Microdeletions in the Y Chromosome of Infertile Men
Jon L. Pryor, M.D., Marijo Kent-First, Ph.D., Ariege Muallem, B.S., Andrew H. Van Bergen, B.S., Wolfram E. Nolten, M.D., Lorraine Meisner, Ph.D., and Kenneth P. Roberts, Ph.D.
Background Some infertile men with azoospermia or severe oligospermiahave small deletions in regions of the Y chromosome. However,the frequency of such microdeletions among men with infertilityin general is unknown. We sought to determine the prevalenceof Y-chromosome microdeletions among infertile men and to correlatethe clinical presentation of the men with specific deletions.
Methods We studied 200 consecutive infertile men. Each man wasevaluated comprehensively for known causes of infertility, andY-chromosome microdeletions were studied with use of the polymerasechain reaction to amplify specific regions of the chromosome.The Y chromosomes of 200 normal men were also analyzed.
Results Fourteen infertile men (7 percent) and four normal men(2 percent) had microdeletions of the Y chromosome. Nine ofthe infertile men had azoospermia or severe oligospermia (spermconcentration, <5 million per milliliter), four had oligospermia(sperm concentration, 5 million to <20 million per milliliter),and one had normospermia (sperm concentration, >20 millionper milliliter). The size and location of the deletions variedand did not correlate with the severity of spermatogenic failure.The fathers of six infertile men with microdeletions were studied;two had the same deletions as their sons, and four had no deletions.
Conclusions A small proportion of men with infertility haveY-chromosome microdeletions, but the size and position of thedeletions correlate poorly with the severity of spermatogenicfailure, and a deletion does not preclude the presence of viablesperm and possible conception.
Infertility affects about 15 percent of all couples attemptingpregnancy,1 with the man responsible in approximately half thecases. It is best defined as the inability to conceive afterone year of unprotected intercourse, and thus the definitionincludes men with subfertility. Proposed causes of infertilityin men include varicocele, obstruction of the spermatic ducts,agglutination of sperm, high semen viscosity, necrospermia,low volume of ejaculate, ejaculatory dysfunction, and high spermdensity; when no cause is known, the man is described as havingidiopathic infertility.2 Many of these diagnostic categoriesare descriptive; for example, a diagnosis of necrospermia doesnot provide any information about why the sperm are dead. Consequently,the estimated proportion of men with idiopathic infertilityis as high as 66 percent, depending on the definition of "idiopathic."3,4
Cytogenetic analysis of men with Y-chromosome translocationshas revealed a region on the long (q) arm of the Y chromosomethat is required for spermatogenesis.5,6 This region includesthe azoospermia factor (AZF) locus, which contains a gene orgenes that are required for normal spermatogenesis. The AZFlocus has been mapped to deletion interval 6, a region in bandq11.23 of the Y chromosome that contains 5 million base pairs.7,8,9Three genes — two members of the YRRM (Y-specific genewith RNA recognition motif) gene family (YRRM1 and YRRM2) andthe DAZ (deleted in azoospermia) gene — have been clonedfrom this region, whereas DAZ and one or more members of theYRRM family have been found to be absent in some men with azoospermiaor severe oligospermia.10,11,12
To date, only men with azoospermia or severe oligospermia havebeen studied for Y-chromosome deletions.10,11,12,13,14,15,16These analyses, which have been limited to the distal euchromatinof the q arm, have revealed deletions in 10 to 15 percent ofthe men studied. The frequency of Y-chromosome microdeletionsin infertile men with less severe abnormalities of the spermconcentration is unknown. Furthermore, how other regions ofthe Y chromosome are involved in infertility has not been studied.We sought to determine the frequency of the Y-chromosome microdeletionsin a large group of infertile men and to determine the phenotypesassociated with specific deletions.
Methods
Study Subjects
We studied 200 consecutive men presenting with infertility atthe urology clinic of the University of Minnesota (Minneapolis)or Reproductive Health Associates (St. Paul, Minn.) and 200normal men. All men who were referred for evaluations of infertilityand met the definition of infertility (one year of unprotectedintercourse not leading to conception) were enrolled in thestudy, regardless of the fertility status of their partners.The infertile men ranged in age from 24 to 52 years (mean, 34).
The men completed detailed questionnaires on their medical andsurgical history, lifestyle habits (such as smoking, alcoholuse, and drug use), exposure to gonadotoxins (such as drugsused in cancer chemotherapy, and solvents), sexual history,and family history. They then underwent a physical examinationthat included an assessment of secondary sexual characteristics,an inspection of the penis, a determination of testicular sizeby orchidometry, an evaluation of the vas deferens and epididymis,and a rectal examination to evaluate the prostate. Each manprovided a minimum of two semen specimens, each after sexualabstinence for two to five days. These specimens were evaluatedon the basis of the criteria of the World Health Organization,except for sperm morphology, which was assessed by the strictcriteria of Kruger et al.17 (with normal morphology definedas the presence of more than 14 percent sperm of normal shape),and the results were averaged.
On the basis of their mean sperm concentrations, the men werecategorized as having azoospermia, severe oligospermia (<5million sperm per milliliter), oligospermia (5 million to <20million sperm per milliliter), or normospermia (>20 millionsperm per milliliter). Testicular biopsies were performed inmost infertile men with azoospermia. The presence of antispermantibodies was determined by the direct immunobead test in semensamples in which sperm agglutination or decreased sperm motilitywas seen and in samples from men with abnormal postcoital testsor idiopathic infertility. In addition, blood samples were obtainedfor DNA extraction and for the measurement of serum testosterone,prolactin, and follicle-stimulating hormone (FSH) by radioimmunoassay.
