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1: Nat Genet. 1999 Dec;23(4):429-32.Click here to read Links

An azoospermic man with a de novo point mutation in the Y-chromosomal gene USP9Y.

Sun C, Skaletsky H, Birren B, Devon K, Tang Z, Silber S, Oates R, Page DC.

Howard Hughes Medical Institute, Whitehead Institute, and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

In humans, deletion of any one of three Y-chromosomal regions- AZFa, AZFb or AZFc-disrupts spermatogenesis, causing infertility in otherwise healthy men. Although candidate genes have been identified in all three regions, no case of spermatogenic failure has been traced to a point mutation in a Y-linked gene, or to a deletion of a single Y-linked gene. We sequenced the AZFa region of the Y chromosome and identified two functional genes previously described: USP9Y (also known as DFFRY) and DBY (refs 7,8). Screening of the two genes in 576 infertile and 96 fertile men revealed several sequence variants, most of which appear to be heritable and of little functional consequence. We found one de novo mutation in USP9Y: a 4-bp deletion in a splice-donor site, causing an exon to be skipped and protein truncation. This mutation was present in a man with nonobstructive azoospermia (that is, no sperm was detected in semen), but absent in his fertile brother, suggesting that the USP9Y mutation caused spermatogenic failure. We also identified a single-gene deletion associated with spermatogenic failure, again involving USP9Y, by re-analysing a published study.

PMID: 10581029 [PubMed - indexed for MEDLINE]

2: Hum Mol Genet. 2000 May 1;9(8):1161-9.Click here to read Links

Deletion and expression analysis of AZFa genes on the human Y chromosome revealed a major role for DBY in male infertility.

Foresta C, Ferlin A, Moro E.

University of Padova, Department of Medical and Surgical Sciences, Clinica Medica 3, 35128 Padova, Italy. forestac@protec.it

Three distinct regions, designated AZFa, b and c from proximal to distal Yq, are required for normal spermato-genesis in humans. Deletions involving AZFa (deletion interval 5C/D) seem to occur less frequently in infertile men and to be associated with a more severe testicular phenotype, with almost complete absence of germ cells. AZFa contains three genes, named USP9Y, DBY and UTY, and presents high homology with the mouse Delta Sxr (b) interval, deletion of which causes a severe spermatogenic impairment. However, the specific role of these genes in human spermatogenesis is still unknown and it is not clear which of them is responsible for the AZFa phenotype. Here we describe a complete sequence map of the AZFa region, the genomic structure of AZFa genes and their deletion analysis in a large number of infertile men characterized by well-defined spermatogenic alterations. Both USP9Y and DBY may cause severe testiculopathies, but DBY appears to be the major AZFa candidate. DBY is frequently deleted in infertile patients and its absence produces severe spermatogenic damage leading to a significant reduction of germ cells or even to their complete absence. Expression analysis of AZFa genes and their X-homologues revealed ubiquitous expression for all of them except DBY; this gene produces a long transcript which is ubiquitously expressed in addition to a shorter transcript which is only expressed in the testis, suggesting a specific role for DBY in the spermatogenic process. This hypothesis is further supported by the high similarity of DBY to other DEAD box proteins belonging to the PL10 subclass.

PMID: 10767340 [PubMed - indexed for MEDLINE]

3: Hum Mol Genet. 2006 Sep 15;15(18):2673-81. Epub 2006 Aug 7.Click here to read Links

Natural transmission of USP9Y gene mutations: a new perspective on the role of AZFa genes in male fertility.

Krausz C, Degl'Innocenti S, Nuti F, Morelli A, Felici F, Sansone M, Varriale G, Forti G.

Andrology Unit, Department of Clinical Physiopathology, University of Florence, Italy. c.krausz@dfc.unifi.it

Deletions of the azoospermia factor (AZF) regions of the Y chromosome are associated with severe spermatogenic failure and represent the most frequent molecular genetic cause of azoospermia and severe oligozoospermia. The exact role of the candidate AZF genes is largely unknown due to both the extreme rarity of naturally occurring AZF gene-specific mutations and the lack of functional assays. Here, we report the fine characterization of two different deletions in the USP9Y gene (one of the two candidate genes in the AZFa region), which have been transmitted through natural conception in two unrelated families. The associated mild testicular phenotype, in both cases, is in sharp contrast with that of the two previously reported infertile patients bearing a mutation of the same gene. In conclusion, to date, the USP9Y gene has been considered as one of the major Y-linked spermatogenesis genes, based on both its position within the AZFa region and previous reports that correlated USP9Y mutation to severe spermatogenic failure and infertility. This view is now substantially changed because our findings clearly demonstrate that during human spermatogenesis, USP9Y is more likely a fine tuner that improves efficiency, rather than a provider of an essential function. More importantly, the observed natural conceptions suggest that the protein is not required for the final sperm maturation process or for the acquisition of sperm fertilizing ability, providing a new perspective on the role played by the USP9Y gene in male fertility.

PMID: 16893908 [PubMed - indexed for MEDLINE]

4: J Endocrinol Invest. 2000 Nov;23(10):646-51.Links

Role of the AZFa candidate genes in male infertility.

Foresta C, Moro E, Rossi A, Rossato M, Garolla A, Ferlin A.

