
PubMed2004

Partial deletions in the AZFc region of the Y chromosome occur in men with impaired as well as normal spermatogenesis.

BACKGROUND: Partial deletions of the AZFc region of the Y chromosome were reported to be a significant risk factor for oligo-/azoospermia. In this study, we assessed the occurrence and frequency of partial AZFc microdeletions in patients with spermatogenic failure and in controls with normal spermatogenesis. METHODS: In a retrospective study design, gr/gr, b1/b3 and b2/b3 deletions were analysed by multiplex PCR in 170 men with normal spermatogenesis and 348 men with non-obstructive oligo-/azoospermia. RESULTS: gr/gr deletions were found in 14 men with oligozoospermia or azoospermia (4.0%) and in three normozoospermic men (1.8%) (NS). b1/b3 deletions were found both in controls (n=1) and in patients (n=1). b2/b3 deletions were significantly more frequent in the normozoospermic (five out of 170) than in the oligo-/azoospermic men (two out of 348). Three novel partial AZFc deletion patterns were found in four oligo-/azoospermic men. No correlation with semen or other clinical parameters was found. CONCLUSIONS: The frequency of gr/gr deletions is not significantly increased in men with oligo-/azoospermia, indicating that they are not sufficient per se to cause spermatogenetic impairment and infertility. b1/b3 and b2/b3 deletions are probably irrelevant for spermatogenesis. Novel deletion patterns found exclusively in infertile men suggest that other, still unexplored partial deletions might contribute to spermatogenic failure.

Case-Control Studies↗
PubMed2004

High frequency of gr/gr chromosome Y deletions in consecutive oligospermic ICSI candidates.

BACKGROUND: The Y chromosome gr/gr microdeletion eliminates two copies of the DAZ gene and several additional transcriptional units and has been associated as a risk factor for infertility. Our objective was to study the presence of the gr/gr deletion in ICSI candidates in our population and to determine whether the laboratory, clinical and ICSI outcome were different in the gr/gr deleted patients. METHODS: Two hundred and eighty-three ICSI candidates were studied. Semen analysis, serum FSH, LH, testosterone, inhibin B, karyotype and detection of sequence tagged sites in the Y chromosome were performed. RESULTS: gr/gr deletions were detected in 11 (5.07%) of 217 oligospermic and in one (1.52%) of 66 azoospermic consecutive ICSI candidates, but in none of 232 controls (P=0.002). The fertility rate was not different in the four patients of the gr/gr deleted group treated by ICSI (64.38%; 47/73) as compared to average results at our center (65.49%; 2393/3654). CONCLUSIONS: gr/gr deletions are a risk factor for spermatogenic failure at our population, but the prognosis of the four patients of the gr/gr deleted group treated by ICSI is not different from that of other ICSI patients.

Base Sequence↗
PubMed2005

Gene deletions in an infertile man with sperm fibrous sheath dysplasia.

BACKGROUND: Asthenozoospermia may sometimes be related to genetic structural defects of the sperm tail detectable by transmission electron microscopy. Dysplasia of the fibrous sheath (DFS) is a genetic sperm defect, characterized by dysplastic development of the axonemal and periaxonemal cytoskeleton. We report the case of an infertile man with normal sperm count and total sperm immotility in which dysplasia of the fibrous sheath, Akap3, Akap4 gene deletions, meiotic segregation of chromosomes 18, X and Y and Y microdeletions were investigated. METHODS: A 32-year-old man with a 3-year history of primary infertility presented at our Regional Referral Center for Male Infertility. Family medical history, lymphocyte karyotype, PCR analysis, physical examination, hormone assays and semen analysis were performed. RESULTS: Ultrastructural sperm evaluation showed dysplasia of the fibrous sheath. Immunostaining of AKAP4 protein was negative in sperm tails. PCR analysis revealed intragenic deletions of the Akap3 and Akap4 genes. Fluorescence in situ hybridization on sperm showed a high frequency of XY disomy. CONCLUSION: In this infertile patient, our results suggest a possible relationship between dysplasia of the fibrous sheath, partial deletions in the Akap3 and Akap4 genes and absence of AKAP4 protein in the fibrous sheath. These findings, however, were not detected in another four patients with dysplasia of the fibrous sheath. Our results require future confirmatory molecular analyses.

