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Year : 2003  |  Volume : 19  |  Issue : 2  |  Page : 103-108

Y chromosome microdeletion and male infertility

Department of Urology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

Correspondence Address:
Rama Devi Mittal
Department of Urology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow - 226 014
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Source of Support: None, Conflict of Interest: None

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Keywords: Azoospermia, AZF, chromosomal defect, ICSI, spermatogenesis.

How to cite this article:
Kesari A, Srivastava A, Mittal RD. Y chromosome microdeletion and male infertility. Indian J Urol 2003;19:103-8

How to cite this URL:
Kesari A, Srivastava A, Mittal RD. Y chromosome microdeletion and male infertility. Indian J Urol [serial online] 2003 [cited 2022 Aug 9];19:103-8. Available from:

   Introduction Top

Infertility affects about 15% of couples, and in 20-25% of cases the problem is due to the male partner. Infertility in male can be caused by several reasons like hormonal abnormalities, varicocele, physical abnormalities, exposure to heavy metals, environmental effect and defective semi­nal parameters. Low sperm count, defect in sperm motil­ity, sperm morphology, quantitative and qualitative abnormalities of sperm production and the genetic factors also lead to infertility. [1]

Genetic defects such as mutations and chromosomal defects have been estimated to account for at least 30% of male infertility. Research in the last 20 years has indicated that the Y-chromosome is necessary for sexual develop­ment and spermatogenesis. [2] Spermatogenesis comprising mitotic, meiotic divisions and terminal differentiation turns spermatids into motile spermatozoa. Although the devel­opmental process of spermatogenesis has been intensively studied our knowledge of genetic control of spermatogen­esis remains limited. [3]

Y chromosome

The Y-chromosome comprises only 2-3% of the hap­loid genome. It is an acrocentric chromosome and conse­quently contains a short arm and a long arm demarcated by a centromeric region essential for chromosome segregation [Figure - 1]. Cytogenetic studies have defined three re­gions i. Pseudoautosomal regions (PAR) which are located at the end of the short arm (PAR1) and at the long arm (PAR2) of the chromosome. ii. Euchromatic regions that are distal to the PAR1 consist of the short arm paracentromeric region. iii. Heterochromatic region comprises distal Yq, and is polymorphic in different populations. The pseudoautosomal region is where the Y-chromosome pairs and exchanges genetic material with pseudoautosomal re­gion of the X-chromosome during meiosis. Consequently, the genes located within this region are inherited in the same manner as the autosomal genes. The majority of the length of the Y-chromosome (95%) is termed as "non­recombining Y" (NRY ). This region represents the only haploid compartment of the human genome and includes the heterochromatic and euchromatic regions of the chro­mosome. The heterochromatic region is assumed to be genetically inert and it is mainly composed of highly re­petitive sequence families, DYZI, DYZ2, containing about 5000 and 2000 copies each respectively. The euchromatic region too has numerous highly repetitive sequences but also contains genes involved in sex-determination (SRY), gonadoblastoma (GB), stature control, Turner stigmata and spermatogenesis. [4]

Genes and gene families of AZFa, AZFb, AZFc and AZFd regions

The Y-chromosome harbors genes important for sper­matogenesis on distal portion of euchromatin segment of the long arm. This spermatogenic locus lying in Yg11.23 demonstrated with high resolution banding techniques is known as azoospermic factor (AZF). [5] Further localiza­tion has placed AZF locus between interval 5 and 6 of the Y-chromosome [6],[7] [Figure - 1]. The locus is further subdivided into four sub-regions (AZFa to AZFd). AZFa region is estimated to be between 1 to 3 Mb in size. Several genes have been identified in this region. These genes include the Drosophila development gene Fats Facets (DFFRY), Dead Box Y (DBY), [8] Ubiquitous TPR motif Y (UTY), and a Tymosin B4Y isoform (TB4Y) [Table - 1]. The AZFb region is estimated to be 1-3 Mb in size. Five genes have been described within this interval. (RBM formerly termed YRRM) RNA binding motif, [9] Chromodomain Y (CDY), XK related Y (XKRY), eukaryotic translation initiation factor 1A (elF-lA) and (SMCY) selected mouse cDNA on the Y. The AZFc is located in close proximity to the heterochromatin, its size is approximately 1.4 Mb and it contains the DAZ gene cluster, [10] 2 copies of PTP-BL re­lated Y (PRY), basic protein Y2 (BPY2), testis transcript Y2 (TTY2), as well as copies of CDY and RBM. [11] The 4th region AZFd lies in between the AZFb and AZFc and this is the smallest of the 4 regions and only little is known about this region. [12] It is not known whether Y-chromo­some harbors a specific set of spermatogenesis genes which act as master regulators of this process or as minor factors which enhances the quality of efficiency of spermatogen­esis. [13] The position of genes within the 4 AZF regions, their expression pattern and the data on their homologs DFFRY and DAZ are suggestive of their involvement in the control of spermatogenesis. [14]