After the evaluation, each man was given one of the followingdiagnoses: varicocele, antisperm antibodies, ejaculatory dysfunction(such as those associated with spinal cord injury or diabetesmellitus in which there was anejaculation or retrograde ejaculation),endocrinopathy (hypogonadotropic hypogonadism or hyperprolactinemia),obstruction of the spermatic duct (azoospermia in the presenceof normal results on testicular biopsy), dysfunction inducedby gonadotoxins (cancer chemotherapy), and infection (urethritisor prostatitis). If a man could not be assigned to one of thesediagnostic categories, he was classified as having idiopathicinfertility, regardless of the results of the semen analysis.
We also obtained blood samples from the fathers of six infertilemen who were found to have Y-chromosome microdeletions. DNAfrom 200 normal men was provided (Promega, Madison, Wis.) froma serum bank of men proved fertile by paternity testing. Thestudy design was approved by the institutional review boardof the University of Minnesota, and all the participants gaveinformed written consent.
Screening for Y-Linked Sequence-Tagged Sites
Genomic DNA was prepared from peripheral-blood lymphocytes (WizardGenomic DNA Purification Kit, Promega) and amplified in multiplexpolymerase chain reactions (PCRs) containing 5 to 8 primer pairs.Each primer pair amplifies a specific region of the Y chromosome(a sequence-tagged site). The reaction products were separatedon 3 percent agarose gels (Metaphor, FMC Bioproducts, Rockland,Me.) and visualized with ethidium bromide. The men were screenedfor 85 sequence-tagged sites specific to the Y chromosome (Figure 1).These sites were derived from the maps of Vollrath et al.,18Affara et al.,19 and Kent-First et al. (unpublished data). Theprimers used for YRRM1 were as described by Ma et al.10 andcorrected by Kobayashi et al.20
Figure 1. Maps of the Y Chromosome in 14 Men with Infertility and Deletions in the Chromosome.
A diagram of the entire chromosome is shown at the top, with certain sequence-tagged sites indicated in deletion intervals 5 and 6 of the q arm. This section of the chromosome is enlarged below, with the results of the analyses of the 14 men with infertility and a normal control appearing as horizontal lines. Three regions (AZFa, or JOLAR; AZFb; and AZFc, or KLARD) are shaded on the map; the names of the sequence-tagged sites appear at the bottom of the figure. In each map, the bars represent sites found to be present, and the solid lines sites not studied but assumed to be present because they fall between sites confirmed as present. Dashes indicate sites found to be deleted. The total number of dashes shown for each patient corresponds to the number of deleted sequence-tagged sites given in Table 2.
The order of the sites was derived from the literature10,12,17 and from the analysis of deletions in this study. Plus signs indicate sites, including those in YRRM1 and YRRM2, whose exact order is not confirmed. Patients 5, 8, 9, 10, 13, and 14 underwent testicular biopsy. Additional information about the patients, including sperm counts, is given in Table 2. KAL-Y denotes Kallmann's syndrome locus, STSP steroid sulfatase pseudogene, and SMCY histocompatibility Y locus. Other abbreviations are spelled out in the text.
An example of the multiplex PCR analysis of DNA from an infertileman with a Y-chromosome deletion and a normal man is shown inFigure 2, where the absence of an amplified DNA fragment indicatesa deletion of that portion of the Y chromosome. Figure 2 showsthe loss of 23 sequence-tagged sites in all. For each bloodsample, the entire DNA analysis was repeated at least threetimes. If the analysis of the first blood sample revealed adeletion of one or more sites, a second sample was obtainedand the analysis was repeated. In each case, the analysis ofthe second sample confirmed the initial result. All the PCRanalyses were done without knowledge of the man's clinical diagnosisor the results of the semen analysis. Every analysis containeda blood sample from a normal man, and samples from a normalwoman were assayed intermittently. When sufficient DNA was available,the PCR findings regarding microdeletions were confirmed bySouthern blot hybridization.21
Figure 2. Results of PCR Amplification of Six Sets of Sequence-Tagged Sites in Y-Chromosome DNA from a Normal Man (A) and a Man with Infertility (B).
The arrowheads indicate the Y-chromosome deletions found in the man with infertility (Patient 1). The conditions of thermocycling were as follows: 94°C for one minute, 61°C for one minute, and 72°C for one minute, for 35 cycles. The DNA products were separated by electrophoresis on a 3 percent Metaphor agarose gel. The PCR analysis shown represents a subgroup of the sequence-tagged sites shown in Figure 1.
Cytogenetic Analysis
For men with microdeletions in the Y chromosome, karyotypingwas performed by standard techniques.22
Results
Among the 200 men with infertility, the most common assigneddiagnoses were idiopathic infertility (102 men, or 51 percent)and varicocele (71 men, or 36 percent) (Table 1). Twenty-sixof the men with infertility (13 percent) had azoospermia, fourof whom had evidence of spermatic-duct obstruction. Thirty men(15 percent) had severe oligospermia, 42 men (21 percent) hadoligospermia, and the remaining 102 (51 percent) had normospermia.
Table 1. Characteristics of 200 Men with Infertility.
Of the 200 infertile men, 14 (7 percent) were found to haveY-chromosome microdeletions (Figure 1 and Table 2). Of these14 men, 6 had azoospermia, 3 had severe oligospermia, 4 oligospermia,and 1 normospermia. Seventy-one percent of the men with deletions(10 of 14) had idiopathic infertility, as compared with 51 percentof the group as a whole (102 of 200). All the men with microdeletionshad normal serum testosterone concentrations, and two had highserum FSH concentrations. Two men, Patients 2 and 11, had fatheredchildren. Patient 2 fathered a child in 1995 at the age of 37years by intrauterine insemination. Patient 11 fathered twochildren, one in 1987 at the age of 29 and one in 1991 at theage of 33.