Department of Medical and Surgical Sciences, University of Padova, Italy. forestac@protec.it

The AZFa region on the Y-chromosome long arm has been recently assembled in a complete sequence map contained in a contig and shown to span more than 1 Mb. It contains three genes, USP9Y, DBY and UTY, but only the former two can be at present considered candidate genes for the infertile phenotype associated with deletion of this interval. These genes have X-homologues and are expressed in many tissues, even if DBY has a shorter transcript expressed in the testis only, strengthening its role in spermatogenesis. Only few patients with gene-specific deletion have been reported and a clear genotype-phenotype relation is still lacking. While deletions or even smaller mutations in USP9Y seem to be associated with a testicular phenotype of severe hypospermatogenesis, patients with deletions of DBY may present both Sertoli cell-only syndrome and severe hypospermatogenesis. On the contrary, the phenotype of patients with deletion of both USP9Y and DBY seem to be invariably azoospermia with a testicular histology of Sertoli cell-only.

PMID: 11097428 [PubMed - indexed for MEDLINE]

5: J Formos Med Assoc. 2001 Sep;100(9):592-7.Links

AZFa candidate gene deletions in Taiwanese patients with spermatogenic failure.

Lin YM, Teng YN, Lee PC, Lin YH, Hsu CC, Lin JS, Kuo PL.

Department of Urology, National Cheng Kung University, College of Medicine, Tainan.

BACKGROUND AND PURPOSE: Deletions of the azoospermia factor subregion a (AZFa) genes in proximal Yq11 are not frequently reported. The majority of AZFa deletions are thought to be associated with more severe testicular phenotypes, such as Sertoli cell-only syndrome. There is a lack of data on AZFa gene deletions in East Asian populations. In this study, we investigated the deletion status of AZFa genes in Taiwanese men with spermatogenic failure. METHODS: One hundred and eighty-three consecutive men with severe oligozoospermia or non-obstructive azoospermia were enrolled in this study. Genomic DNA was extracted from peripheral blood samples and polymerase chain reaction (PCR) was performed using primers specific to four AZFa genes: AZFaT1, DFFRY, DBY, and UTY. Sequence-tagged site markers (sY740, sY630, sY86, sY85, sY87, sY709, and sY88) were used to define the position of deletions. One hundred and twenty fertile men with normal spermatogenesis were enrolled as controls. RESULTS: Of the 183 patients, two showed single AZFa gene deletions, resulting in an overall frequency of 1.1%. One of these two patients had DFFRY deletion and the other had DBY deletion; their testicular phenotypes were Sertoli cell-only syndrome and hypospermatogenesis, respectively. Neither patient had deletions extending from AZFa through AZFb or AZFc. CONCLUSION: Our results suggest that AZFa gene deletion is infrequent in Taiwanese patients with severe oligozoospermia or non-obstructive azoospermia.

PMID: 11695273 [PubMed - indexed for MEDLINE]

6: Urology. 1998 May;51(5):816-9.Click here to read Links

Identification of spermatozoa and round spermatids in the ejaculates of men with spermatogenic failure.

Hendin BN, Patel B, Levin HS, Thomas AJ Jr, Agarwal A.

Department of Urology, Cleveland Clinic Foundation, Ohio 44195, USA.

OBJECTIVES: As many as 10% of infertile men have azoospermia caused by spermatogenic failure or ductal obstruction. The histologic diagnoses associated with spermatogenic failure--Sertoli cell-only syndrome, maturation arrest, and hypospermatogenesis--do not necessarily represent global changes in the affected testis, as occasional seminiferous tubules may still produce mature germ cells. Intracytoplasmic sperm injection (ICSI) allows individual sperm that have been isolated from testicular tissue to fertilize oocytes. This study assessed whether mature germ cells (either round spermatids or spermatozoa) were present in the ejaculates of patients with spermatogenic failure. METHODS: All semen analyses performed at our tertiary care institution from January 1993 through December 1995 were reviewed to identify azoospermic men with spermatogenic failure. During this period, our laboratory employed Nuclear-Fast Red and picroindigocarmine staining (NF-PICS) of cytospin slides to identify rare spermatozoa and spermatids in otherwise azoospermic ejaculates. RESULTS: Of 3005 analyses reviewed, 20 azoospermic men whose infertility was solely attributable to spermatogenic failure were identified. The histologic diagnoses were germinal cell aplasia (n = 7), complete maturation arrest (n = 6), incomplete maturation arrest (n = 3), and hypospermatogenesis (n = 4). Using the NF-PICS technique, mature germ cells were identified in the ejaculates of 15 men (75%), and 9 men (45%) had fully formed spermatozoa present. CONCLUSIONS: In the clinical management of azoospermic infertile men, the NF-PICS technique may be used to identify men who have some degree of testicular spermatogenesis. This might obviate the need for the purely diagnostic testis biopsy that is performed before therapeutic biopsy for testicular sperm extraction in conjunction with ICSI.

PMID: 9610597 [PubMed - indexed for MEDLINE]

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7: J Clin Endocrinol Metab. 2000 Nov;85(11):4069-73.Click here to read Links

Male infertility caused by a de novo partial deletion of the DAZ cluster on the Y chromosome.

