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Schematic representation of the Y chromosome showing different regions/genes involved in spermatogenesis and Y-linked copy number variations. A) AZoospermia Factor (AZF)a, AZFb, and AZFc regions are located on the long arm of the Y chromosome (Yq) with an overlap between AZFb and AZFc; the TSPY1 gene is present on the short arm of the Y chromosome (Yp) arranged in a tandemly repeated array. B) AZFc region showing the location of multicopy genes and transcription units in the reference sequence (Y hapogroup R). The arrows with the same motifs represent repeated homologous sequences, which may undergo NAHR. C) The "b2/b4" deletion (complete AZFc deletion) removing all AZFc genes is depicted. Three alternative breakpoints for gr/gr deletion(s) are shown which all remove half of the AZFc gene content. An example of partial AZFc duplication (gr/gr) is shown (similarly to the gr/gr deletion, different breakpoints may give origin to different types of gr/gr duplications).
Source publication
Since the first definition of the AZoospermia Factor (AZF) regions, the Y chromosome has become an important target for studies aimed to identify genetic factors involved in male infertility. This chromosome is enriched with genes expressed exclusively or prevalently in the testis and their absence or reduction of their dosage is associated with sp...
Contexts in source publication
Context 1
... microdeletions: the AZF deletions Microdeletions of the Y chromosome are the most frequent known genetic cause of spermatogenic failure in infertile men, second only to the Klinefelter syndrome (5). The first association between azoospermia (absence of spermato- zoa in the ejaculate) and microscopically detectable dele- tions of the long arm of the Y chromosome (Yq) has been demonstrated by Tiepolo and Zuffardi, in 1976 (6). They proposed the existence of a spermatogenesis factor, the AZF, encoded by a gene on distal Yq. With the develop- ment of molecular genetic tools it became possible to cir- cumscribe the AZF region, in which microdeletions arise, and to highlight a certain deletion pattern with 3 recurrent- ly deleted sub-regions in proximal, middle and distal Yq11, designated AZFa, AZFb and AZFc, respectively (7,8) (Fig. ...
Context 2
... AZFc region consists almost entirely of repetitive se- quence blocks called 'amplicons' which are arranged in direct and/or inverted repeats (12,21). The region con- tains multicopy genes expressed specifically in the testis and their dosage may vary according to different types of rearrangements. The first AZFc candidate gene isolated from the AZFc re- gion on the long arm of the human Y chromosome was DAZ (Deleted in AZoospermia), which is specifically tran- scribed in the adult testis (22). The DAZ gene belongs to a gene family consisting of 3 members: BOULE on chro- mosome 2, DAZ-Like (DAZL) on chromosome 3 and DAZ, on the Yq. Members of this gene family are expressed exclusively in germ cells and encode testis-specific RNA- binding proteins that contain a highly conserved RNA- Recognition Motif (RRM) and a unique DAZ repeat (23). With regard to the reference sequence (corresponding to a Y chromosome belonging to haplogroup R), DAZ is present on the Y chromosome in 4 copies (DAZ1, DAZ2, DAZ3, and DAZ4). The AZFc region also harbors CDY1, present in 2 copies (CDY1a and CDY1b). CDY protein products have been identified as histone acetyltrans- ferases with a strong preference for histone 4 (24), thus are likely to be involved in both spermatogenic histone replacement and DNA transcription. Other genes in- volved in AZFc deletions are BPY2, the function of which is still unknown, and 5 transcription units TTTY3, TTTY4, TTTY17, CSPG4LY, and GOLGA2LY. Due to its structure, the AZFc region is particularly sus- ceptible to NAHR events which may cause the formation of both partial deletions or duplications and therefore al- ter the AZFc gene dosage (Fig. 2). Although a number of different partial AZFc deletions have been described, only one of them resulted to be clinically relevant. This is the "gr/gr" deletion, named after the fluorescent probes ("green" and "red") used when it was detected for the first time (21). It removes half of the AZFc gene content, including two DAZ copies, one CDY1 copy, and one BPY2 copy. The clinical significance of the gr/gr deletion has been the object of a long debate. Controversies are mainly related to a number of selection biases (lack of ethnic/geographic matching of cases and controls; inap- propriate selection of infertile and control men) and methodological issues (lack of confirmation of gene loss) (25)(26)(27). Moreover, another potential confounding factor derives from the fact that the frequency and phenotypic expression may vary among different ethnic groups, on the basis of the Y chromosome background; for exam- ple, in specific Y haplogroups, such as D2b, Q3, and Q1, common in Japan and certain areas of China, the dele- tion is fixed and apparently does not have any negative effect on spermatogenesis (28,29). The presence of gr/gr deletion in Caucasian normozoospermic controls (al- though at a significantly lower frequency) prompted us to evaluate whether the Y background could influence the phenotypic variability in Caucasians, as well (30). It has been previously described that the loss of DAZ1/DAZ2 and CDY1 is prevalent (or even specific) in carriers with impaired sperm production (31-33) while it was hypothesized that the restoration of normal AZFc gene dosage in case of gr/gr deletion followed by b2/b4 duplication may explain the lack of effect on sperm count ...