Y chromosome microdeletions

The involvement of AZF region in spermatogenesis was proposed because deletions in this region resulted in in­fertility. [15] Most of deletions on Y chromosome are not usually detectable by routine karyotyping. Instead, only submicroscopic deletions called microdeletions have been detected in subgroup of infertile men currently classified as idiopathic azoospermic. [16],[17] With the advent of polymer­ase chain reaction (PCR) and construction of a Y chromo­some sequences tagged sites (STSs, short tracts of DNA that act as a landmarks to define position on a physical map), [18] microdeletions can be identified in AZF region of oligozoospermic and azoospermic men. Vollrath and col­leagues [19] enhanced the resolution of this map by develop­ing more than 200 STSs for deletion analysis. There are 20-25 STSs that cover the major deletion region of Y chro­mosome and are most commonly used. Validation of microdeletion by Southern hybridization by using PCR­amplified STSs as probes is important to confirm dele­tions. [17],[20] However there are few point mutations which cannot be detected by either PCR or Southern hybridiza­tion. Although the microdeletions are interspersed through­out the interval 6, there are 2 areas that have a high proportion of microdeletions. This region extends from sY131 to sY138 and from sY144 to sY158. The micro­deletion present in Y chromosome are not continuous as there may be deletion in 6A and 6D but 6B and 6C may remain intact. [21]

Microdeletions and clinical phenotype

Sperm retrieval is possible from the testes of infertile men and the fact that these sperm can be used to achieve fertilization through intracytoplasmic sperm injection (ICSI) raises the possibility of genetic transmission of in­fertility. [22],[23],[24] Several studies correlate the size and position of the deletion with the infertile phenotype. Ultimately, accurate information will only be available to the clini­cian and patient when diagnostic procedures that detect specific gene deletion/mutations of known significance to spermatogenesis are developed. Vogt et al [7] proposed that the Y-chromosome microdeletions follow a certain dele­tion pattern. Early studies attempted to assign specific in­fertility phenotypes to each regions of AZF, deletions occurring in AZFa result in type 1 Sertoli cell only syn­drome (SCOS) with no spermatogonia, deletions in AZFb results in spermatogenic arrest (SGA) usually at sperma­tocyte stage, and deletions in AZFc are associated to type II SCOS and some spermatogonia are seen with limited spermatogenesis or hypospermatogenesis. Microdeletions restricted to the AZFd region may present with mild oligospermia or even normal sperm counts with abnormal sperm morphology. [2] Despite some apparently conflicting findings reported in the literature some general genotype/ phenotype tendencies are observed. i. Microdeletions have been found in males affected by azoospermia or severe oligospermia. ii. A higher frequency of Yq deletions are found in idiopathic infertile patients. [25] iii. Widening of de­letions may take place when transmitted from father to son. [26] iv. Large deletions are in general associated with a more severe spermatogenic defect. [9] v. AZFa is less com­mon than AZFc, AZFc, and AZFb deletions are most fre­quent and are associated with a variety of spermatogenic failure. [14]

Incidence of microdeletion

The incidence of microdeletion varies from 1% to 35% in different studies [27] [Table - 2]. There are many different fac­tors which influence these studies. Usually study popula­tions are often variable, ranging from azoospermic, oligozoospermic to normospermic patients. While major­ity of clinical studies selected patients with idiopathic azoo­spermia or oligospermia, a few others include unselected infertile men with known or unknown cause of infertility. Unfortunately there is no agreement between studies regard­ing definition of idiopathic infertility. Patients with abnor­mal andrological findings, such as varicocele and history of cryptorchidism are considered as idiopathic in some studies and as non idiopathic in others. In general studies with low patient number report a higher frequency of deletions [16] than those where the number of patients are higher. [12] Another variable which may also affect the frequency of Yq dele­tions is marker density or the position of markers. How­ever. recently it has been noted that there is no statistically significant correlation between the frequency of micro­deletion and the numbers of STS markers used. [17] Finally, differences in frequency and/or localization between dif­ferent studies may reflect genuine population variances, perhaps related to Y-chromosome haplotypes, genetic background or environmental influences. [36]