Moro E, Ferlin A, Yen PH, Franchi PG, Palka G, Foresta C.

Department of Medical and Surgical Sciences, Clinica Medica 3, University of Padova, Italy.

Deletions in distal Yq interval 6 represent the cause of 10-15% of idiopathic severe male infertility and map to a region defined AZFc (azoospermia factor c). The testis-specific gene DAZ is considered a major AZFc candidate, and its deletion has been associated with a severe disruption in spermatogenesis. However, DAZ is actually a multicopy gene family consisting of seven clustered copies spanning about 1 megabase. Only deletions removing the entire DAZ gene cluster together with other genes have been reported in infertile males. Because no case of spermatogenic failure has been traced to intragenic deletions, point mutations, or even deletions not involving all the DAZ copies, the definitive proof for a requirement of DAZ for spermatogenesis is still debatable. Here we report the first case of a partial deletion of the DAZ cluster removing all but one of the copies. This deletion is present in a patient affected with severe oligozoospermia who had a testicular phenotype characterized by a great quantitative reduction of germ cells (severe hypospermatogenesis). The absence of this deletion in the fertile brother of the patient suggests that this de novo mutation indeed caused the spermatogenic failure.

PMID: 11095434 [PubMed - indexed for MEDLINE]

8: Urology. 2004 Jan;63(1):131-6; discussion 136.Click here to read Links

Transcriptional levels of four Y chromosome-linked AZF genes in azoospermic men and their association with successful sperm retrieval.

Kuo PL, Lin YH, Teng YN, Hsu CC, Lin JS, Lin YM.

Department of Obstetrics and Gynecology, National Cheng Kung University College of Medicine, Tainan, Taiwan.

OBJECTIVES: To investigate the transcriptional levels of four azoospermia factor genes in the testis of azoospermic men and to investigate the association between transcriptional levels and the results of sperm retrieval. METHODS: Thirty-eight azoospermic men with normal karyotype and without Y chromosome gene deletions were enrolled. The amounts of USP9Y (ubiquitin specific protease 9, Y chromosome), DBY (dead box on the Y), RBMY1 (RNA-binding motif on the Y, 1), and DAZ (deleted in azoospermia) transcripts were examined by quantitative competitive-reverse transcriptase-polymerase chain reaction. The steady-state concentrations of mRNA encoding for each gene in each testicular sample were normalized by the amounts of a housekeeping gene (glyceraldehyde phosphate dehydrogenase [GAPDH]). Differences in the transcript ratios (gene transcript/GAPDH transcript) among patients with different testicular histologic findings (normal spermatogenesis, hypospermatogenesis, maturation arrest, Sertoli cell-only syndrome) were analyzed. For each gene, the association between the transcript ratios and the results of sperm retrieval was evaluated. RESULTS: No statistically significant difference was found in the transcript ratios of USP9Y and DBY among the four histologic patient groups (P = 0.33 and P = 0.21, respectively). In contrast, statistically significant decreases were found in the transcript ratios of RBMY1 and DAZ in patients with spermatogenic failure (P = 0.0002 and P = 0.002, respectively). The transcript ratios of USP9Y and DBY were not associated with the results of sperm retrieval, and the transcript ratios of RBMY1 and DAZ revealed a positive association with successful sperm retrieval. CONCLUSIONS: The decreased transcriptional levels of RBMY1 and DAZ in patients with spermatogenic failure may reflect the generalized loss of germ cells. The transcriptional levels of RBMY1 and DAZ may have the potential of becoming useful parameters in the prediction of successful sperm retrieval.

PMID: 14751364 [PubMed - indexed for MEDLINE]

9: Mol Reprod Dev. 1999 May;53(1):27-41.Click here to read Links

Defining regions of the Y-chromosome responsible for male infertility and identification of a fourth AZF region (AZFd) by Y-chromosome microdeletion detection.

Kent-First M, Muallem A, Shultz J, Pryor J, Roberts K, Nolten W, Meisner L, Chandley A, Gouchy G, Jorgensen L, Havighurst T, Grosch J.

Promega Corporation, Department of Obstetrics and Gynecology, University of Wisconsin, Madison 53711, USA.