A Kinase Anchor Proteins↗
PubMed2006

Decrease of both stem cell factor and clusterin mRNA levels in testicular biopsies of azoospermic patients with constitutive or idiopathic but not acquired spermatogenic failure.

BACKGROUND: Sertoli cells nurse germ cells during spermatogenesis, and alterations of Sertoli cell functions have been suggested in cases of spermatogenic failures. METHODS: In this work, we measured stem cell factor (SCF) and clusterin mRNA levels, by quantitative RT-PCR, in RNA extracted from testicular biopsies of 49 azoospermic patients classified according to testicular histology as having normal spermatogenesis or spermatogenic failure. RESULTS: When related to the percentage of Sertoli cells counted on a histological section of a neighbouring tissue sample, SCF and clusterin mRNA levels were significantly lower in the 'spermatogenic failure' group compared with the control group (P = 0.0297 and P = 0.0043, respectively). These levels were also significantly lower in the cases of 'constitutive' (cryptorchidism and Yq microdeletion) and 'idiopathic' spermatogenic failures when compared with the control group; conversely, they were not significantly decreased in the group with 'acquired spermatogenic failure' (orchitis, testicular traumatism, chemoradiotherapy and varicocele). CONCLUSIONS: These data further demonstrate an alteration of Sertoli cell functions in some human spermatogenic failures and suggest that a lack of Sertoli cell maturation may be involved in cases of constitutive or idiopathic spermatogenic failures.

Adult↗
PubMedDate not supplied

The pathophysiology of varicoceles in the light of current molecular and genetic information.

Varicoceles are a common cause of male infertility, but despite data being obtained from animal models and human studies the pathophysiology remains unclear. Recently, molecular and genetic information has been reported on men with varicoceles which may shed new light onto the causes of decreased semen parameters and poor sperm function. Here, a number of studies are reviewed in an attempt to develop a working hypothesis for the relationship of varicoceles and infertility. New studies on testicular tissue of men with varicoceles have demonstrated increased apoptosis among developing germ cells, which may be the cause of oligospermia. Other studies with semen have shown increased levels of reactive oxygen species (ROS) in association with poor sperm motility. Recent studies of morphologically abnormal spermatozoa have demonstrated disruption of the sperm head actin by cadmium, a cation reported to be present in high concentrations among some men with varicoceles. Finally, microdeletions of the alpha-1 subunit of the sperm calcium channels in a proportion of men with varicoceles suggests a genetic defect leading to abnormal acrosomal function. The intent of this review was to explain the pathophysiology of varicoceles, and the findings seem to support a 'co-factor' hypothesis. In order for varicoceles to be associated with infertility, they exist as 'co-factors' along with other molecular/genetic problems.

Acrosome Reaction↗
PubMedDate not supplied

Selected genetic factors associated with male infertility.

Studies into the mechanisms underlying spermatogenesis, the process by which spermatogonia undergo meiosis to become spermatozoa, have identified a number of genetic determinants of male infertility. Indeed, a more comprehensive knowledge of the genetic regulation of spermatogenesis has alleviated the dependence on the use of idiopathic infertility as a classification for sterile men for whom a cause for their infertility is unknown, as genetic factors become more accountable for this phenotype. This review focuses on selected areas implicated in male infertility including: (i) autosomal and sex chromosomal abnormalities; (ii) genetic disorders associated with impaired gonadotrophin secretion or action; (iii) microdeletions within regions of the Y-chromosome containing candidate gene families for spermatogenesis; (iv) the genetic nexus between cystic fibrosis and congenital bilateral absence of the vas deferens; and (v) insights into human infertility as gleaned from animal studies into mechanisms involving the Bcl-2 family of apoptosis regulators and the interaction between the c-kit encoded tyrosine kinase receptor and its ligand, stem cell factor. As significant advances continue to further knowledge of the genetic basis of male infertility, such as those leading to an understanding of the aforementioned areas, greater progress can be made to rectify or at least ameliorate social stigmas associated with sterility.