Context 3
... the last years, Y-linked CNV analyses have been extended to the short arm of the Y chromosome which contains a TSPY1 gene array with variable number of TSPY1 copies (46, 47 and references therein). The TSPY1 belongs to a protein superfamily comprising SET and NAP, which are activating factors of the replication pro- cess. Indeed, TSPY1 is abundantly expressed in early stages of tumorigenesis in gonadoblastoma and could be potentially involved in other human cancers (48). Ex- pression analysis in the testis indicates the involvement of the TSPY1 in spermatogenesis as a pro-proliferative fac- tor (48). In fact, TSPY1 is mainly expressed in gono- cytes/pre-spermatogonia of embryonic testis and in sper- matogonia and spermatocytes at meiotic prophase I in adult testis. A role in early fetal germ cells development has also been addressed by Schoner et al. (49) who pro- vided evidence of TSPY1 ability to partially rescue sper- matogenesis and fertility in transgenic Kit W-v /Kit W-v mice. TSPY1 is unusual in being arranged in a tandem array of 20.4 Kb of repeated units, bearing a single active TSPY1 copy each (Fig. 2). Although copy number varies among individuals within a range of 11 to 76 (26,46,50,51), the majority of men (about 65% of the Italian population) re- main within a restricted interval (21 to 35 copies) (46). The evolutionary conservation of multiple TSPY1 copies on the Y chromosome of other mammals as well as the above mentioned limited variation in copy number in hu- mans suggest that a minimum TSPY1 copy number is like- ly to be maintained through selection (52). Only few stud- ies have focused on the eventual TSPY1 influence on spermatogenesis and frustratingly they all reached 3 dif- ferent conclusions, probably due to study design biases (46, 50, 51). Indeed, crucial for a reliable analysis is the TSPY1 CNV susceptibility to stratification biases. As a matter of fact, significantly different means of TSPY1 copy number were found among different Y haplogroups (46,53), highlighting the importance of Y haplogroups-match- ing between cases and controls. The only available study to date in which cases and controls were matched for Y hgr distribution has been performed in the Italian popu- lation by our group. The method used for the detection of TSPY1 copy number was validated against pulsed-field gel electrophoresis (the gold standard method) (46). The initially published study population has been recently en- larged and previous results confirmed i.e. a significantly lower TSPY1 copy number in 212 infertile men with ab- normal sperm parameters compared to 168 normo- zoospermic subjects (28.5±7.9 vs 32.6±10.1, respective- ly; p<0.001) has been found. The relevance of TSPY1 CNV in spermatogenesis is also attested by the positive correlation observed with sperm count both in infertile and normozoospermic subjects (Fig. 3). In the light of these findings, low TSPY1 copy number can be regarded as a new genetic risk factor for male infertility with po- tential clinical consequences and should be taken into consideration in the context of a multigenic approach to idiopathic ...
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Background
Alterations at the molecular level in spermatozoa and seminal plasma can affect male fertility. The objective of this study was to determine if analysis of differential expression of proteins in varying semen parameters can serve as potential biomarkers for male infertility.
Methods
The differential expression of proteins in the seminal...
Citations
... In addition, modern genetic tolls allow the identification of minor DNA alterations. On the long arm of the Y chromosome, for instance, the azoospermia factor (AZF) regions have multiple genes associated with fertility [5], that are susceptible to microdeletion and/ or microduplication due to their ampliconic sequences organized as palindromes prone to nonallelic homologous recombination [6]. ...
Objectives
Male infertility accounts for approximately 30% of cases of reproductive failure. The characterization of genetic variants using cytogenomic techniques is essential for the adequate clinical management of these patients. We aimed to conduct a cytogenetic investigation of numerical and structural rearrangements and a genomic study of Y chromosome microdeletions/microduplications in infertile men derived from a single centre with over 14 years of experience.