Cytogenetic and molecular deletion analyses of azoospermic and oligozoospermic males have suggested the existence of AZoospermia Factor(s) (AZF) residing in deletion intervals 5 and 6 of the human Y-chromosome and coinciding with three functional regions associated with spermatogenic failure. Nonpolymorphic microdeletions in AZF are associated with a broad spectrum of testicular phenotypes. Unfortunately, Sequence Tagged Sites (STSs) employed in screening protocols range broadly in number and mapsite and may be polymorphic. To thoroughly analyze the AZF region(s) and any correlations that may be drawn between genotype and phenotype, we describe the design of nine multiplex PCR reactions derived from analysis of 136 loci. Each multiplex contains 4-8 STS primer pairs, amplifying a total of 48 Y-linked STSs. Each multiplex consists of one positive control: either SMCX or MIC2. We screened four populations of males with these STSs. Population I consisted of 278 patients diagnosed as having significant male factor infertility: either azoospermia, severe oligozoospermia associated with hypogonadism and spermatogenic arrest or normal sperm counts associated with abnormal sperm morphology. Population II consisted of 200 unselected infertile patients. Population III consisted of 36 patients who had previously been shown to have aneuploidy, cytological deletions or translocations involving the Y-chromosome or normal karyotypes associated with severe phenotype abnormalities. Population IV consisted of 920 fertile (control) males. The deletion rates in populations I, II and III were 20.5%, 7% and 58.3%, respectively. A total of 92 patients with deletions were detected. The deletion rate in population IV was 0.87% involving 8 fertile individuals and 4 STSs which were avoided in multiplex panel construction. The ability of the nine multiplexes to detect pathology associated microdeletions is equal to or greater than screening protocols used in other studies. Furthermore, the data suggest a fourth AZF region between AZFb and AZFc, which we have termed AZFd. Patients with microdeletions restricted to AZFd may present with mild oligozoospermia or even normal sperm counts associated with abnormal sperm morphology. Though a definitive genotype/phenotype correlation does not exist, large deletions spanning multiple AZF regions or microdeletions restricted to AZFa usually result in patients with Sertoli Cell Only (SCO) or severe oligozoospermia, whereas microdeletions restricted to AZFb or AZFc can result in patients with phenotypes which range from SCO to moderate oligozoospermia. The panel of nine multiplexed reactions, the Y-deletion Detection System (YDDS), provides a fast, efficient and accurate method of assessing the integrity of the Y-chromosome. To date, this study provides the most extensive screening of a proven fertile male population in tandem with 514 infertile males, derived from three different patient selection protocols.

PMID: 10230814 [PubMed - indexed for MEDLINE]

10: APMIS. 2003 Jan;111(1):115-26; discussion 126-7.Click here to read Links

Polymorphic DAZ gene family in polymorphic structure of AZFc locus: Artwork or functional for human spermatogenesis?

Vogt PH, Fernandes S.

Section Molecular Genetics & Infertility, Department Gynecol. Endocrinol. & Reproductive Medicine, University of Heidelberg, D-69115 Heidelberg, Germany. peter_vogt@med.uni-heidelberg.de

Human spermatogenesis is regulated by a network of genes located on autosomes and on sex chromosomes, but especially on the Y chromosome. Most results concerning the germ cell function of the Y genes were obtained by genomic breakpoint mapping studies of the Y chromosome of infertile patients. Although this approach has the benefit of focussing on those Y regions that contain most likely the Y genes of functional importance, its major drawback is the fact that fertile control samples were often missing. In fertile men, molecular and cytogenetic analyses of the Y chromosome has revealed highly polymorphic chromatin domains especially in the distal euchromatic part (Yq11.23) and in the heterochromatic part (Yq12) of the long arm. In sterile patients cytogenetic analyses mapped microscopically visible Y deletions and rearrangements in the same polymorphic Y regions. The presence of a Y chromosomal spermatogenesis locus was postulated to be located in Yq11.23 and designated as AZoospermia Factor (ZF). More recently, molecular deletion mapping in Yq11 has revealed a series of microdeletions that could be mapped to one of three different AZF loci: AZFa in proximal Yq11 (Yq11.21), AZFb and AZFc in two non-overlapping Y-regions in distal Yq11 (Yq11.23). This view was supported by the observation that AZFa and AZFb microdeletions were associated with a specific pathology in the patients' testis tissue. Only AZFc deletions were associated with a variable testicular pathology and in rare cases AZFc deletions were even found inherited from father to son. However, AZFc deletions were found with a frequency of 10-20% only in infertile men and most of them were proved to be "de novo", i.e. the AZFc deletion was restricted to the patient's Y chromosome. Based mainly on positional cloning experiments of testis cDNA clones and on the Y chromosomal sequence now published in GenBank, a first blueprint for the putative gene content of the AZFc locus can now be given and the gene location compared to the polymorphic DNA domains. This artwork of repetitive sequence blocks called AZFc amplicons raised the question whether the AZFc chromatin is still part of the heterochromatic domain of the Y long arm well known for its polymorphic extensions or is decondensed and part of the Yq11.23 euchromatin? We discuss also the polymorphic DAZ gene family and disclose putative origins of its molecular heterogeneity in fertile and infertile men recently identified by the analyses of Single Nucleotide Variants (SNVs) in this AZFc gene locus.

PMID: 12752250 [PubMed - indexed for MEDLINE]

11: Fertil Steril. 2002 May;77(5):897-903.Click here to read Links

Gene-based screening for Y chromosome deletions in Taiwanese men presenting with spermatogenic failure.

Lin YM, Lin YH, Teng YN, Hsu CC, Shinn-Nan Lin J, Kuo PL.