Animals↗
PubMed2005

Spermatozoal nuclear determinants of reproductive outcome: implications for ART.

A male factor is implicated in more than 50% of couples treated with IVF. However, neither the routine testing of male fertility potential nor its treatment address the specific mechanisms by which spermatozoal factors may impact upon reproductive outcome. An important function of spermatozoa is to deliver the paternal genome to the oocyte. Recently, a number of acquired spermatozoal nuclear factors that may have implications on reproductive outcome have been described. These include non-specific DNA strand breaks, numerical abnormalities in spermatozoal chromosome content, Y chromosome microdeletions and alterations in the epigenetic regulation of paternal genome. The exact mechanisms by which these factors affect reproduction are unknown and their implications for assisted reproduction technology outcome need to be further investigated. These recent findings point to the need for novel and more personalized approaches to test and treat male factor infertility.

Chromosomes, Human, Y↗
PubMed1992

Pattern of p53 gene mutations in breast cancers of women of the midwestern United States.

BACKGROUND: Mutation in the p53 gene is the most common genetic lesion in human cancers. The pattern of mutation in the p53 gene differs among cancers and may be a useful epidemiological tool for identification of factors contributing to carcinogenesis. PURPOSE: Our purpose was to determine if the pattern of p53 mutation in breast carcinomas in our population of women residing in the midwestern region of the United States is similar to the pattern of p53 mutation in breast cancers in patients from other regions of the United States and Europe and in other epithelial tumors. METHODS: With a technique we recently developed for the analysis of p53 mutations in genomic DNA from tumor cell clusters in touch preparations of solid tumors, we sequenced exons 5-9 and adjacent splice junctions of the gene in 44 breast cancers. Cells from each tumor were also stained with three monoclonal antibodies which recognize different epitopes of the p53 protein. RESULTS: We detected p53 mutations in 14 (32.6%) of 44 breast carcinomas. Only half of the mutations were missense changes. The other half included five microdeletions (three producing frame-shifts), one single-base substitution generating a stop codon, and one single-base substitution generating a splice junction abnormality. Nuclear expression of p53 antigen was present in eight of 44 cancers, including six with hemizygous missense mutations in the p53 gene. CONCLUSIONS: The pattern of p53 mutations in our breast cancer population differs from that reported in breast cancer populations by other investigators in which most p53 mutations were missense. Among 14 mutations in our population, at least five drastically altered the structure of p53, suggesting that a recessive mechanism of inactivation of the p53 gene may be more common than in other populations. IMPLICATIONS: Differences in the pattern of p53 mutation in breast cancers in Midwestern women and in breast cancers in other populations may reflect selection bias or small sample sizes currently available. However, our data are compatible with the possibility that an endogenous or exogenous factor influences p53 carcinogenesis in some women with breast cancer in the Midwest to a greater extent than in other regions of the United States and Europe.

Adult↗
PubMed1993

Spectrum of mutation and frequency of allelic deletion of the p53 gene in ovarian cancer.

