This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Krausz, C. Articles by McElreavey, K. Search for Related Content PubMed PubMed Citation Articles by Krausz, C. Articles by McElreavey, K.

A High Frequency of Y Chromosome Deletions in Males with Nonidiopathic Infertility¹

Immunogénétique Humaine, INSERM U-276, Institut Pasteur (C.K., L.Q.-M., S.B., N.S.-T., G.P., T.B., M.F., K.M.), Paris, France; Laboratoire d’Histologie, Biologie de la Reproduction et Cytogenetique, Hôpital Tenon (J.-P.S., J.-P.D.), Paris, France; Institut Pasteur (H.R.), Casablanca, Morroco; Médecine de la Reproduction (D.D.), Paris, France; Service d’Urologie (G.A.) and Service de Gynecologie Obstetrique (J.M.A.), Hôpital Tenon, Paris, France; Hajnal Imre Egeszsegtudomanyi Intezet (E.E.), Budapest, Hungary; Clinique de la Dhuys (J.P.T.), Paris, France; Buda Children Hospital (A.T.), Budapest, Hungary; Cytogénétique, CHU Mulhouse (E.J.), France; and CHU (G.P.), Caen, France

Address all correspondence and requests for reprints to: Dr. Ken McElreavey, Immunogenetique Humaine, Institut Pasteur, 25 rue du Dr Roux, Paris Cedex 15, France 75724.

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
Microdeletions of the long arm of the human Y chromosome are associated with spermatogenic failure and have been used to define three regions of Yq (AZFa, AZFb, and AZFc) that are recurrently deleted in infertile males. In a blind study we screened 131 infertile males (46 idiopathic and 85 nonidiopathic) for Y chromosome microdeletions. Nineteen percent of idiopathic males, with an apparently normal 46,XY chromosome complement had microdeletions of either the AZFa, AZFb, or AZFc region. There was no strict correlation between the extent or location of the deletion and the phenotype. The AZFb deletions did not include the active RBM gene. Significantly, a high frequency of microdeletions (7%) was found in patients with known causes of infertility and a 46,XY chromosome complement. These included deletions of the AZFb and AZFc regions, with no significant difference in the location or extent of the deletion compared with the former group. It is recommended that all males with reduced or absence sperm counts seeking assisted reproductive technologies be screened for deletions of the Y chromosome.

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
AN AVERAGE of 10% of couples encounter difficulties to procreate and consult infertility clinics (1). In about half of cases, sperm production is defective, either quantitatively or qualitatively. Approximately one third to one half of these cases are classified as idiopathic (2), but they may have an unidentified genetic anomaly. Microdeletions of Yq have used to define three nonoverlapping regions associated with a failure of spermatogenesis, termed AZFa, AZFb, and AZFc (3). A number of clinical studies have used Y chromosome-specific, sequence-tagged site (STS) PCR markers to identify microdeletions in DNA from peripheral blood lymphocytes of infertile males. There is a lack of agreement concerning genotype/phenotype correlations or the frequency and/or position of Yq microdeletions. The frequency of AZFc deletions varies considerably between investigations, from less than 1% to more than 35% (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17). Attempts have also been made to correlate the position and extent of the deletions with dysfunction of different phases of male germ cell development, but studies have failed to define a strict genotype/phenotype correlation (7, 10, 11, 12).

These observations raise several important issues. Differences in deletion frequency may be due to 1) absence of a standardized screening methodology (protocol); 2) recruitment biases between studies, as the majority of the reports describe the analysis of only males with idiopathic infertility or have excluded obstructive azoospermia; 3) they may reflect genuine population differences in the frequency of deletions, perhaps related to a combination of particular Y chromosome haplotypes, genetic background, or environmental influences; or 4) marker density or the genomic markers selected could not only influence the estimation of deletion frequency, but also may affect the interpretation of genotype/phenotype relationships. The possibility that microdeletions may be present in nonidiopathic males also raises important ethical issues regarding patient management.