Department of Urology, National Cheng Kung University, Tainan, Taiwan

OBJECTIVE: To develop a simple and rapid protocol for detecting deletions of the Y chromosome and to evaluate the feasibility of gene-based screening in men with spermatogenic failure. DESIGN: Prospective case study. SETTING: University-based reproductive clinics and genetics laboratory. PATIENT(S): Two hundred two infertile men presenting with severe oligozoospermia and nonobstructive azoospermia. INTERVENTION(S): Fifteen gene-specific primers were used to detect deletions of Y chromosome genes in men with spermatogenic failure. A multiplex polymerase chain reaction amplification system was developed to facilitate rapid screening. Another 24 markers for sequence-tagged sites (STS) were used to ensure the adequacy of gene-based screening. MAIN OUTCOME MEASURE(S): Detection of deletions of Y chromosome genes. RESULT(S): Of 180 patients evaluated, 19 (10.6%) had deletions of one or more genes, including DFFRY, DBY, RBM1, DAZ, CDY1, and BPY2. A second round of STS-based screenings did not show an increase in the deletion rate but more clearly defined the extent of deletion in 14 of the 19 patients. In most patients, deletions detected by gene-based screening were similar to those detected by STS markers. CONCLUSION(S): Gene-based screening with multiplex polymerase chain reaction is a rational alternative for detecting deletions of Y chromosome genes in infertile men.

PMID: 12009341 [PubMed - indexed for MEDLINE]

12: Hum Reprod. 1999 Jul;14(7):1710-6.Click here to read Links

Human male infertility and Y chromosome deletions: role of the AZF-candidate genes DAZ, RBM and DFFRY.

Ferlin A, Moro E, Garolla A, Foresta C.

Department of Medical and Surgical Sciences, Clinica Medica 3, University of Padova, Via Ospedale 105, 35128 Padova, Italy.

Microdeletions in Yq11 overlapping three distinct 'azoospermia factors' (AZFa-c) represent the aetiological factor of 10-15% of idiopathic azoospermia and severe oligozoospermia, with higher prevalence in more severe testiculopathies, such as Sertoli cell-only syndrome. Using a PCR-based screening, we analysed Yq microdeletions in 180 infertile patients affected by idiopathic Sertoli cell-only syndrome and different degrees of hypospermatogenesis, compared with 50 patients with known causes of testicular alteration, 30 with obstructive azoospermia, and 100 normal fertile men. In idiopathic severe testiculopathies (Sertoli cell-only syndrome and severe hypospermatogenesis), a high prevalence of microdeletions (34.5% and 24.7% respectively) was found, while milder forms were not associated with Yq alteration. No deletions were found in testiculopathies of known aetiology, obstructive azoospermia, normal fertile men and male relatives of patients with deletions. Deletions in the AZFc region involving the DAZ gene were the most frequent finding and they were more often observed in severe hypospermatogenesis than in Sertoli cell-only syndrome, suggesting that deletions of this region are not sufficient to cause complete loss of the spermatogenic line. Deletions in AZFb involving the RBM gene were less frequently detected and there was no correlation with testicular phenotype, with an apparent minor role for such gene in spermatogenesis. The DFFRY gene was absent in a fraction of patients, making it a candidate AZFa gene. Our data suggest that larger deletions involving more than one AZF-candidate gene are associated with a more severe testicular phenotype.

PMID: 10402373 [PubMed - indexed for MEDLINE]

13: Fertil Steril. 2007 Jun;87(6):1291-300. Epub 2007 Feb 12.Click here to read Links

A simplified gene-specific screen for Y chromosome deletions in infertile men.

Teng YN, Lin YH, Tsai YC, Hsu CC, Kuo PL, Lin YM.

Department of Early Childhood Education and Nursery, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.

OBJECTIVE: To test the diagnostic efficiency of a gene-specific, five-marker screening strategy for the detection of Y chromosome deletions. DESIGN: Prospective case study. SETTING: University genetics laboratory and reproductive clinics. PATIENT(S): Six hundred twenty-seven infertile men and 212 fertile men. INTERVENTION(S): Peripheral blood samples were screened for Y chromosome deletions in a triple-blind fashion using three protocols: protocol I consisted of five gene-specific markers, including USP9Y, DBY, SMCY, RBM1, and DAZ; protocol II included 14 gene-specific markers; and protocol III consisted of six sequence-tagged sites (STSs) markers recommended by EAA/EMQN. MAIN OUTCOME MEASURE(S): Deletion status of Y chromosome genes or sequence-tagged sites. RESULT(S): Protocols I and II identified the same 41 infertile patients with Y deletions. Protocol III identified 38 infertile patients with Y deletions, and all 38 patients were also identified by protocols I and II. One patient with isolated USP9Y deletion and two patients with isolated DBY deletions, as detected by protocols I and II, could not be identified by protocol III. CONCLUSION(S): We observed mostly consistent results between our protocols and the EAA/EMQN protocol. This gene-specific, five-marker screening panel provides the same diagnostic efficiency as the EAA/EMQN protocol and may be considered an alternative to the EAA/EMQN protocol.

PMID: 17296183 [PubMed - indexed for MEDLINE]

14: Andrologia. 2007 Oct;39(5):190-5.Click here to read Links

Mutation analysis of the X-chromosome linked, testis-specific TAF7L gene in spermatogenic failure.

Akinloye O, Gromoll J, Callies C, Nieschlag E, Simoni M.

Department of Chemical Pathology, College of Health Sciences, Ladoke Akintola University of Technology, Osogbo, Osun State, Nigeria.