BACKGROUND: The p53 gene encodes a nuclear phosphoprotein present in low levels in normal human cells. The wild-type form of this protein functions to restrain inappropriate cellular proliferation. Approximately one half of human epithelial ovarian cancers have mutations in the p53 gene and overexpress the mutant protein product. Deletion of one allele of the p53 gene also frequently occurs in these cancers. PURPOSE: We sought to define the spectrum of mutations in the p53 gene in epithelial ovarian cancer with respect to both the specific codons involved and the type of mutations observed. We also examined the frequency of allelic deletion of the p53 gene in cancers containing p53 gene mutations. METHODS: Tissue samples from the epithelial ovarian cancers of 62 patients were obtained during initial laparotomy. Histologic examination was done to ensure that the experimental samples used in this study contained more than 75% cancer cells. Total RNA was extracted from these samples and separately from matched control noncancerous regions of the surgical specimen or white blood cells. The purified RNAs were reverse transcribed to generate cDNA copies of exons 4-10 of the p53 gene. Two rounds of polymerase chain reaction (PCR) were conducted to produce enough template for DNA sequence analysis of the regions of interest within the p53 gene. Dideoxy sequencing of at least two independent productions of each amplified DNA template was done to confirm the validity of the mutations found. Allelic deletions were identified by PCR and gel electrophoretic techniques to examine three polymorphisms within the p53 gene in cancer-normal DNA pairs. RESULTS: We identified 45 mutations in exons 5-8 of the p53 gene, where mutations frequently have been found in other cancer types. An additional mutation was identified in exon 4. Overall, 72% of the mutations were transitions, 24% transversions, and 4% microdeletions. Allelic deletion of the other p53 allele was seen in 67% of ovarian cancers in which a p53 mutation was present. Germ-line p53 mutations were not found in any patients whose cancers had p53 mutations. CONCLUSIONS AND IMPLICATIONS: Like p53 mutations in other types of human cancers, those in epithelial ovarian cancers are diverse and occur frequently in exons 5-8. The predominance of transition mutations suggests that p53 mutations in ovarian cancer arise because of spontaneous errors in DNA synthesis and repair rather than the direct interaction of carcinogens with DNA. These molecular data are consistent with data from epidemiologic studies that have failed to demonstrate a convincing relationship between exposure to environmental carcinogens and the development of ovarian cancer.

Alleles↗
PubMed1997

Genomic imprinting: potential function and mechanisms revealed by the Prader-Willi and Angelman syndromes.

The Prader-Willi (PWS) and Angelman (AS) syndromes are two clinically distinct syndromes which result from lack of expression of imprinted genes within chromosome 15q11-q13. These two syndromes result from 15q11-q13 deletions, chromosome 15 uniparental disomy (UPD), imprinting centre mutations and, for AS, probable mutations in a single gene. The differential phenotype results from a paternal genetic deficiency in PWS patients and a maternal genetic deficiency in AS patients. Within 15q11-q13, four genes (SNRPN, IPW, ZNF127, FNZ127) and two expressed sequence tags (PAR1 and PAR5) have been found to be expressed only from the paternally inherited chromosome, and therefore all must be considered candidate genes involved in the pathogenesis of PWS. A candidate AS gene (UBE3A) has very recently been identified. The mechanisms of imprinted gene expression are not yet understood, but it is clear that DNA methylation is involved in both somatic cell expression and inheritance of the imprint. The presence of DNA methylation imprints that distinguish the paternally and maternally inherited alleles is a common characteristic of all known imprinted genes which have been studied extensively, including SNRPN and ZNF127. Recently, several PWS and AS patients have been found that have microdeletions in a region upstream of the SNRPN gene referred to as the imprinting centre, or IC. Paternal IC deletions in PWS patients and maternal IC deletions in AS patients result in uniparental DNA methylation and uniparental gene expression at biparentally inherited loci. The IC is a novel genetic element which controls initial resetting of the parental imprint in the germline for all imprinted gene expression over a 1.5-2.5 Mb region within chromosome 15q11-q13.

Angelman Syndrome↗
PubMed1998

Human chromosome deletions in Yq11, AZF candidate genes and male infertility: history and update.

Human chromosome deletions in Yq11 seem to occur frequently as de novo mutation events in men with idiopathic azoospermia or severe oligozoospermia. However, the molecular extensions of these deletions are variable. They can be large and therefore visible under the microscope or small, not visible under the microscope, and containing the deletion of one or more DNA loci recently mapped in an apparently consecutive order along the Yq11 chromosome region. The results of 20 extensive microdeletion screening programmes have now corroborated the prevalence of the deletion of three non-overlapping DNA regions in proximal, middle and distal Yq11, which were designated earlier as AZFa, AZFb and AZFc. Deletions of single DNA loci were also reported, but as de novo and as polymorphic mutation events. Their clinical significance with regard to the men's infertility should therefore initially be handled with caution. Multiple Y genes expressed in human testis have now been mapped to each AZF region. At least one of them should be functional in human spermatogenesis and, if mutated, cause azoospermia. However, gene-specific mutations leading to the azoospermia phenotype have not yet been found for any of these AZF candidate genes. This might raise the question as to whether an AZF gene really exists in Yq11 or if the azoospermia phenotypes are only observed after deletion of a complete AZF region, after deletion of its complete gene content.