Results
We evaluated 151 infertile men in a transversal study using peripheral blood karyotypes and 15 patients with normal karyotypes through genomic investigation by multiplex ligation-dependent probe amplification (MLPA) or polymerase chain reaction of sequence-tagged sites (PCR-STS) techniques. Out of the 151 patients evaluated by karyotype, 13 presented chromosomal abnormalities: two had numerical alterations, and 11 had structural chromosomal rearrangements. PCR-STS detected a BPY2 gene region and RBMY2DP pseudogene region microdeletion in one patient. MLPA analysis allowed the identification of one patient with CDY2B_1 and CDY2B_2 probe duplications (CDY2B and NLGN4Y genes) and one patient with BPY2_1, BPY2_2, and BPY2_4 probe duplications (PRY and RBMY1J genes).
... However, as a diagnostic limitation, the G-banded karyotype does not allow the identi cation of minor DNA alterations. On the long arm of the Y chromosome, for instance, the azoospermia factor (AZF) regions have multiple genes associated with fertility [4] that are susceptible to microdeletion and/or microduplication due to their ampliconic sequences organized as palindromes prone to nonallelic homologous recombination [5]. ...
Objectives
Male infertility accounts for approximately 30% of cases of reproductive failure. The characterization of genetic variants using cytogenomic techniques is essential for the adequate clinical management of these patients. We aimed to conduct a cytogenetic investigation of numerical and structural rearrangements and a genomic study of Y chromosome microdeletions/microduplications in infertile men derived from a single centre with over 14 years of experience.
Results
We evaluated 151 infertile men in a transversal study using peripheral blood karyotypes and 15 patients with normal karyotypes through genomic investigation by multiplex ligation-dependent probe amplification (MLPA) or polymerase chain reaction of sequence-tagged sites (PCR-STS) techniques. Out of the 151 patients evaluated by karyotype, 13 presented chromosomal abnormalities: 2 had numerical alterations, and 11 had structural chromosomal rearrangements. PCR-STS detected a BPY2 gene region and RBMY2DP pseudogene region microdeletion in one patient. MLPA analysis allowed the identification of one patient with CDY2B_1 and CDY2B_2 probe duplications (CDY2B gene) and one patient with BPY2_1, BPY2_2, and BPY2_4 probe duplications (BPY2 gene).
... Another cause of genome instability is CNVs-a phenomenon characterized by the presence of repeated genome sections with the number of repeats in the genome varying between individuals. A classic and simple example of CNVs related to male infertility is microdeletions in the AZF locus of the Y chromosome [32][33][34]. The nature of the Y chromosome AZF regions, rich in repetitive sequences, makes it prone to frequent rearrangements, often leading to full or partial AZF deletions [35,36]. ...
Genome instability may play a role in severe cases of male infertility, with disrupted spermatogenesis being just one manifestation of decreased general health and increased morbidity. Here, we review the data on the association of male infertility with genetic, epigenetic, and environmental alterations, the causes and consequences, and the methods for assessment of genome instability. Male infertility research has provided evidence that spermatogenic defects are often not limited to testicular dysfunction. An increased incidence of urogenital disorders and several types of cancer, as well as overall reduced health (manifested by decreased life expectancy and increased morbidity) have been reported in infertile men. The pathophysiological link between decreased life expectancy and male infertility supports the notion of male infertility being a systemic rather than an isolated condition. It is driven by the accumulation of DNA strand breaks and premature cellular senescence. We have presented extensive data supporting the notion that genome instability can lead to severe male infertility termed “idiopathic oligo-astheno-teratozoospermia.” We have detailed that genome instability in men with oligo-astheno-teratozoospermia (OAT) might depend on several genetic and epigenetic factors such as chromosomal heterogeneity, aneuploidy, micronucleation, dynamic mutations, RT, PIWI/piRNA regulatory pathway, pathogenic allelic variants in repair system genes, DNA methylation, environmental aspects, and lifestyle factors.
... The group that produced the Italian study has theorized subsequently that because of the variation across the populations, controlling for Y haplogroups during these studies is important. This group expanded on their initial study, increasing their study size to 212 men having abnormal semen parameters compared to 168 men with normal semen parameters and continued to find a significantly lower TSPY1 copy number in the infertile group (28.5±7.9 vs. 32.6±10.1 copies) (66). A very thorough study out of China in 2013 examined 2,272 Han Chinese men and found seven distinct Y haplogroups. ...