The precise temporal and spatial expressions of specific transcription regulation factors (TRF) have long been considered essential for spermatogenesis. Recently, it has been speculated that mammals have evolved more specialised TRF genes. In the human, the TAF7L gene may be essential for maintenance of spermatogenesis. In this study, we investigated the possible role of the TAF7L gene located on the X chromosome in testicular function and spermatogenic failure. In a case-controlled retrospective study, we recruited 16 infertile males with consistent, nonobstructive azoospermia and with normal serum follicle-stimulating hormone (FSH) levels. Twenty age-matched men with normal spermatogenesis with the same ethnic background (Caucasian) were recruited as controls. Their genomic DNA was screened for sequence changes in the coding regions and part of the flanking introns of the TAF7L gene by direct sequencing. Amino acid sequence was compared with the NCBI standard sequence (BC043391). Semen analysis and hormone evaluation were performed. We observed six sequence variations in four patients, consisting of two point mutations, one each in exon 9 and 13 and one six-basepair deletion in exon 13 with concomitant changes in amino acid. One additional nucleotide exchange was observed in intron 8. Most of these changes were also found in eight controls with the exception of changes in exon 13. A meta-analysis including the present study and literature data suggests a possible association of the point mutation in exon 13 with infertility. There was no association or relationship with reproductive hormones. In conclusion, the sequence variants in the cDNA sequence observed are common polymorphisms. The changes in intron 8 appear novel. We report for the first time that most of the alterations are not associated with gonadal dysfunction, while the sequence variant in exon 13 may represent a risk factor for spermatogenic failure.

PMID: 17714218 [PubMed - indexed for MEDLINE]

15: Int J Androl. 2003 Oct;26(5):286-95.Click here to read Links

Cytogenetic and molecular analysis of the Y chromosome: absence of a significant relationship between CAG repeat length in exon 1 of the androgen receptor gene and infertility in Indian men.

Dhillon VS, Husain SA.

Cytogenetics Laboratory, Department of Biosciences, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi, India. dhillonvs@yahoo.com.au

The genetic basis of male infertility remains unclear in the majority of cases. Recent studies have indicated an association between microdeletions of the azoospermia factor a (AZFa)-AZFc regions of Yq and severe oligospermia or azoospermia. Increased (CAG)n repeat lengths in the androgen receptor (AR) gene have also been reported in infertile men. Therefore, in order to assess the prevalence of these genetic defects to male infertility, 183 men with non-obstructive azoospermia (n = 70), obstructive azoospermia (n = 33), severe oligospermia (n = 80) and 59 fertile men were examined cytogenetically and at molecular level for Yq deletions, microdeletions, and AR-CAG repeat lengths along with hormonal profiles [luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone (T)]. We used high resolution cytogenetics to detect chromosome deletions and multiplex polymerase chain reaction (PCR) involving 27 sequence-tagged site (STS) markers on Yq to determine the rate and extent of Yq microdeletions. PCR amplification with primers flanking exon 1 of AR gene was used to determine the AR-(CAG)n repeat lengths. Hormonal profiles (LH, FSH and T levels) were also analysed in infertile and fertile men. Testicular biopsies showed Sertoli cell only (SCO) morphology, maturation arrests (MA) and hypospermatogenesis. No chromosome aberrations were found in infertile men but there was a significant increase (p < 0.001) in the association of acrocentric chromosomes including the Y chromosome. Yq microdeletions were found in 16 non-obstructive azoospermic men (16 of 70; 22%) and seven severe oligospermic individuals (seven of 80; 8.7%) and most of them had deletions in the sY240 locus. No Yq microdeletions were detected in patients with obstructive azoospermia. No statistically significant difference in the mean length of CAG repeats in AR gene was observed between infertile and fertile men (22.2 +/- 1.5 and 21.5 +/- 1.4 respectively). No significant increase or decrease in levels of LH, FSH and T was observed in infertile and fertile men. In some infertile men, significantly elevated levels of FSH alone or in combination with LH were found to be indicative of failure of spermatogenesis and/or suggestive of testicular failure. Y-chromosome microdeletions contribute to infertility in some patients but no relationship could be established with the (CAG)n repeat lengths in exon 1 of the AR gene in infertile Indian men.

PMID: 14511217 [PubMed - indexed for MEDLINE]

16: J Urol. 2007 Aug;178(2):608-12; discussion 612. Epub 2007 Jun 13.Click here to read Links

Uniform testicular maturation arrest: a unique subset of men with nonobstructive azoospermia.

Hung AJ, King P, Schlegel PN.

James Buchanan Brady Urology Foundation, Department of Urology, Center for Male Reproductive Medicine and Microsurgery, New York Presbyterian Hospital, Weill Medical College of Cornell University, New York, New York 10021, USA.