Here, we examined DNA samples from 131 consecutive men presenting with infertility, associated with reduced or absent sperm counts. We report Yq microdeletions in 19% of males diagnosed as idiopathic and in 7% of males with infertility due to known causes. The position and extent of the Y deletions were not significantly different between idiopathic and nonidiopathic groups.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References

 
Subjects

One hundred and thirty-one unrelated males presenting with infertility associated with reduced or absence sperm counts were recruited in this study. They were subjected to detailed clinical investigations, including cytogenetic and endocrinology studies, physical examination, and, when possible, histology of a testis biopsy. Details of the groups of patients are summarized in Table 1. Individuals were defined as azoospermic or severe oligozoospermic (<5 x 10⁶) or oligozoospermic (<20 x 10⁶) according to the criteria of the WHO. Serum FSH and testosterone levels were measured using RIA. Testicular volume was evaluated using an orchidometer. Each patient was tested for the presence of antisperm antibodies. As a control group, 50 men who had fathered at least 2 children were included in the study.

Genomic DNA was extracted from peripheral blood lymphocytes using standard techniques. Where sufficient DNA was available, Southern blotting was performed on DNA to confirm the absence of Y chromosome markers. The STS primers and the conditions of amplification were described previously (6, 18). PCR amplifications found to be negative were repeated at least three times to confirm the deletion of a given marker. All investigations were performed without knowledge of the clinical diagnosis or the karyotype. The order of the markers shown has been previously published (10, 19, 20). All amplifications were performed separately. The testis determining gene SRY was used as a positive control in each case. A normal fertile male and a female were used as positive and negative controls for each STS amplification. PCR products were analyzed on a 2% agarose gel. The STS primers tested on each subject were SRY, sY81, sY85, sY86, sY87, sY88, sY95, sY114, sY116, sY125, sY127, sY131, sY145, sY147, sY152, sY154, sY155, sY158, sY159, sY160, sY254, and sY255. Men deleted for any of these markers were further analyzed using markers contiguous to the deleted marker (Fig. 1).

View larger version (39K): [in this window] [in a new window]   Figure 1. A schematic representation of the human Y chromosome showing, on top, the deletion intervals defined by Vergnaud and colleagues (18 ). The positions of genes and gene families are indicated. Below, sequence-tagged sites are shown that correspond to the position of each deletion interval. Patient number is indicated to the left of the panel, which shows the extent of the deletion for each patient. Solid bars indicate the presence of STS markers, and shaded bars indicate sites that were not tested but were assumed to be positive. Open bars indicate markers that were not studied in the patient. Dashes indicate markers that were found to be negative. The positions of AZFa, AZFb, and AZFc are shown.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

The clinical findings are summarized in Table 1. Of the 131 individuals included in this study, sperm counts revealed azoospermia (the complete absence of spermatozoa; 63% of cases), oligozoospermia (5–20 millions/mL; 30% of cases), severe oligozoospermia (<5 million/mL; 5% of cases), or asthenoteratozoospermia (abnormalities of sperm morphology; <2% of cases). Based on the clinical findings, nonidiopathic infertility was diagnosed in 85 cases. Of the 85 cases, cytogenetic investigations revealed chromosome anomalies in 13 of these cases. These included 2 SRY-positive 46,XX males, 2 men with Klinefelter’s syndrome, and 2 chromosomal translocations. In 46 cases, oligo- or azoospermia was diagnosed as idiopathic associated with an apparently normal 46,XY chromosome complement (see Table 1).

Microdeletions

Clinical details of males with Yq deletions are summarized in Table 2. The position and extent of the deletions are shown schematically in Fig. 1. Noncytogenetically detectable microdeletions were detected in 14 of the 131 individuals with an 46,XY karyotype (I1-I9, S1-S4, and M1). If individuals with a chromosomal anomaly are excluded from the calculation, the number of men with a microdeletion of Yq associated with idiopathic infertility is 9 of 46 (19%), and the number with nonidiopathic infertility is 5 of 72 (7%). This latter figure excludes 13 men with cytogenetically detectable anomalies.