The Y chromosome is essential for testis development and spermatogenesis. It is a chromosome with the lowest gene density owing to its medium size but paucity of coding genes. The Y chromosome is unique in that the majority of its structure is highly repetitive sequences, with the majority of these limited genes occurring in 9 amplionic sequences throughout the chromosome. The repetitive nature has its benefits as it can be protective against gene loss over many generations, but it can also predispose the Y chromosome to having wide variations of the number of gene copies present in these repeated sequences. This is known as copy number variation. Copy number variation is not unique to the Y chromosome but copy number variation is a well-known cause of male infertility and having effects on spermatogenesis. This is most commonly seen as deletions of the AZF sequences on the Y chromosome. However, there are other implications for copy number variation beyond just the AZF deletions that can affect spermatogenesis and potentially have other health implications. Copy number variations of TSPY1, DAZ, CDY1, RBMY1, the DYZ1 array, along with minor deletions of gr/gr, b1/b3, and b2/b3 have all be implicated in affecting spermatogenesis. UTY copy number variations have been implicated in risk for cardiovascular disease, and other deletions within gr/gr and the AZF sequences have been implicated in cancer and neuropsychiatric diseases. This review sets out to describe the Y chromosome and unique susceptibility to copy number variation and then to examine how this growing body of research impacts spermatogenesis and other health factors.
... 29 A proposed mechanism for the disparate outcomes associated with deletions of AZFa, AZFb, AZFc, AZFbc, and AZFabc focuses on the importance of the DAZ gene, which is a copy number variant (CNV) located in four nearly identical copies in the AZFc reference sequence (DAZ1, DAZ2, DAZ3, and DAZ4). 30,31 While it is understood that most genes contained within AZF are critical to successful spermatogenesis, it is believed that two additional, analogous copies of the DAZ gene, known as DAZL (Daz-Like), are located on the autosomal chromosome 3, in addition to its copies contained in AZFc. Unlike the other YCMs discussed, when AZFc alone is absent, it is proposed that the autosomal gene copies of DAZL can serve to "rescue" spermatogenesis and therefore facilitate the production of rare sperm required for retrieval via mTESE. ...
Deletions within the male-specific region of the Y-chromosome, known as Y-Chromosome Microdeletions (YCMs), are present in as many as 5% and 10% of severe oligospermic and azoospermic men, respectively. These microdeletions are distinguished by which segment of the Y chromosome is absent, identified as AZFa (the most proximal segment), AZFb (middle), and AZFc (distal). The reported prevalence of YCMs within the world’s populations of infertile men displays vast heterogeneity, ranging from less than 2% to over 24% based on region and ethnicity. AZFc is the most commonly identified YCM, and its phenotypic presentation provides for the highest chance for fertility through artificial reproductive techniques. Conversely, deletions identified in the subregions of AZFa, AZFb, or any combination of regions containing these segments, are associated with low probabilities of achieving pregnancy. A putative mechanism explaining this discrepancy lies within the expression of autosomal, DAZ-like genes which could serve to “rescue” wild type AZFc gene expression and hence spermatogenesis. Nevertheless, recent reports challenge this dogma and stress the importance of further analysis when an AZFb deletion is detected. The screening thresholds to determine which oligospermic and azoospermic men are tested for potential YCMs has been recently contested. More recent literature supports lowering the threshold from 5 million sperm/mL of ejaculate to 1 million/mL as the frequency of YCMs in men with sperm concentrations between 1 and 5 million sperm/mL is very low (~0.8%). As such, subsequent guidelines should recommend a lower screening threshold. While YCMs are extremely common globally, the understanding of their clinical significance in the field remains scattered and without consensus. Furthermore, very little is currently known about partial deletions within the AZFc region, such as b1/b3, b2/b3, and gr/gr. Hence, this review aimed to summarize and discuss modern trends in the epidemiology, screening guidelines, and clinical considerations pertaining to YCMs.
... New high-throughput methods have been instrumental for analysing multiple DNA molecules in parallel in large cohort studies. Indeed, NGS, such as WES (whole exome sequencing) and WGS (whole genome sequencing), allow also detecting single nucleotide variants (SNVs) and copy number variations (CNVs) potentially related to male infertility phenotypes [3,[20][21][22][23][24][25][26][27]. Whilst WES offers a global view of coding regions, it does not identify variants in non-coding regions, such as promoters, enhancer regions and untranslated region (UTR). ...