PURPOSE: We evaluated the clinical characteristics of men with uniform testicular maturation arrest and nonobstructive azoospermia or severe oligospermia, including the frequency of genetic defects and outcome of intracytoplasmic sperm injection with or without testicular sperm extraction. MATERIALS AND METHODS: We identified a group of 32 men with nonobstructive azoospermia or severe oligospermia, uniform maturation arrest (single spermatogenic pattern on biopsy), and normal follicle-stimulating hormone (7.6 IU/l or less). These patients were identified from 150 intracytoplasmic sperm injection candidates with severe oligospermia (less than 10,000/cc) and 600 men with nonobstructive azoospermia undergoing attempted testicular sperm extraction-intracytoplasmic sperm injection between November 1995 and September 2006. These patients were characterized based on the frequency of genetic anomalies (karyotype or Y chromosome microdeletions). Rates of sperm retrieval by testicular sperm extraction, fertilization and pregnancy after ICSI were measured. RESULTS: Genetic anomalies were more common (45%) in men with uniform maturation arrest and normal follicle-stimulating hormone than other men with nonobstructive azoospermia (17%) undergoing testicular sperm extraction at our center (p <0.001). They had a lower sperm retrieval rate with testicular sperm extraction compared to other nonobstructive azoospermia patients (41% vs 60%, p = 0.05). Fertilization rate (37%) and clinical pregnancy (13%) were significantly less common than in other men with nonobstructive azoospermia (54% and 49%, respectively, p <0.01). CONCLUSIONS: Patients with uniform maturation arrest and normal follicle-stimulating hormone are a clinically definable subgroup of men with nonobstructive azoospermia that have different treatment outcomes. They have a higher incidence of chromosomal abnormalities and Y chromosome microdeletions compared to other men with nonobstructive azoospermia. Despite having normal follicle-stimulating hormone and typically normal testicular volume, sperm retrieval may be difficult and the chance of successful pregnancy is limited.

PMID: 17570432 [PubMed - indexed for MEDLINE]

17: Hum Mol Genet. 2000 Sep 22;9(15):2291-6.Click here to read Links

Deletion of azoospermia factor a (AZFa) region of human Y chromosome caused by recombination between HERV15 proviruses.

Sun C, Skaletsky H, Rozen S, Gromoll J, Nieschlag E, Oates R, Page DC.

Howard Hughes Medical Institute, Whitehead Institute, and Department of Biology, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA.

Deletion of any of three regions of the human Y chromosome results in spermatogenic failure and infertility. We previously sequenced one of these regions, azoospermia factor a (AZFa) and found that it spanned approximately 800 kb. By sequence-tagged site (STS) content mapping, we roughly defined deletion breakpoints in two unrelated, azoospermic men with AZFa deletions. The positions of proximal and distal breakpoints were similar in the two men. Hypothesizing that the deletions might have been generated by homologous recombination, we searched electronically for DNA sequence similarities between the proximal and distal breakpoint regions. These comparisons revealed the most striking sequence similarities anywhere along or near the AZFa region. In the proximal breakpoint region, we identified a 10 kb provirus of the recently defined HERV15 class of endogenous retroviruses. In the distal breakpoint region, we found a second HERV15 provirus, 94% identical in DNA sequence to the first and in the same orientation. (A partial LINE insertion in this distal provirus proved to be the basis of the previously described DYS11/p12f polymorphism.) The AZFa deletions in the two men differed slightly, but all breakpoints fell within the HERV15 proviruses. Indeed, sequencing of deletion junctions from the two men revealed that homologous recombination had occurred within large domains of absolute sequence identity between the proximal and distal proviruses. When combined with published STS mapping data for other AZFa-deleted men, our findings suggest that recombination between these two HERV15 proviruses could account for most AZFa deletions.

PMID: 11001932 [PubMed - indexed for MEDLINE]

18: Mol Hum Reprod. 1996 Dec;2(12):943-50.Click here to read Links

The incidence and possible relevance of Y-linked microdeletions in babies born after intracytoplasmic sperm injection and their infertile fathers.

Kent-First MG, Kol S, Muallem A, Ofir R, Manor D, Blazer S, First N, Itskovitz-Eldor J.

Promega Corp., Madison, WI 53711, USA.

Microdeletions linked to deletion intervals 5 and 6 of the Y chromosome have been associated with male factor infertility. Members from at least two gene families lie in the region containing azoospermia factor (AZF), namely YRRM and DAZ. With the advent of intracytoplasmic sperm injection (ICSI), it is possible for men with severe male factor infertility to produce a child. The genetic consequences of such a procedure have been questioned. This report describes the first study of a population (32 couples) of infertile fathers and their sons born after ICSI. The objectives were firstly to determine the incidence and map location of Y chromosome microdeletions and to compare the frequencies with other population studies involving severe male factor infertility, and secondly to formulate a working hypothesis concerning developmental aetiology of Y chromosome microdeletions. The incidence of microdeletions in the ICSI population was shown to be 9.4% (within the range 9-18% reported for populations of severe male factor infertility patients). Microdeletions in two out of three affected father/son pairs mapped in the region between AZFb and AZFc and the third involved a large microdeletion in AZFb and AZFc. Of three affected father/son pairs, microdeletions were detected in the blood of one infertile propositus father and three babies. Assuming that the gonomes of the ICSI-derived babies are direct reflections of those of their fathers germ lines, it is possible that two of three infertile fathers were mosaic for intact Y and microdeleted Y chromosomes. In such cases, the developmental aetiology of the microdeletion may be due to a de-novo microdeletion arising as a post-zygotic mitotic error in the infertile propositus father, thus producing a mosaic individual who may or may not transmit the deletion to his ICSI-derived sons depending on the extent of primordial germ cell mosaicism. In one of three affected fathers, the microdeletion detected in his blood was also detected in his ICSI-derived son. In this case the de-novo event giving rise to the microdeletion may have occurred due to a post- (or pre-) meiotic error in the germ line of this father's normally fertile father (i.e. the ICSI-derived baby's grandfather).