Interstitial microdeletions of the AZFc region were found in five individuals (3.8% of the total cases). All five deletions resulted in the loss of all of the AZFc region including the DAZ gene cluster (I5, I7, I8, S1, and S3). Southern blot analysis confirmed the presence of deletions in the majority of the cases (I2, I4, I7, I8, I9, CA2, CA3, CA4, CA6, CA7, S2, S3, and M1). Representative Southern blots are shown in Fig. 2, A and B.

View larger version (78K): [in this window] [in a new window]   Figure 2. Representative Southern blots of the Yq deletions. A, Hybridization with the eIF1A complementary DNA. A male and female common band is present. A male specific band of 4 kb corresponds to the eIF1AY isoform. Individuals CA2 (lane 9), CA4 (lane 10)k and CA7 (lane 12) are deleted for eIF1AY. B, Hybridization with a DAZ gene fragment. A male and female common band is observed of 2.1 kb in size. Male-specific bands of 3 and 1.6 kb are present. Individuals in lane 2 (7:8:10 and 11) who lack the male-specific fragments correspond to the cases I4:S3:I7:CA6 and CA7, respectively.

Genotype/phenotype relationships

Microdeletions were observed in 19% of males diagnosed as idiopathic and in 7% of males diagnosed as nonidiopathic associated with an apparently 46,XY chromosome complement (see Fig. 1). There was no obvious difference in the position or extent of the deletions between these two groups, with the exception of one patient diagnosed as having idiopathic azoospermia. He had a microdeletion of three contiguous markers in the AZFa region.

Four patients with large AZFb deletions were azoospermic (I3, I6, S4, and M1). Patient S4 is affected by hypogonadotropic hypogonadism, and he was repeatedly treated with gonadotropins without any success. In one patient (M1) with an AZFb microdeletion, gonadal histology was available. This individual was diagnosed as nonidiopathic, with a combination of both varicocele and dysjunction of the epididymus and testis. Gonadal histology revealed spermatogenic arrest at the spermatocyte II phase. Although this observation would appear to support the conclusions of Vogt and colleagues, that AZFb deletions are associated with spermatogenic arrest at the spermatocyte stage (3), other patients harboring partial AZFb microdeletions presented with a range of infertile phenotypes, including oligozoospermia (only sY114 deleted, I2) and severe oligozoospermia (proximal AZFb region deleted, I1, S2).

Deletions of AZFc are associated with a wide range of phenotypical features. Among the idiopathic patients, two had severe oligozoospermia (I4 and I8), and two had azoospermia (I5 and I7). Gonad histology revealed Sertoli cell only syndrome in I5 and spermatogenesis arrest during meiosis in patient I7. In the nonidiopathic group with deletion of the entire AZFc region, two patients (S1 and S3) presented in their medical history trauma of testis and orchiditis, respectively. Patient S1 had severe oligozoospermia associated with hypospermatogenesis, whereas S3 presented azoospermia associated with spermatogenesis arrest at a premeiotic stage. In the latter case the Y chromosome deletion rather than the orchiditis could be responsible for the spermatogenic arrest.

Although these data indicate that there is a considerable variation in the phenotype between men with similar Yq deletions, patients that carried deletions involving only one or a small number of markers had a less severe phenotype regardless of the position of the deletion. Patient I2 presented with oligozoospermia associated with the absence of marker sY114. Those individuals carrying larger deletions had a variable, although, in general, more severe, phenotype. It is difficult to interpret genotype/phenotype relationships in the group of patients who had cytogenetically detectable deletions of Yq (CA1-CA7), because in most cases the deletion was associated with a chromosomal mosaicism that was detected in peripheral blood lymphocytes. Large Yq deletions that include the heterochromatic region and the Yq/Xq pseudoautosomal region may be directly responsible for the mosaicism.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Although we have found deletions in 19% and 7% of patients with idiopathic and nonidiopathic infertility, respectively, associated with a 46,XY chromosome complement, it is probable that this figure is an underestimate. A higher density of markers may reveal other microdeletions. Some infertile men may have point mutations or other microrearrangements in Y-specific genes. PCR analysis only indicates the presence or absence of a particular locus, other rearrangements, such as duplications and triplications, would not be detected. Both duplication and triplication events are relatively frequent in the Yq region (21, 22, 23) and may also result in dysregulation of gene. The PCR technique cannot detect mosaicism. Some infertile men may have cell populations in peripheral blood leukocytes that have a normal Y chromosome and yet have some sperm populations that carry Y deletions. In a recent study, two infertile men who did not carry a deletion in peripheral blood cells conceived sons by assisted reproduction who had Yq microdeletions, indicating that the two fathers were mosaic for Y chromosome deletions (24).