PurposeTo develop and assess a novel custom next-generation sequencing (NGS) panel for male infertility genetic diagnosis.MethodsA total of 241 subjects with diagnosis of idiopathic infertility ranging from azoospermia to normozoospermia were sequenced by a custom NGS panel including AR, FSHB, FSHR, KLHL10, NR5A1, NANOS1, SEPT12, SYCP3, TEX11 genes. Variants with minor allele frequency < 1% were confirmed by Sanger sequencing.ResultsNineteen missense variants were detected in 23 subjects with abnormal sperm count, whilst no variants were identified in normozoospermic men. Of identified variants, we prioritized variants classified as pathogenic and of uncertain significance (VUS) (63.1%, 12/19). No missense variants were found in males with normal seminal parameters (0/67). Therefore, the prevalence of variants was significantly higher in patients with spermatogenic impairment (16/174 vs 0/67, p = 0.007).Conclusion
This study confirms the utility to apply NGS panel for infertility diagnosis in order to find new genetic variants potentially linked to male infertility with much higher accuracy than standard tests suggested by guidelines. Indeed, based on biological significance, prevalence in the general population and clinical data of patients, it is plausible that identified variants in this study might be linked to quantitative spermatogenic impairment, although further studies are needed.
... The results of several genome-wide association studies (GWAS) indicate no overlapping SNVs (Aston & Carrell, 2009;Aston, Krausz, Laface, Ruiz-Castane, & Carrell, 2010;Hu et al., 2014;Sato et al., 2015;Zhao et al., 2012). Several studies have investigated the CNV load in different male infertility scenarios (Tuttelmann et al., 2011;Krausz et al., 2011;Lopes et al., 2013;Lo Giacco et al., 2014). Well-known CNV relate to the Y chromosome, including AZF microdeletions, which may lead to loss of essential genes for spermatogenesis (Krausz & Riera-Escamilla, 2018). ...
Male infertility is a complex condition with a strong genetic and epigenetic background. This review discusses the importance of genetic and epigenetic factors in the pathophysiology of male infertility. The interplay between thousands of genes, the epigenetic control of gene expression, and environmental and lifestyle factors, which influence genetic and epigenetic variants, determines the resulting male infertility phenotype. Currently, karyotyping, Y‐chromosome microdeletion screening and CFTR gene mutation tests are routinely performed to investigate a possible genetic aetiology in patients with azoospermia and severe oligozoospermia. However, current testing is limited in its ability to identify a variety of genetic and epigenetic conditions that might be implicated in both idiopathic and unexplained infertility. Several epimutations of imprinting genes and developmental genes have been postulated to be candidate markers for male infertility. As such, development of novel diagnostic panels is essential to change the current landscape with regard to prevention, diagnosis and management. Understanding the underlying genetic mechanisms related to the pathophysiology of male infertility, and the impact of environmental exposures and lifestyle factors on gene expression might aid clinicians in developing individualised treatment strategies.
... Secondly, 45,X/46,X,i(Yp) formation results in duplication of the Yp pseudoautosomal region and deletion of Yq pseudoautosomal region, outcomes that may disrupt meiotic pairing of chromosomes X and Y and thereby preclude progression through meiosis. Finally, mitotic instability and resultant X0 mosaicism in the germline may also contribute to spermatogenic defects [Lange et al., 2009;Krausz et al., 2011Krausz et al., , 2014Lindhardt Johansen et al., 2012]. ...
The Y-chromosome genes are primarily involved in sex determination, stature control, spermatogenesis, and fertility. Among structural rearrangements of the Y chromosome, the isochromosome of Yp, i(Yp), appears to be the most uncommon. We describe a detailed evolution of puberty in a boy with 45,X/46,X,i(Yp). Array CGH found 2 cell lines, one with i(Yp) and the other with monosomy X. Genetic analysis of currently known genes involved in Kallmann syndrome/normosomic central hypogonadotropic hypogonadism showed no abnormality. The patient presented with a pubertal course suggestive of a delayed puberty with gynecomastia, reduced growth rate, and infertility that need testosterone treatment to induce the appearance of the secondary sex characteristics. This patient shows the potential effects of i(Yp) and emphasizes the importance of appropriate management of puberty in people with 45,X/46,X,i(Yp). Early hormone treatment, concerns regarding fertility, emotional support, and a successful transition to adult care may help improve the physical and psychosocial well-being of affected patients.