Table 2. Findings in Men with Infertility Who Had Microdeletions in the Y Chromosome.
Microdeletions of the Y chromosome were found in 4 of the 200normal men (2 percent). Two normal men had deletions of siteSY207, and two had deletions of the adjacent site SY272 (Figure 1).The deletion in Patient 11, who had fathered two children,was limited to these two sites. The large deletions in Patients1 and 5 also included these two sites. The microdeletions inthe remaining 11 infertile men did not overlap with those inthe normal men.
The deletions detected in 12 of the 14 infertile men eitherwere completely within deletion interval 6 or included someportion of it (Figure 1). However, one man (Patient 6) had acompletely intact q arm, and a small deletion in the proximalportion of the p arm. A second man (Patient 10) had a deletionin the proximal portion of deletion interval 5. The deletionsranged greatly in size; Patient 5 was missing 53 of the sequence-taggedsites studied, whereas Patients 2, 6, 7, and 14 were missingonly 1 site. The three men with the largest deletions (Patients1, 5, and 9) all had azoospermia or severe oligospermia. Theremaining men had small deletions, none of them in the regionof the DAZ gene. Three men (Patients 2, 3, and 4) had deletionsonly in the region of YRRM1 and YRRM2; two of these men hadoligospermia, and one had severe oligospermia. Patients 7 and14 had deletions of the same sites; the former had normospermia,and the latter had azoospermia. Overall, there was no correlationbetween the sperm concentration and the size or the locationof the deletions.
Six men with azoospermia or severe oligospermia who had microdeletionsunderwent testicular biopsy (Table 2). Four of these men (Patients5, 8, 9, and 10) had severe defects of spermatogenesis. Patient8 had the same histologic features as Patient 9, but a muchsmaller deletion. Similarly, the biopsy specimens from Patients5 and 10 revealed only Sertoli cells and no germ cells, butthe deletions in these patients differed substantially. Twoof the four men with spermatic-duct obstruction and normal testicular-biopsyspecimens had microdeletions.
Cytogenetic analysis revealed morphologically normal Y chromosomesin 11 of the 12 infertile men whose karyotypes were obtained.Only Patient 5 had an abnormal-appearing Y chromosome.
In the six fathers of infertile men whose Y chromosomes we studied,two (the fathers of Patients 9 and 11) had microdeletions identicalto those of their sons, and four (the fathers of Patients 3,8, 12, and 13) had no microdeletions. Paternity was establishedin these six fathers by DNA analysis of short tandem-repeatpolymorphisms at nine loci.
Discussion
We found microdeletions in the Y chromosome in 7 percent ofan unselected group of infertile men. Among the men with azoospermiaor severe oligospermia, 16 percent (9 of 56) had deletions,a proportion consistent with those (10 to 15 percent) reportedpreviously.11,12,14 If we considered only the men with azoospermia,the frequency of deletions increased to 23 percent. However,some men with Y-chromosome deletions had sperm concentrationsof 5 million per milliliter or above. Thus, microdeletions arenot necessarily associated with azoospermia or very low spermconcentrations. In addition, not all the men with deletionshad idiopathic infertility. Specifically, four such men hadother possible causes of their infertility: two had spermatic-ductobstruction, and two had varicoceles. Although varicoceles areassociated with infertility, only one man in six with a varicocelepresents with infertility.23 Therefore, the primary cause ofthe infertility of the two men with varicoceles may well havebeen the microdeletion in the Y chromosome. Likewise, if reconstructivemicrosurgery did not restore fertility in the two men with spermatic-ductobstruction, the Y-chromosome deletion might explain their infertility.
It is possible to have a deletion in the Y chromosome and tofather children. Two of the infertile men we studied fatheredchildren at least once, and the fathers of two of the infertilemen had microdeletions identical to those of their sons. Asdiscussed below, the deletion in the father of Patient 11 maynot have affected his fertility. However, the father of Patient9 reportedly had low sperm concentrations, was able to fatheronly one child, and then adopted other children, suggestingthat in his case the deletion did affect fertility. Deletionsin the fathers of men with infertility that are similar or identicalto those in their sons have been reported previously.12,24 Thus,an inherited deletion in the Y chromosome can cause subfertility.
Some Y-chromosome microdeletions represent normal polymorphismsof the Y chromosome, as appeared to be true of the small deletionswe found in four fertile men.24,25 It is possible that in somemen with infertility Y-chromosome microdeletions are fortuitousand unrelated to the men's infertility. This was likely to bethe case in Patient 11, who had a small deletion in the sameregion as the deletions we found in the four fertile men. Theabsence of Y-chromosome microdeletions in the normal men thatresembled the deletions in most of the infertile men suggeststhat the deletions in the latter contributed to their infertility.
No strict correlation between particular deletions and spermatogenesiswas found in this study, but some trends were apparent. First,all the large deletions were associated with azoospermia, butsmall deletions were not necessarily associated with less severedefects in the sperm concentration. Second, deletions were foundin several locations on the Y chromosome, with the majorityin deletion interval 6. Recently, Reijo et al. described 12men with azoospermia who had deletions in the Y chromosome (selectedfrom 89 men with azoospermia), and they cloned the DAZ genefrom deletion interval 6.11 We found that many of the deletionsin interval 6 that were associated with azoospermia were outsidethe region of the DAZ gene. This corroborates the recent observationby Najmabadi et al.12 that not all deletions in men with azoospermiaare in DAZ. In addition to the deletions in the q arm of theY chromosome that we identified, a deletion confined to theproximal region of the p arm was found in one man. However,since his father was not studied, the importance of this deletionis questionable.