Several genes on the Y chromosome have been proposed as candidate infertility genes. In AZFa, the DFFRY gene encodes a protein involved in desubiquitination and has been proposed to play a role in gametogenesis (25, 26). Recently, an active copy of the RBM gene family has been mapped to distal AZFb (interval 6B in the region of sY142-sY145) (27, 28). All males in the current study who carried AZFb interstitial deletions were not deleted for this region, suggesting that the active copy of RBM is not removed. Although it is possible that these microdeletions may have caused dysregulation of gene expression by a position effect, it is equally likely that these deletions result in the absence of another gene(s) necessary for normal spermatogenesis. Recently, Lahn and Page described a number of genes and gene families on the Y chromosome, including two that have been tentatively mapped to the 5L deletion interval, a region that is recurrently deleted in our group of AZFb-deleted individuals (29). These are the genes, chromodomain Y (CDY), and XK-related Y (XKRY), both of which are expressed specifically in testis.

The DAZ gene family has been proposed as candidate genes for the AZFc phenotype (6, 7, 30). However, deletions have been described within the AZFc region that do not include the DAZ gene family (8, 9, 16). In this study all of the deletions included DAZ (sY254-sY255).

Y Chromosome polymorphisms

In the majority of cases in this study, male relatives of the patients in the Yq-deleted group were unavailable for study, and hence, we do not known whether the deletions are inherited. However, the majority of the deletions are large in both the idiopathic and nonidiopathic groups and hence are unlikely to represent polymorphisms. The marker sY114 has been used by Vogt and co-workers (31) in a screen of males of known fertility failed to detect deletions of this marker. The sequence of sY114 is derived from the plasmid pYHa34, isolated by Vogt and colleagues using sequences derived from Drosophila Y chromosome sequences encoding fertility factors. Interestingly, the nuclear localization of the Drosophila DAZL1 homolog, Boule, is dependent on the presence of a single fertility factor on the short arm of the Drosophila Y chromosome. The Drosophila Y chromosome encodes six fertility loci, each spanning four or more megabases of DNA. These repetitive sequences are transcribed stage specifically in the nucleus of the primary spermatocyte as continuous long transcription units. During their transcription the ribonucleic acid accumulates specific nuclear proteins, which can be observed under light microscopy as distinct intranuclear structures (termed lampbrush structures or Y loops). The absence of the ks-1 fertility locus results in the cytoplasm localization of Boule in primary spermatocytes and does not seem to interfere with spermatid differentiation, indicating that that the role of Boule in meiotic entry is independent of its nuclear localization. As suggested by Wasserman and colleagues, the Y chromosome loops may serve as a storage for boule and other ribonucleic acid-binding proteins (32). The breakdown of the lampbrush Y chromosome loops that occurs at the end of the spermatocyte growth phase may result in the release of these factors in a synchronous fashion (32).