... In support of some functional constraints is the observation that the loss or partial deletion of Y ampliconic gene copies is linked to infertility in humans. For example, TSPY copy number was linked to both infertility [11] and sperm count [11][12][13]. The long arm of the human Y chromosome includes three azoospermia factor regions (AZFa, AZFb, and AZFc), which cover most of the ampliconic genes families and are active during different phases of spermatogenesis [14]. ...
... The long arm of the human Y chromosome includes three azoospermia factor regions (AZFa, AZFb, and AZFc), which cover most of the ampliconic genes families and are active during different phases of spermatogenesis [14]. Complete or partial deletion of these regions is linked to azoospermia and arrest of spermatogenesis [2,12,[14][15][16]. Presumably, copy number decrease linked with infertility is accompanied by a reduction in gene expression of the affected Y ampliconic gene families, however this is yet to be demonstrated. ...
The Y chromosome harbors nine multi-copy ampliconic gene families expressed exclusively in testis. The gene copies within each family are >99% identical to each other, which poses a major challenge in evaluating their copy number. Recent studies demonstrated high variation in Y ampliconic gene copy number among humans. However, how this variation affects expression levels in human testis remains understudied. Here we developed a novel computational tool Ampliconic Copy Number Estimator (AmpliCoNE) that utilizes read sequencing depth information to estimate Y ampliconic gene copy number per family. We applied this tool to whole-genome sequencing data of 149 men with matched testis expression data whose samples are part of the Genotype-Tissue Expression (GTEx) project. We found that the Y ampliconic gene families with low copy number in humans were deleted or pseudogenized in non-human great apes, suggesting relaxation of functional constraints. Among the Y ampliconic gene families, higher copy number leads to higher expression. Within the Y ampliconic gene families, copy number does not influence gene expression, rather a high tolerance for variation in gene expression was observed in testis of presumably healthy men. No differences in gene expression levels were found among major Y haplogroups. Age positively correlated with expression levels of the HSFY and PRY gene families in the African subhaplogroup E1b, but not in the European subhaplogroups R1b and I1. We also found that expression of five out of six Y ampliconic gene families is coordinated with that of their non-Y (i.e. X or autosomal) homologs. Indeed, five ampliconic gene families had consistently lower expression levels when compared to their non-Y homologs suggesting dosage regulation, while the HSFY family had higher expression levels than its X homolog and thus lacked dosage regulation.
... Linear R 2 values are reported in the figure, both P < 0.001. Developments in genomic technologies led to the discovery of numerous CNVs in infertile men (Krausz et al., 2011;T€ uttelmann et al., 2011). Therefore, it is now well accepted that changes in DNA content, in conjunction with other genetic or environmental factors, may compromise fertility by altering spermatogenesis or sperm function. ...
Background
Copy number variations (CNVs) play an important role in the onset of several diseases, and recently research focused on the relationship between these structural variants and diseases of the reproductive tract, including male infertility and cryptorchidism.
Objectives
To evaluate the contribution of copy number variations of E2F1 gene to idiopathic male infertility and the factors influencing expression of this gene.
Materials and Methods
We performed a retrospective study on 540 subjects recruited from September 2014 to February 2015. TaqMan CNV assay was used to analyze E2F1 CNV. Real‐time PCR was used to assess E2F1 and HSP70 expression level in heat stressed and transfected cells with three E2F1 copies.
Results
We found a significant difference in the frequency of altered E2F1 copies in patients (12/343, 3.5%) compared with controls (0/197) (p = 0.005). Six patients with E2F1 CNV had history of cryptorchidism, but the prevalence between men with idiopathic infertility (6/243, 2.5%) and infertile men with history of cryptorchidism (6/100, 6.0%) was not statistically different (p = 0.1). E2F1 expression increased under heat stress conditions, especially in cells carrying more copies of gene and this was associated with increased expression of HSP70.
Discussion
Our data suggest that an abnormal E2F1 expression caused by multiple copies of E2F1 gene predisposes to the onset of infertility and that the risk further increases if subjects with altered E2F1 copies have stressful conditions, such as heat stress or history of cryptorchidism.
Conclusion
This study shows a link between E2F1 CNV and male infertility, suggesting that the increased risk of spermatogenic impairment associated with higher E2F1 copies might be due to higher susceptibility to stressful conditions.