Ma et al.10 and Henegariu et al.26 have described Y-chromosomedeletions in infertile men that define two regions associatedwith azoospermia: JOLAR (in the proximal q arm) and KLARD (inthe distal q arm). More recently, Vogt et al.24 described threemen with azoospermia who had microdeletions occurring betweenthe deletions in JOLAR and KLARD; they termed this intermediateregion AZFb and designated the JOLAR region AZFa, and the KLARDregion AZFe (Figure 1). On the basis of the testicular histologyin these men, the deletion of AZFa was associated with the presenceonly of Sertoli cells, the deletion of AZFb with the developmentalarrest of germ cells at the pachytene stage, and the deletionof AZFc with the developmental arrest of germ cells at the spermatidstage. In our study, Patient 10 had an AZFa deletion, and hisbiopsy specimen revealed only Sertoli cells; Patient 8 had adeletion in AZFc and had spermatogenic arrest. Patient 5 hadan intact AZFa region, but his biopsy sample revealed only Sertolicells. Patients 2, 4, and 7 had AZFc deletions but not azoospermia,and Patients 13 and 14 (with azoospermia) had deletions in AZFcalthough their biopsy specimens showed normal spermatogenesis.From our results it is impossible to attribute a given phenotypeto a given deletion interval. Finally, 11 of the 12 men withY-chromosome microdeletions whose karyotypes we determined werecytogenetically normal, showing that a PCR-based assay is neededto detect microdeletions in the Y chromosome.
The correlation between Y-chromosome deletions and infertility,and the relative absence of such deletions in fertile men, suggesta cause-and-effect relation between the deletions and infertility.As compared with other known causes of infertility, Y-chromosomedeletions are relatively frequent (7 percent), and their frequencyincreases with the severity of the spermatogenic defect. However,Y-chromosome microdeletions cannot be predicted on the basisof clinical findings or even the results of semen analyses.The role of analyses of Y-chromosome microdeletions in evaluatingmen with infertility remains to be determined. With the adventof intracytoplasmic sperm injections, the potential for passingon these defects to offspring is real and should be consideredwhen infertile couples are counseled about this procedure.
Source Information
From the Departments of Urologic Surgery (J.L.P., A.H.V.B., K.P.R.), Cell Biology and Neuroanatomy (J.L.P., K.P.R.), and Obstetrics and Gynecology (J.L.P.), University of Minnesota Medical School, Minneapolis; the Promega Corporation, Madison, Wis. (M.K.-F., A.M.); and the Departments of Meat and Animal Science (A.M.), Medicine (W.E.N.), and Preventive Medicine (L.M.), University of Wisconsin, Madison.
Address reprint requests to Dr. Roberts at the Department of Urologic Surgery, Box 394 UMHC, 420 Delaware St. S.E., Minneapolis, MN 55455.
References
Mosher WD. Reproductive impairments in the United States, 1965-1982. Demography 1985;22:415-430. [Medline]
Greenberg SH, Lipshultz LI, Wein AJ. Experience with 425 subfertile male patients. J Urol 1978;119:507-510. [Medline]
Dubin L, Amelar RD. Etiologic factors in 1294 consecutive cases of male infertility. Fertil Steril 1971;22:469-474. [Medline]
Hendry WF, Sommerville IF, Hall RR, Pugh RCB. Investigation and treatment of the subfertile male. Br J Urol 1973;45:684-692. [Medline]
Tiepolo L, Zuffardi O. Localization of factors controlling spermatogenesis in the nonfluorescent portion of the human Y chromosome long arm. Hum Genet 1976;34:119-124. [CrossRef][Medline]
Chandley AC, Gosden JR, Hargreave TB, Spowart G, Speed RM, McBeath S. Deleted Yq in the sterile son of a man with a satellited Y chromosome (Yqs). J Med Genet 1989;26:145-153. [Abstract]
Vergnaud G, Page DC, Simmler M-C, et al. A deletion map of the human Y chromosome based on DNA hybridization. Am J Hum Genet 1986;38:109-124. [Medline]
Andersson M, Page DC, Pettay D, et al. Y;autosome translocations and mosaicism in the aetiology of 45,X maleness: assignment of fertility factor to distal Yq11. Hum Genet 1988;79:2-7. [CrossRef][Medline]
Bardoni B, Zuffardi O, Guioli S, et al. A deletion map of the human Yq11 region: implications for the evolution of the Y chromosome and tentative mapping of a locus involved in spermatogenesis. Genomics 1991;11:443-451. [Medline]
Ma K, Inglis JD, Sharkey A, et al. A Y chromosome gene family with RNA-binding protein homology: candidates for the azoospermia factor AZF controlling human spermatogenesis. Cell 1993;75:1287-1295. [CrossRef][Medline]
Reijo R, Lee TY, Salo P, et al. Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat Genet 1995;10:383-393. [CrossRef][Medline]
Najmabadi H, Huang V, Yen P, et al. Substantial prevalence of microdeletions of the Y-chromosome in infertile men with idiopathic azoospermia and oligozoospermia detected using a sequence-tagged site-based mapping strategy. J Clin Endocrinol Metab 1996;81:1347-1352. [Abstract]
Vogt P, Chandley AC, Hargreave TB, Keil R, Ma K, Sharkey A. Microdeletions in interval 6 of the Y chromosome of males with idiopathic sterility point to disruption of AZF, a human spermatogenesis gene. Hum Genet 1992;89:491-496. [Medline]
Nagafuchi S, Namiki M, Nakahori Y, Kondoh N, Okuyama A, Nakagome Y. A minute deletion of the Y chromosome in men with azoospermia. J Urol 1993;150:1155-1157. [Medline]
Stuppia L, Mastroprimiano G, Calabrese G, Peila R, Tenaglia R, Palka G. Microdeletions in interval 6 of the Y chromosome detected by STS-PCR in 6 of 33 patients with idiopathic oligo- or azoospermia. Cytogenet Cell Genet 1996;72:155-158. [Medline]
Reijo R, Alagappan RK, Patrizio P, Page DC. Severe oligozoospermia resulting from deletions of azoospermia factor gene on Y chromosome. Lancet 1996;347:1290-1293. [CrossRef][Medline]
Kruger TF, Acosta AA, Simmons KF, Swanson RJ, Matta JF, Oehninger S. Predictive value of abnormal sperm morphology in in vitro fertilization. Fertil Steril 1988;49:112-117. [Medline]
Vollrath D, Foote S, Hilton A, et al. The human Y chromosome: a 43-interval map based on naturally occurring deletions. Science 1992;258:52-59. [Free Full Text]
Affara N, Bishop C, Brown W, et al. Report of the Second International Workshop on Y chromosome mapping 1995. Cytogenet Cell Genet 1996;73:34-72.