Mechanism of Y deletions

It has been estimated that between 50–70% of the nonrecombining region of human Y chromosome is composed of a variety of highly repeated DNA elements, the majority of which appear to be unique to the human Y chromosome (33). Deletions of the Y chromosome are likely to be consequence of these repeated elements causing intrachromosomal recombination. The instability of the Y chromosome is illustrated by the transmission of a Y deletion from a fertile father to his infertile son (34). The deletion was found to be larger in the son than in the father. Evidence suggests that both genetic and environmental factors may be effective in invoking deletion formation. Edwards and Bishop (35) suggested that orchidism as the primary cause of infertility is rarely defined. Recently, Pyror and colleagues identified Yq microdeletions in four individuals classified as nonidiopathic. These were two azoospermic men with varicocele and two men with spermatic duct obstruction. However, these microdeletions could be unrelated polymorphisms, as a similar microdeletion was reported in a normal fertile male in the same study. Here, for the first time, we describe a significant percentage of large Yq deletions of the AZFb and AZFc regions associated with nonidiopathic infertility, including hypogonadotropic hypogonadism, trauma, orchitis, bilateral cryptorchidism, and epidydimal-testicular dysjunction. In males with a known cause of infertility, the possibility that Y chromosome microdeletions may also contribute to spermatogenic failure should be explored, particularly where detailed gonad histology indicates spermatogenetic arrest.

Intracytoplasmic sperm injection (ICSI) is the technique of choice in severe male factor infertility and consists of the insertion of a single spermatozoon or spermatid into the cytoplasm of a mature oocyte (36). Concerns have been expressed that this method may allow genetic defects to be added to the gene pool (37). Although several studies have not found any evidence for an increased malformation rate among children conceived using ICSI, it is possible that the genetic anomalies causing the infertility could be transmitted to male offspring (38). ICSI is a relatively new technique, and the long term genetic effects are unknown. Our findings that Yq deletions can occur in 19% of males diagnosed with idiopathic infertility and, significantly, in 7% of nonidiopathic infertile males raise important questions concerning the screening of Y deletions and genetic counseling. Current protocols recommend that men with idiopathic severe oligozoospermia or nonobstructive azoospermia be screened for Y chromosome deletions. On the basis of our data we recommend a more extended screening program to include all men, idiopathic and nonidiopathic, seeking ICSI treatment who present with a sperm concentration of less than 5 x 10⁶/mL.

	Footnotes

 
¹ This work was supported by the Association pour la Recherche sur le Cancer, the Programme Hôpitalier de Recherche Clinique (AOM 96142), and a grant "post vert" from Institut Nationale de la Santé e de la Recherche Medicale (INSERM).

Received August 19, 1998.

Revised April 23, 1999.