PMID: 9237238 [PubMed - indexed for MEDLINE]

19: J Reprod Immunol. 2002 Jan;53(1-2):37-44.Click here to read Links

Molecular analysis of the Y chromosome AZFc region in Japanese infertile males with spermatogenic defects.

Sawai H, Komori S, Koyama K.

Laboratory of Developmental Biology and Reproduction, Institute for Advanced Medical Sciences, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya-shi, 663-8501, Japan. sawai@hyo-med.ac.jp

Cytogenetic and molecular studies of azoospermic and oligozoospermic males have suggested the presence of azoospermia factors (AZF) in the human Y chromosome. Deletion in three Y chromosomal regions--AZFa, AZFb and AZFc--has been reported to disrupt spermatogenesis and cause infertility. Several candidate genes responsible for spermatogenesis have been identified in these regions and some of them are thought to be functional in human spermatogenesis. Here we report on clinical and molecular studies of Y chromosome micro-deletions in Japanese. In these studies the data from 157 infertile Japanese men with azoospermia and oligozoospermia was analyzed and divided into 5 categories based on spermatozoa count. Sixteen sets of primers were used for polymerase chain reaction (PCR) to amplify sequence tagged site markers. One common deletion in the AZFc region was identified in infertile men. On the other hand, no deletions around the AZFc region were identified in fertile men. Japanese infertile men in our study had a common deletion in the AZFc region of the Y chromosome. A genomic clone was obtained by PCR screening of the P1 phage artificial chromosome (PAC) library. This clone was analyzed by Southern blotting using a PCR amplified probe of sY240. Our analysis of the genomic sequence of the clone suggests that this locus may contain specific genes for spermatogenesis.

PMID: 11730902 [PubMed - indexed for MEDLINE]

20: Zhonghua Nan Ke Xue. 2004 Feb;10(2):94-9, 102.Links

[Seminiferous tubule scores used for quantitative assessment of spermatogenic function of patients with azoospermia]

[Article in Chinese]

Li G, Xin Z, Yuan Y, Yang X, Xia T, Liu W, Fu J, Tian L, Na Y.

Department of Urology, First Hospital, Institute of Urology, Peking University, Beijing 100034, China.

OBJECTIVE: To investigate the clinical reliability of quantitative evaluation by seminiferous tubule scores on spermatogenesis dysfunction, using the testis tissues of azoospermia patients for analysis of histological changes. METHODS: One hundred and twelve Chinese patients with azoospermia underwent open testicular biopsy and their testicular biopsy specimens were evaluated by 10-score (on testicular biopsy) and 5-Grade (on seminiferous tubule spermatogenesis) scale. The 112 patient, 22 to 46 years old [(29.0 +/- 4.4) years old] included 105 cases of obstructive and 7 cases non-obstructive azoospermia. Of the total number, there were 96 primary infertile cases and 16 secondary infertile cases with infertile marriage of 2-12 years [(4.0 +/- 2.8) years]. Various seminiferous tubule characteristics were categorized by 10-score as follows: [1] degenerating Sertoli cells and no germinal epithelium; [2] no germ cells and only Sertoli cells; [3] no spermatids and primary spermatocytes and only spermatogonia; [4] no spermatids and few primary spermatocytes; [5] no spermatids and numerous primary spermatocytes; [6] no mature spermatids and few round immature spermatids; [7] no mature spermatids and numerous round immature spermatids; [8] < 20 mature spermatids/tubules, germinal epithelium height < 80 microns and spermiation absent; [9] > 20 mature spermatids/tubules, germinal epithelium height < 80 microns and spermiation rarely < 80 microns; [10] > 20 mature spermatids/tubule and germinal epithelium height 80 microns and spermiation common. Seminiferous tubule spermatogenesis was catagorized by 5-Grade scale as follows: [1] tubular sclerosis; [2] sertoli cell only; [3] arrested spermatogenesis; [4] reduced spermatogenesis; [5] intact spermatogenesis. RESULTS: In terms of the 10-score scale on testicular biopsy, scores of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 corresponded with total patient numbers of 5 (4.5%), 38(33.9%), 2(1.8%), 6(5.4%), 2(1.8%), 17(15.2%), 6(5.4%), 19(17%), 10(8.9%) and 7(6.3%), respectively. According to the 5-Grade scale on the seminiferous tubule spermatogenesis, Grades 1, 2, 3, 4 and 5 corresponded with 5(4.5%), 38(33.9%), 33(29.5%), 29(25.9%) and 7 (6.3%), respectively. Tubular diameter, the thickness of the lamina propria, the height of the germinal epithelium and serum FSH correlated with the average seminiferous tubule scores (P < 0.01). CONCLUSION: The seminiferous tubule scores obtained through testicular biopsy may provide important quantitative information concerning the etiology and pathogenesis and of azoospermia may serve as a helpful guide to the fundamental, clinical and therapeutical study of element, clinic and therapy.

PMID: 15027179 [PubMed - indexed for MEDLINE]

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