Kobayashi K, Mizuno K, Hida A, et al. PCR analysis of the Y chromosome long arm in azoospermia patients: evidence for a second locus required for spermatogenesis. Hum Mol Genet 1994;3:1965-1967. [Erratum, Hum Mol Genet 1995;4:974.] [Free Full Text]
Sambrook J, Fritsch EF, Maniatis T. Molecular cloning: a laboratory manual. 2nd ed. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory, 1989.
Verma RS, Babu A. Human chromosomes: principles and techniques. 2nd ed. New York: McGraw-Hill, 1995:11.
Vogt PH, Edelmann A, Kirsch S, et al. Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum Mol Genet 1996;5:933-943. [Free Full Text]
Torroni A, Semino O, Scozzari R, et al. Y chromosome DNA polymorphisms in human populations: differences between Caucasoids and Africans detected by 49a and 49f probes. Ann Hum Genet 1990;54:287-296. [Medline]
Henegariu O, Hirschmann P, Kilian K, et al. Rapid screening of the Y chromosome in idiopathic sterile men, diagnostic for deletions in AZF, a genetic Y factor expressed during spermatogenesis. Andrologia 1994;26:97-106. [Medline]
Abu-Musa, A. A., Nassar, A. H., Usta, I. M.
(2008). Attitude of women with IVF and spontaneous pregnancies towards prenatal screening. Hum Reprod
0: den291v1-6
[Abstract][Full Text]
Bowdin, S., Allen, C., Kirby, G., Brueton, L., Afnan, M., Barratt, C., Kirkman-Brown, J., Harrison, R., Maher, E. R, Reardon, W.
(2007). A survey of assisted reproductive technology births and imprinting disorders. Hum Reprod
22: 3237-3240
[Abstract][Full Text]
Hadjkacem-Loukil, L., Ayadi, I., Bahloul, A., Ayadi, H., Ammar-Keskes, L.
(2007). Tag STS in the AZF Region Associated With Azoospermia in a Tunisian Population. J Androl
28: 652-658
[Abstract][Full Text]
Gallardo, T. D., John, G. B., Shirley, L., Contreras, C. M., Akbay, E. A., Haynie, J. M., Ward, S. E., Shidler, M. J., Castrillon, D. H.
(2007). Genomewide Discovery and Classification of Candidate Ovarian Fertility Genes in the Mouse. Genetics
177: 179-194
[Abstract][Full Text]
Bhasin, S.
(2007). Approach to the Infertile Man. J. Clin. Endocrinol. Metab.
92: 1995-2004
[Abstract][Full Text]
Kleiman, S.E., Yogev, L., Hauser, R., Botchan, A., Maymon, B.B.-S., Paz, G., Yavetz, H.
(2007). Expression profile of AZF genes in testicular biopsies of azoospermic men. Hum Reprod
22: 151-158
[Abstract][Full Text]
Hellani, A., Al-Hassan, S., Al-Duraihim, A., Coskun, S.
(2005). Y chromosome microdeletions: are they implicated in teratozoospermia?. Hum Reprod
20: 3505-3509
[Abstract][Full Text]
Seli, E., Sakkas, D.
(2005). Spermatozoal nuclear determinants of reproductive outcome: implications for ART. Hum Reprod Update
11: 337-349
[Abstract][Full Text]
Lynch, M., Cram, D.S., Reilly, A., O'Bryan, M.K., Baker, H.W.G., de Kretser, D.M., McLachlan, R.I.
(2005). The Y chromosome gr/gr subdeletion is associated with male infertility. Mol Hum Reprod
11: 507-512
[Abstract][Full Text]
Stouffs, K., Lissens, W., Tournaye, H., Van Steirteghem, A., Liebaers, I.
(2005). The choice and outcome of the fertility treatment of 38 couples in whom the male partner has a Yq microdeletion. Hum Reprod
20: 1887-1896
[Abstract][Full Text]
Hewitson, L.
(2004). Primate models for assisted reproductive technologies. Reproduction
128: 293-299
[Abstract][Full Text]
Benoff, S. H., Millan, C., Hurley, I. R., Napolitano, B., Marmar, J. L.
(2004). Bilateral increased apoptosis and bilateral accumulation of cadmium in infertile men with left varicocele. Hum Reprod
19: 616-627
[Abstract][Full Text]
Rao, L., Babu, A., Kanakavalli, M., Padmalatha, V., Singh, A., Singh, P. K., Deenadayal, M., Singh, L.