Accepted June 4, 1999.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Hull MGR, Glazener CM, Kelly NJ, et al. 1985 Population study of causes, treatment and outcome of infertility. Br Med J. 291:1693–1697.
2. Hargreave TB. 1994 Human infertility. In; Hargreave TB, ed. Male infertility, 2nd Ed. London: Springer Verlag; 1–16.
3. Vogt PH, Edelmann A, Kirsh S, et al. 1996 Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum Mol Genet. 5:933–943.[Abstract/Free Full Text]
4. Tiepolo L, Zuffardi O. 1976 Localization of factors controlling spermatogenesis in the non fluorescent portion of the human Y chromosome long arm. Hum Genet. 34:119–124.[CrossRef][Medline]
5. Kobayashi K, Mizuno K, Hida A, et al. 1994 PCR analysis of the Y chromosome long arm in azoospermic patients: evidence for a second locus required for spermatogenesis. Hum Mol Genet. 3:1965–1967.[Abstract/Free Full Text]
6. Reijo R, Lee TY, Salo P, et al. 1995 Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat Genet. 10:383–393.[CrossRef][Medline]
7. Reijo R, Alagappan RK, Patrizio P, Page DC. 1996 Severe oligospermia resulting from deletions of azoospermia factor gene on Y chromosome. Lancet. 347:1290–1293.[CrossRef][Medline]
8. Stuppia L, Mastroprimiano G, Calabrese G, Peila R, Tenaglia R, Palka G. 1996 Microdeletions in interval 6 of the Y chromosome detected by STS-PCR in 6 of 33 patients with idiopathic oligo- and azoospermia. Cytogenet Cell Genet. 72:155–158.[Medline]
9. Najmabadi H, Huang V, Yen P, et al. 1996 Substantial prevalence of microdeletions of the Y-chromosome in infertile men with idiopathic azoospermia and oligospermia detected using a sequence tagged site based mapping strategy. J Clin Endocrinol Metab. 81:1347–1352.[Abstract]
10. Pryor JL, Kent-First M, Muallen A, et al. 1997 Microdeletions in the Y chromosome of infertile men. N Engl J Med. 336:534–539.[Abstract/Free Full Text]
11. Simoni M, Gromoll J, Dworniczak B, et al. 1997 Screening for deletions of the Y chromosome involving the DAZ (Deleted in AZoospermia) gene in azoospermia and severe oligospermia. Fertil Steril. 67:542–547.[CrossRef][Medline]
12. Qureshi SJ, Ross AR, Ma K, et al. 1996 PCR screening for Y chromosome microdeletions: a first step towards the diagnosis of genetically determinined spermatogenic failure in men. Mol Hum Reprod. 2:775–779.[Abstract/Free Full Text]
13. Kremer JAM, Tuerling JHAM, Meuleman, et al. 1997 Microdeletions of the Y chromosome and intracytoplasmic sperm injection: from gene to clinic. Hum Reprod. 12:687–691.[Abstract/Free Full Text]
14. Foresta C, Ferlin A, Garolla A, Rossato M, Barbaux S, De Bortoli A. 1997 Y-chromosome deletions in idiopathic severe testiculopathies. J Clin Endocrinol Metab. 82:1075–1080.[Abstract/Free Full Text]
15. van der Ven K, Montag M, Peshka B, et al. 1997 Combined cytogenetic and Y chromosome microdeletion screening in males undergoing intracytoplasmic sperm injection. Mol Hum Reprod. 3:699–704.[Abstract/Free Full Text]
16. Simoni M, Kamishke A, Nieschlag E. 1998 Current status of the molecular diagnosis of Y-chromosomal microdeletions in the workup of male fertility. Hum Rep. 13:1764–1768.
17. Girardi SK, Mielnik A, Schlegel PN. 1997 Submicroscopic deletions in the Y chromosome of infertile men. Hum Reprod. 12:1635–1641.[Abstract/Free Full Text]
18. Vollrath D, Foote S, Hilton A, et al. 1992 The human Y chromosome: a 43-interval map based on naturally occurring deletions. Science. 258:52–59.[Abstract/Free Full Text]
19. Brown GM, Furlong RA, Sargent CA, et al. 1998 Characterisation of the coding sequence and fine mapping of the human DFFRY gene and comparative expression analysis and mapping to the SXR(B) interval of the mouse Y chromosome of the Dffry gene. Hum Mol Genet. 7:97–107.[Abstract/Free Full Text]