Biological Factors↗
PubMed2000

Validation of a simple Yq deletion screening programme in an ICSI candidate population.

This study reports on the validation of a diagnostic screening programme for Yq deletions in a population of infertile men. First, an unselected group of 402 intracytoplasmic sperm injection (ICSI) candidate patients was screened prospectively by means of three polymerase chain reactions (PCR) each with one marker in the region AZFa, AZFb or AZFc. With this screening strategy, eight males (2.2%) were found to carry a deletion in Yq11. Secondly, a subgroup of males were further analysed by multiplex PCR with 27 sequence-tagged sites. In this group of 229 cytogenetically normal males with azoospermia, cryptozoospermia or extreme oligozoospermia, including some patients with varicocele or a history of cryptorchidism, only one additional microdeleted patient was found with the multiplex PCR. Hence we obtained a frequency of 2.2% (9/402) or 4% (9/229) in the unselected and selected patient groups respectively. We conclude that in a diagnostic programme for Yq deletions in ICSI candidates it might be sufficient to use only four markers representing the three AZF regions and a more distal region in AZFc. In this way, it is possible to detect most, if not all, Yq deletions which might be the causal factor in the patient's infertility.

Gene Deletion↗
PubMed2002

Identification and characterization of the cynomolgus monkey chromodomain gene cynCDY, an orthologue of the human CDY gene family.

Microdeletions within the AZF (azoospermia factor) a, b and c regions of the Y chromosome can be detected worldwide in 1-10% of infertile men. AZFc, containing genes such as DAZ, CDY, RBMY and others, is most frequently deleted and associated with oligo- or azoospermia. The function of the different genes within AZFc is not yet understood. Here we report the identification and first characterization of the cynomolgus monkey (Macaca fascicularis) homologue of the human CDY gene. cynCDY encodes a 541 aa protein, which like human CDY possesses two putative functional domains: an N-terminal chromodomain, possibly involved in heterochromatin interactions, and a C-terminal domain showing similarity to enoyl-CoA-isomerase, which is involved in fatty acid oxidation. Northern analysis and in-situ hybridization experiments revealed testis- and stage-specific expression of cynCDY mRNA, mainly confined to round and elongating spermatids. Fluorescence in-situ hybridization (FISH) performed on monkey metaphase chromosomes displayed exclusively Y-specific signals in Yq12.1. Using fibre FISH, short signal stretches that indicate the presence of three CDY copies could be visualized, although their integrity or function remains unknown. cynCDY is similar to human CDY with features of a retrotransposon, but different in the 3'UTR. It seems to represent a more ancestral form of CDY and its characterization yields insights into the evolution of candidate genes for AZF.

Amino Acid Sequence↗
PubMed2005

A deletion of a novel heat shock gene on the Y chromosome associated with azoospermia.

Deletions of the Y chromosome are a significant cause of spermatogenic failure. Three major deletion intervals have been defined and termed AZFa, AZFb and AZFc. Here, we report an unusual case of a proximal AZFb deletion that includes the Y chromosome palindromic sequence P4 and a novel heat shock factor (HSFY). This deletion neither include the genes EIF1AY, RPS4Y2 nor copies of the RBMY1 genes. The individual presented with idiopathic azoospermia. We propose that deletions of the testis-specific HSFY gene family may be a cause of unexplained cases of idiopathic male infertility. This deletion would not have been detected using current protocols for Y chromosome microdeletion screens, therefore we recommend that current screening protocols be extended to include this region and other palindrome sequences that contain genes expressed specifically in the testis.

Chromosome Deletion↗
PubMed2006

No association found between gr/gr deletions and infertility in Brazilian males.