(2004). Chromosomal Abnormalities and Y Chromosome Microdeletions in Infertile Men With Varicocele and Idiopathic Infertility of South Indian Origin. J Androl
25: 147-153
[Abstract][Full Text]
Leslie, G.I., Gibson, F.L., McMahon, C., Cohen, J., Saunders, D.M., Tennant, C.
(2003). Children conceived using ICSI do not have an increased risk of delayed mental development at 5 years of age. Hum Reprod
18: 2067-2072
[Abstract][Full Text]
Hopps, C.V., Mielnik, A., Goldstein, M., Palermo, G.D., Rosenwaks, Z., Schlegel, P.N.
(2003). Detection of sperm in men with Y chromosome microdeletions of the AZFa, AZFb and AZFc regions. Hum Reprod
18: 1660-1665
[Abstract][Full Text]
Thangaraj, K., Gupta, N. J., Pavani, K., Reddy, A. G., Subramainan, S., Rani, D. S., Ghosh, B., Chakravarty, B., Singh, L.
(2003). Y Chromosome Deletions in Azoospermic Men in India. J Androl
24: 588-597
[Abstract][Full Text]
Thangaraj, K., Joshi, M. B., Reddy, A. G., Rasalkar, A. A., Singh, L.
(2003). Sperm Mitochondrial Mutations as a Cause of Low Sperm Motility. J Androl
24: 388-392
[Abstract][Full Text]
Moore, F. L., Jaruzelska, J., Fox, M. S., Urano, J., Firpo, M. T., Turek, P. J., Dorfman, D. M., Pera, R. A. R.
(2003). Human Pumilio-2 is expressed in embryonic stem cells and germ cells and interacts with DAZ (Deleted in AZoospermia) and DAZ-Like proteins. Proc. Natl. Acad. Sci. USA
100: 538-543
[Abstract][Full Text]
Pasqualotto, F. F., Lucon, A. M., Hallak, J., Goes, P. M., Saldanha, L. B., Arap, S.
(2003). Induction of spermatogenesis in azoospermic men after varicocele repair. Hum Reprod
18: 108-112
[Abstract][Full Text]
Teng, Y.-N., Lin, Y.-M., Lin, Y.-H., Tsao, S.-Y., Hsu, C.-C., Lin, S.-J., Tsai, W.-C., Kuo, P.-L.
(2002). Association of a Single-Nucleotide Polymorphism of the Deleted-in-Azoospermia-Like Gene with Susceptibility to Spermatogenic Failure. J. Clin. Endocrinol. Metab.
87: 5258-5264
[Abstract][Full Text]
Oates, R. D., Silber, S., Brown, L. G., Page, D. C.
(2002). Clinical characterization of 42 oligospermic or azoospermic men with microdeletion of the AZFc region of the Y chromosome, and of 18 children conceived via ICSI. Hum Reprod
17: 2813-2824
[Abstract][Full Text]
Zubenko, G. S., Stiffler, J. S., Hughes III, H. B., Fatigati, M. J., Zubenko, W. N.
(2002). Genome Survey for Loci That Influence Successful Aging: Sample Characterization, Method Validation, and Initial Results for the Y Chromosome. AJGP
10: 619-630
[Abstract][Full Text]
Luetjens, C.M., Gromoll, J., Engelhardt, M., von Eckardstein, S., Bergmann, M., Nieschlag, E., Simoni, M.
(2002). Manifestation of Y-chromosomal deletions in the human testis: a morphometrical and immunohistochemical evaluation. Hum Reprod
17: 2258-2266
[Abstract][Full Text]
Rolf, C., Gromoll, J., Simoni, M., Nieschlag, E.
(2002). Natural transmission of a partial AZFb deletion of the Y chromosome over three generations: Case report. Hum Reprod
17: 2267-2271
[Abstract][Full Text]
Tielemans, E., Burdorf, A., te Velde, E., Weber, R., van Kooij, R., Heederik, D.
(2002). Sources of Bias in Studies among Infertility Clients. Am J Epidemiol
156: 86-92
[Abstract][Full Text]
Zeyneloglu, H. B., Baltaci, V., Duran, H. E., Erdemli, E., Batioglu, S.
(2002). Achievement of pregnancy in globozoospermia with Y chromosome microdeletion after ICSI: Case report. Hum Reprod
17: 1833-1836
[Abstract][Full Text]
Kirsch, S, Weiss, B, Kleiman, S, Roberts, K, Pryor, J, Milunsky, A, Ferlin, A, Foresta, C, Matthijs, G, Rappold, G A
(2002). Localisation of the Y chromosome stature gene to a 700 kb interval in close proximity to the centromere. J. Med. Genet.
39: 507-513
[Full Text]
Katz, M.G., Chu, B., McLachlan, R., Alexopoulos, N.I., de Kretser, D.M., Cram, D.S.
(2002). Genetic follow-up of male offspring born by ICSI, using a multiplex fluorescent PCR-based test for Yq deletions. Mol Hum Reprod
8: 589-595
[Abstract][Full Text]
Gatta, V, Stuppia, L, Calabrese, G, Morizio, E, Guanciali-Franchi, P, Palka, G
(2002). A new case of Yq microdeletion transmitted from a normal father to two infertile sons. J. Med. Genet.
39: e27-27
[Full Text]
Kolettis, P. N.
(2002). The Evaluation and Management of the Azoospermic Patient. J Androl
23: 293-305
[Full Text]
Buonadonna, A.L., Cariola, F., Caroppo, E., Carlo, A.D., Fiorente, P., Valenzano, M.C., D'Amato, G., Gentile, M.