20. Affara N, Bishop C, Brown W, et al. 1996 Report of the second international workshop on Y chromosome mapping 1995. Cytogenet Cell Genet., 73:33–76.
21. Jobling MA, Samara V, Pandya A, et al. 1996 Recurrent duplication and deletion polymorphism on the long arm of the Y chromosome in normal males. Hum Mol Genet. 5:1767–1775.[Abstract/Free Full Text]
22. Santos FR, Gerelsaikhan T, Munkhtuja B, Oxvnsuren T, Epplen JT, Pena SD. 1996 Geographic differences in the allele frequencies of the human Y-linked tetranucleotide polymorphism DYS19. Hum Genet. 97:309–313.[CrossRef][Medline]
23. Spurdle AB, Jenkins T. 1994 The specific pDP31 rearrangement polymorphism in Southern African populations. Hum Hered. 44:261–265.[CrossRef][Medline]
24. Kent-First MG, Kol S, Muallen A, Blazer S, Hskovitz-Eldor J. 1996 Infertility in intracytoplasmic-sperm-injection-derived sons. Lancet. 348:332.
25. Jones MH, Furlong RA, Burkin H, et al. 1996 The Drosophila developmental gene fat facets has a human homologue in Xp11.4 which escapes X-inactivation and has related sequences on Yq11.2. Hum Mol Genet. 5:1695–1701.[Abstract/Free Full Text]
26. Fischer-Vize JA, Rubin GM, Lehmann R. 1992 The fat tacets gene is required for Drosophila eye and embryo development. Development. 116:985–1000.[Abstract]
27. Elliott DJ, Millar MR, Oghene K, et al. 1997 Expression of RBM in the nuclei of human germ cells is dependent on a critical region of the Y chromosome long arm. Proc Natl Acad Sci USA. 94:3848–3853.[Abstract/Free Full Text]
28. Ma K, Inglis JD, Sharkey A, et al. 1993 A Y chromosome gene family with RNA-binding protein homology: candidates for the azoospermia factor AZF controlling spermatogenesis. Cell. 75:1287–1295.[CrossRef][Medline]
29. Lahn BT, Page DC. 1997 Functional coherence of the human Y chromosome. Science. 278:675–680.[Abstract/Free Full Text]
30. Saxena R, Brown LG, Hawkins T, et al. 1996 The DAZ gene cluster on the human Y chromosome arose from an autosomal gene that was transposed, repeatedly amplified and pruned. Nat Genet. 14:292–299.[CrossRef][Medline]
31. Vogt P, Keil R, Kohler M, et al. 1991 Selection of DNA sequences from interval 6 of the human Y chromosome with homology to a Y chromosomal fertility gene sequence of Drosophila hydei. Hum Genet. 86:341–349.[Medline]
32. Cheng MH, Maines JZ, Wasserman SA 1998 Biphasic subcellular localisation of the DAZL-related protein Boule in Drosophila spermatogenesis. Dev Biol. 204:567–576.
33. Cooke H, Fantes J, Green D. 1983 Structure and evolution of human Y chromosome DNA. Differentiation. 23(Suppl):S48–S55.
34. Stuppia L, Calabrese G, Franchi PG, et al. 1996 Widening of a Y-chromosome interval-6 deletion transmitted from a father to his infertile son accounts for an oligozoospermia critical region distal to the RBM1 and DAZ genes. Am J Hum Genet. 59:1393–1395.[Medline]
35. Edwards RG, Bishop CE. 1997 On the origin and frequency of Y chromosome deletions responsible for severe male infertility. Mol Hum Reprod. 3:549–454.[Abstract/Free Full Text]
36. Van Steirteghem AC. 1993 High fertilization and implantation rates after intracytoplasmic sperm injection. Hum Reprod. 8:1061–1066.[Abstract/Free Full Text]
37. de Kretser D. 1995 The potential of intracytoplasmic sperm injection (ICSI) to transmit genetic defects causing male infertility. Reprod Fertil Dev. 7:137–142.[CrossRef][Medline]
38. Bonduelle M, Jons H, Hofmans K, Liebaers I, Van Steirteghem A. 1995 Comparative follow up study of 130 children born after intracytoplasmic sperm injection and children born after in-vitro fertilization. Hum Reprod. 10:3327–3331.[Abstract/Free Full Text]