The Y chromosome carries several spermatogenesis genes distributed in three regions: AZFa, AZFb and AZFc. Microdeletions in these regions have been seen in 10% of sterile males with azoospermia or oligozoospermia, the most frequent of them being characterized by a complete deletion of AZFc region. A partial AZFc deletion named gr/gr has been singled out as a risk factor for spermatogenic failure. However, other authors have diagnosed it as a polymorphic deletion with no clinical relevance. We decided to investigate the association of gr/gr deletion and infertility in Brazilian males. We analysed 350 individuals (110 azoospermic, 122 fertile and 118 presumably fertile) and observed 12 g/gr deletions: five in infertile men (4.5%), three among fertile males (2.5%) and four in probably fertile individuals (3.4%). These differences were not statistically significant. Then, we decided to ascertain whether the clinical impact of the gr/gr deletion was associated with the type of Y chromosome. We have identified Y-chromosome haplogroups using 22 unique event polymorphisms (UEPs). Among the individuals with the gr/gr deletion, we found haplogroups R, K*, F*, E1, E3b2 and E3b*, all of which are common in white Brazilian males, and none revealed a particular association with infertility. Taken together, these results show no evidence of association between the occurrence of gr/gr deletion and male infertility.

Brazil↗
PubMed2006

Two novel missense and one novel nonsense CFTR mutations in Iranian males with congenital bilateral absence of the vas deferens.

Congenital bilateral absence of the vas deferens (CBAVD) is a frequent cause of obstructive azoospermia. Nearly 75% of men with CBAVD have at least one detectable common cystic fibrosis (CF) transmembrane conductance regulator (CFTR) mutation. To study the involvement of CFTR mutations in the Iranian population with presumed low CF frequency, we analysed 112 Iranian CBAVD males. Three Iranian CBAVD males with no clinical CF phenotype indicated by a normal karyotype, normal pancreatic function and sweat chloride concentration and no Y chromosome microdeletions were studied for CFTR mutations, IVS8-5T mutations and M470V exon 10 missense polymorphism. The entire coding sequence of each gene was analysed using a combination of the denaturing gradient-gel electrophoresis or by single-strand conformation analysis and direct DNA sequencing. Also, 52 fertile males were tested as controls to rule out polymorphism. This approach allowed us to detect one novel nonsense mutation (K536X) in the nucleotide-binding domain 1 (NBD1) region and two novel missense mutations (Y122H and T338A) in the M2 and M6 regions of CFTR gene in our studied population, which were not reported previously. Also, the conservation of changed nucleotide and amino acid in mutated regions was analysed by aligning with nine different species. K536X nonsense mutation (transversion) was found in the first NBD (NBF1), which plays an important regulatory role in CFTR function. It was, therefore, considered as a severe allele responsible for elevated sweat chloride levels and obstructive azoospermia. Because Y122H and T338A mutations were compound heterozygote with the IVS8-5T, it is difficult to judge the severity of these mutations and their role in the CBAVD phenotype.

Amino Acid Sequence↗
PubMed1991

Mutation screening of bleomycin-induced V79 Chinese hamster hprt mutants using multiplex polymerase chain reaction.

We have shown by the filter hybridization technique that bleomycin (BLM) induces different types of mutations at the hprt gene locus of V79 Chinese hamster cells. DNA of mutants identified by Southern blots as partial deletions was subjected to further analysis using multiplex polymerase chain reaction (PCR) to localize the endpoints of the deletions over the hprt gene. The PCR analysis revealed that deletions occur in all parts of the hprt gene but are distributed non-randomly. Deletions occurred most frequently at the 3'-end of the hprt gene suggesting a possible existence of a hot spot for deletions in this region; exons 1, 2 and 3 appeared to be less affected by deletions. As PCR can detect microdeletions which are below the limit of resolution of Southern blot hybridization we analysed 25 HPRT- mutants with Southern wild-type pattern to distinguish between point mutations and small deletions. Of these HPRT- mutants, all except five showed PCR amplification products identical to that of V79 wild-type cells. These results are consistent with previous Southern analyses indicating that a large portion of BLM-induced HPRT- mutants are real point mutations. Five mutants, however, showed differences in fragment sizes of single PCR products or did not yield one single exon fragment and thus are probably the result of deletions which were not to be detected by Southern analyses.

Animals↗