(2002). Molecular and cytogenetic characterization of an azoospermic male with a de-novo Y;14 translocation and alternate centromere inactivation. Hum Reprod
17: 564-569
[Abstract][Full Text]
Peterlin, B., Kunej, T., Sinkovec, J., Gligorievska, N., Zorn, B.
(2002). Screening for Y chromosome microdeletions in 226 Slovenian subfertile men. Hum Reprod
17: 17-24
[Abstract][Full Text]
Jaruzelska, J., Korcz, A., Wojda, A., Jedrzejczak, P., Bierla, J., Surmacz, T., Pawelczyk, L., Page, D. C, Kotecki, M.
(2001). Mosaicism for 45,X cell line may accentuate the severity of spermatogenic defects in men with AZFc deletion. J. Med. Genet.
38: 798-802
[Full Text]
Calogero, A. E., Garofalo, M. R., Barone, N., De Palma, A., Vicari, E., Romeo, R., Tumino, S., D'Agata, R.
(2001). Spontaneous regression over time of the germinal epithelium in a Y chromosome-microdeleted patient: Case report. Hum Reprod
16: 1845-1848
[Abstract][Full Text]
Foresta, C., Moro, E., Ferlin, A.
(2001). Prognostic value of Y deletion analysis: The role of current methods. Hum Reprod
16: 1543-1547
[Abstract][Full Text]
Larriba, S., Bassas, L., Egozcue, S., Gimenez, J., Ramos, M. D., Briceno, O., Estivill, X., Casals, T.
(2001). Adenosine Triphosphate-Binding Cassette Superfamily Transporter Gene Expression in Severe Male Infertility. Biol. Reprod.
65: 394-400
[Abstract][Full Text]
Krausz, C., Rajpert-De Meyts, E., Frydelund-Larsen, L., Quintana-Murci, L., McElreavey, K., Skakkebaek, N. E.
(2001). 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.
86: 2638-2642
[Abstract][Full Text]
Makrinou, E., Fox, M., Lovett, M., Haworth, K., Cameron, J. M., Taylor, K., Edwards, Y. H.
(2001). TTY2: A Multicopy Y-Linked Gene Family. Genome Res
11: 935-945
[Abstract][Full Text]
Krausz, C., McElreavey, K.
(2001). Y chromosome microdeletions in `fertile' males. Hum Reprod
16: 1306-1306
[Full Text]
Foresta, C., Moro, E., Ferlin, A.
(2001). Y Chromosome Microdeletions and Alterations of Spermatogenesis. Endocr. Rev.
22: 226-239
[Abstract][Full Text]
Kleiman, S.E., Maymon, B.B.-S., Yogev, L., Paz, G., Yavetz, H.
(2001). The prognostic role of the extent of Y microdeletion on spermatogenesis and maturity of Sertoli cells. Hum Reprod
16: 399-402
[Abstract][Full Text]
Simoni, M.
(2001). Molecular diagnosis of Y chromosome microdeletions in Europe: state-of-the-art and quality control. Hum Reprod
16: 402-409
[Abstract][Full Text]
Liow, S. L., Yong, E. L., Ng, S. C.
(2001). Prognostic value of Y deletion analysis: How reliable is the outcome of Y deletion analysis in providing a sound prognosis?. Hum Reprod
16: 9-12
[Abstract][Full Text]
Reijo, R. A., Dorfman, D. M., Slee, R., Renshaw, A. A., Loughlin, K. R., Cooke, H., Page, D. C.
(2000). DAZ Family Proteins Exist Throughout Male Germ Cell Development and Transit from Nucleus to Cytoplasm at Meiosis in Humans and Mice. Biol. Reprod.
63: 1490-1496
[Abstract][Full Text]
Blanco, P., Shlumukova, M., Sargent, C. A, Jobling, M. A, Affara, N., Hurles, M. E
(2000). Divergent outcomes of intrachromosomal recombination on the human Y chromosome: male infertility and recurrent polymorphism. J. Med. Genet.
37: 752-758
[Abstract][Full Text]
Sun, C., Skaletsky, H., Rozen, S., Gromoll, J., Nieschlag, E., Oates, R., Page, D. C.
(2000). Deletion of azoospermia factor a (AZFa) region of human Y chromosome caused by recombination between HERV15 proviruses. Hum Mol Genet
9: 2291-2296
[Abstract][Full Text]
Saut, N., Terriou, P., Navarro, A., Levy, N., Mitchell, M. J.
(2000). The human Y chromosome genes BPY2, CDY1 and DAZ are not essential for sustained fertility. Mol Hum Reprod
6: 789-793
[Abstract][Full Text]
Le Bourhis, C., Siffroi, J. P., McElreavey, K., Dadoune, J. P.
(2000). Y chromosome microdeletions and germinal mosaicism in infertile males. Mol Hum Reprod
6: 688-693
[Abstract][Full Text]
Krausz, C., Quintana-Murci, L., McElreavey, K.
(2000). Prognostic value of Y deletion analysis: What is the clinical prognostic value of Y chromosome microdeletion analysis?. Hum Reprod
15: 1431-1434
[Abstract][Full Text]
Foresta, C., Ferlin, A., Moro, E.
(2000). Deletion and expression analysis of AZFa genes on the human Y chromosome revealed a major role for DBY in male infertility. Hum Mol Genet
9: 1161-1169
[Abstract][Full Text]
Van Landuyt, L., Lissens, W., Stouffs, K., Tournaye, H., Liebaers, I., Van Steirteghem, A.
(2000). Validation of a simple Yq deletion screening programme in an ICSI candidate population. Mol Hum Reprod
6: 291-297
[Abstract][Full Text]
Venables, J.P., Elliott, D.J., Makarova, O.V., Makarov, E.M., Cooke, H.J., Eperon, I.C.