This article has been cited by other articles:

				L. Hadjkacem-Loukil, I. Ayadi, A. Bahloul, H. Ayadi, and L. Ammar-Keskes Tag STS in the AZF Region Associated With Azoospermia in a Tunisian Population J Androl, September 1, 2007; 28(5): 652 - 658. [Abstract] [Full Text] [PDF]

				A. Ferlin, B. Arredi, E. Speltra, C. Cazzadore, R. Selice, A. Garolla, A. Lenzi, and C. Foresta Molecular and Clinical Characterization of Y Chromosome Microdeletions in Infertile Men: A 10-Year Experience in Italy J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 762 - 770. [Abstract] [Full Text] [PDF]

				A. Tessari, E. Salata, A. Ferlin, L. Bartoloni, M.L. Slongo, and C. Foresta Characterization of HSFY, a novel AZFb gene on the Y chromosome with a possible role in human spermatogenesis Mol. Hum. Reprod., April 1, 2004; 10(4): 253 - 258. [Abstract] [Full Text] [PDF]

				A Ferlin, E Moro, A Rossi, B Dallapiccola, and C Foresta The human Y chromosome's azoospermia factor b (AZFb) region: sequence, structure, and deletion analysis in infertile men J. Med. Genet., January 1, 2003; 40(1): 18 - 24. [Abstract] [Full Text] [PDF]

				C.M. Luetjens, J. Gromoll, M. Engelhardt, S. von Eckardstein, M. Bergmann, E. Nieschlag, and M. Simoni Manifestation of Y-chromosomal deletions in the human testis: a morphometrical and immunohistochemical evaluation Hum. Reprod., September 1, 2002; 17(9): 2258 - 2266. [Abstract] [Full Text] [PDF]

				E. Kostova, S. Rottger, W. Schempp, and J. Gromoll Identification and characterization of the cynomolgus monkey chromodomain gene cynCDY, an orthologue of the human CDY gene family Mol. Hum. Reprod., August 1, 2002; 8(8): 702 - 709. [Abstract] [Full Text] [PDF]

				B. Peterlin, T. Kunej, J. Sinkovec, N. Gligorievska, and B. Zorn Screening for Y chromosome microdeletions in 226 Slovenian subfertile men Hum. Reprod., January 1, 2002; 17(1): 17 - 24. [Abstract] [Full Text] [PDF]

				C. Kamp, K. Huellen, S. Fernandes, M. Sousa, P.N. Schlegel, A. Mielnik, S. Kleiman, H. Yavetz, W. Krause, W. Kupker, et al. High deletion frequency of the complete AZFa sequence in men with Sertoli-cell-only syndrome Mol. Hum. Reprod., October 1, 2001; 7(10): 987 - 994. [Abstract] [Full Text] [PDF]

				C. Foresta, E. Moro, and A. Ferlin Prognostic value of Y deletion analysis: The role of current methods Hum. Reprod., August 1, 2001; 16(8): 1543 - 1547. [Abstract] [Full Text] [PDF]

				C. Krausz, E. Rajpert-De Meyts, L. Frydelund-Larsen, L. Quintana-Murci, K. McElreavey, and N. E. Skakkebaek Double-Blind Y Chromosome Microdeletion Analysis in Men with Known Sperm Parameters and Reproductive Hormone Profiles: Microdeletions Are Specific for Spermatogenic Failure J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2638 - 2642. [Abstract] [Full Text] [PDF]

				C. Krausz and K. McElreavey Y chromosome microdeletions in `fertile' males Hum. Reprod., June 1, 2001; 16(6): 1306 - 1306. [Full Text] [PDF]

				C. Foresta, E. Moro, and A. Ferlin Y Chromosome Microdeletions and Alterations of Spermatogenesis Endocr. Rev., April 1, 2001; 22(2): 226 - 239. [Abstract] [Full Text]

				S.E. Kleiman, B.B.-S. Maymon, L. Yogev, G. Paz, and H. Yavetz The prognostic role of the extent of Y microdeletion on spermatogenesis and maturity of Sertoli cells Hum. Reprod., March 1, 2001; 16(3): 399 - 402. [Abstract] [Full Text] [PDF]

				N. Saut, P. Terriou, A. Navarro, N. Levy, and M. J. Mitchell The human Y chromosome genes BPY2, CDY1 and DAZ are not essential for sustained fertility Mol. Hum. Reprod., September 1, 2000; 6(9): 789 - 793. [Abstract] [Full Text] [PDF]

				O. Blagosklonova, F. Fellmann, M.-C. Clavequin, C. Roux, and J.-L. Bresson AZFa deletions in Sertoli cell-only syndrome: a retrospective study Mol. Hum. Reprod., September 1, 2000; 6(9): 795 - 799. [Abstract] [Full Text] [PDF]

				C. Krausz, L. Quintana-Murci, and K. McElreavey Prognostic value of Y deletion analysis: What is the clinical prognostic value of Y chromosome microdeletion analysis? Hum. Reprod., July 1, 2000; 15(7): 1431 - 1434. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Krausz, C. Articles by McElreavey, K. Search for Related Content PubMed PubMed Citation Articles by Krausz, C. Articles by McElreavey, K.