(2000). RBMY, a probable human spermatogenesis factor, and other hnRNP G proteins interact with Tra2{beta} and affect splicing. Hum Mol Genet
9: 685-694
[Abstract][Full Text]
Goodwin, L. O., Karabinus, D. S., Pergolizzi, R. G., Benoff, S.
(2000). L-type voltage-dependent calcium channel {alpha}-1C subunit mRNA is present in ejaculated human spermatozoa. Mol Hum Reprod
6: 127-136
[Abstract][Full Text]
Vogel, T., Speed, R.M., Teague, P., Cooke, H.J.
(1999). Mice with Y chromosome deletion and reduced Rbm genes on a heterozygous Dazl1 null background mimic a human azoospermic factor phenotype. Hum Reprod
14: 3023-3029
[Abstract][Full Text]
Chang, P. L., Sauer, M. V., Brown, S.
(1999). Y chromosome microdeletion in a father and his four infertile sons. Hum Reprod
14: 2689-2694
[Abstract][Full Text]
Krausz, C., Quintana-Murci, L., Barbaux, S., Siffroi, J.-P., Rouba, H., Delafontaine, D., Souleyreau-Therville, N., Arvis, G., Antoine, J. M., Erdei, E., Taar, J. P., Tar, A., Jeandidier, E., Plessis, G., Bourgeron, T., Dadoune, J.-P., Fellous, M., McElreavey, K.
(1999). A High Frequency of Y Chromosome Deletions in Males with Nonidiopathic Infertility. J. Clin. Endocrinol. Metab.
84: 3606-3612
[Abstract][Full Text]
Foresta, C., Moro, E., Garolla, A., Onisto, M., Ferlin, A.
(1999). Y Chromosome Microdeletions in Cryptorchidism and Idiopathic Infertility. J. Clin. Endocrinol. Metab.
84: 3660-3665
[Abstract][Full Text]
M.Dorfman, D., R.Genest, D., Pera, R. A.R.
(1999). Human DAZL1 encodes a candidate fertility factor in women that localizes to the prenatal and postnatal germ cells. Hum Reprod
14: 2531-2536
[Abstract][Full Text]
Ferlin, A., Moro, E., Onisto, M., Toscano, E., Bettella, A., Foresta, C.
(1999). Absence of testicular DAZ gene expression in idiopathic severe testiculopathies. Hum Reprod
14: 2286-2292
[Abstract][Full Text]
Kamischke, A., Gromoll, J., Simoni, M., Behre, H.M., Nieschlag, E.
(1999). Transmission of a Y chromosomal deletion involving the deleted in azoospermia (DAZ) and chromodomain (CDY1) genes from father to son through intracytoplasmic sperm injection: Case report. Hum Reprod
14: 2320-2322
[Abstract][Full Text]
Sargent, C. A, Boucher, C. A, Kirsch, S., Brown, G., Weiss, B., Trundley, A., Burgoyne, P., Saut, N., Durand, C., Levy, N., Terriou, P., Hargreave, T., Cooke, H., Mitchell, M., Rappold, G. A, Affara, N. A
(1999). The critical region of overlap defining the AZFa male infertility interval of proximal Yq contains three transcribed sequences. J. Med. Genet.
36: 670-677
[Abstract][Full Text]
Slee, R., Grimes, B., Speed, R. M., Taggart, M., Maguire, S. M., Ross, A., McGill, N. I., Saunders, P. T. K., Cooke, H. J.
(1999). A human DAZ transgene confers partial rescue of the mouse Dazl null phenotype. Proc. Natl. Acad. Sci. USA
96: 8040-8045
[Abstract][Full Text]
Ferlin, A., Moro, E., Garolla, A., Foresta, C.
(1999). Human male infertility and Y chromosome deletions: role of the AZF-candidate genes DAZ, RBM and DFFRY. Hum Reprod
14: 1710-1716
[Abstract][Full Text]
Krausz, C., Bussani-Mastellone, C., Granchi, S., McElreavey, K., Scarselli, G., Forti, G.
(1999). Screening for microdeletions of Y chromosome genes in patients undergoing intracytoplasmic sperm injection. Hum Reprod
14: 1717-1721
[Abstract][Full Text]
Page, D. C., Silber, S., Brown, L. G.
(1999). Men with infertility caused by AZFc deletion can produce sons by intracytoplasmic sperm injection, but are likely to transmit the deletion and infertility. Hum Reprod
14: 1722-1726
[Abstract][Full Text]
Calogero, A. E., Garofalo, M. R., D'Agata, R.
(1999). Factors influencing the variable incidence of Y chromosome microdeletions in infertile patients. Hum Reprod
14: 275-275
[Full Text]
Kleiman, S.E., Yogev, L., Gamzu, R., Hauser, R., Botchan, A., Lessing, J.B., Paz, G., Yavetz, H.
(1999). Genetic evaluation of infertile men. Hum Reprod
14: 33-38
[Abstract][Full Text]
Tut, T. G., Ghadessy, F. J., Trifiro, M. A., Pinsky, L., Yong, E. L.
(1997). Long Polyglutamine Tracts in the Androgen Receptor Are Associated with Reduced Trans-Activation, Impaired Sperm Production, and Male Infertility. J. Clin. Endocrinol. Metab.
82: 3777-3782
[Abstract][Full Text]
Lahn, B. T., Page, D. C.
(1997). Functional Coherence of the Human Y Chromosome. Science
278: 675-680
[Abstract][Full Text]
de Kretser, D. M., Burger, H. G.
(1997). The Y Chromosome and Spermatogenesis. NEJM
336: 576-578
[Full Text]
Previous