Fertility and Y chromosome

There are a few reports of fertile men who have been found to harbor some deletions on Y chromosome par­ticularly in AZFc region. Based on several studies, it is now believed that AZFc region is not critical for sperma­togenesis. However, the men carrying AZFc deletions may have reduced sperm count and the condition worsens with age. [28] In many cases, the sons inheriting the deletion are infertile. [37]

Assisted reproductive techniques and Y deletions

The occurrence of Y deletion in infertile men has sig­nificant implications for assisted reproductive technolo­gies particularly intra cytoplasmic sperm injection (ICSI) [23] as it avoids unnecessary medical (hormonal and non hor­monal) and surgical (varicocele operation) treatments. Recently it has been reported that the type of Y chromosome microdeletion in azoospermic patients could have some prognostic value. AZFc deletion and partial AZFb deletion are associated with sperm retrieval in 50% of cases, while in cases of AZFb deletion, probability of finding sperm is virtually nil. However retrieved sperms are found to be fully fertile in both ICSI and IVF procedures. Open testicular biopsy is the most reliable method to obtain tes­ticular sperm, less invasive techniques such as testicular fine-needle aspiration and percutaneous needle biopsy are feasible alternatives in selected groups of patients. [38] Cryo­TESE is a good alternative to TESE/ICSI in azoospermic men and it avoids unnecessary stimulation in the female partner. [39] In case ICSI allows partners of infertile men to become pregnant, it is possible that Y deletions may be transmitted to the male offspring. [24] This raises issues of informed consent and ethical concerns. Substantial preva­lence of Y deletions in infertile men and the potential risk of transmitting this genetic disorder to their offspring pro­vide a compelling rationale for screening of infertile men prior to ICSI. Since certain Y deletion are associated with a progressive change from oligospermia to azoospermia, [29] preventive therapy (cryoconservation) of sperm for suc­cessive assisted reproduction techniques could be proposed to affected sons. [40]

   Conclusions Top

Although substantial research has been made in the field of Y chromosome, several challenges now face those re­searching spermatogenesis genes on the Y chromosome. Biochemical and functional studies on those genes in the AZFa, AZFb, AZFc, AZFd regions are underway to gain insight and their roles in regulating germ cells differentia­tion. Future research is needed to understand the role of the RBM and DAZ proteins, and for those genes that are X-Y homologs. The field is moving fast and will expand in the next few years to provide the beginnings of a mo­lecular understanding of the genetic pathways controlling male germ cell differentiation. Genotype/phenotype cor­relation should become clearer with more accurate patient selection criteria, and improved clinical and histopatho­logical investigations. Studies on normospermic men rather than fertile males will provide evidence about the type of polymorphic deletions. Currently most research activities are concentrated on characterization of microdeletions and discovery of genes in the region, but only little is known about the biological functions of the protein encoded by Y chromosome genes. RNA processing is an important as­pect of germ cell differentiation. As more is known about the biological roles of these factors and the biochemical function and pathways with which these genes are involved, it may be possible to develop designer drugs that permit spermatogenesis to proceed normally.

   Acknowledgement Top

We thank Dr. Balraj Mittal, Additional Professor, De­partment of Medical Genetics for critical reading of the manuscript. The work was supported by grant for an intra­mural project provided by the Sanjay Gandhi Postgradu­ate Institute of Medical Sciences, Lucknow.

   References Top

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28.Pryor JL, Kent-First MG, Muallem A, Van Bergen AH, Nolten WE, Meisner L, et al. Microdeletion in the Y chromosome of infertile men. New Eng J Med 1997; 336: 534-539.  Back to cited text no. 28    
29.Foresta C, Ferlin A, Garolla A, Rossato M, Barbaux S, De Bortoli A. Y chromosome deletions in idiopathic severe testiculopathies. J Clin Endo and Metab 1997; 82: 1075-1080.  Back to cited text no. 29    
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35.Rajesh Raman, A Rajesh. Y chromosome deletions in male infertil­ity. Proceeding of XXVI Annual Conference of the Indian Society of Human Genetics (ISHG 2001) : 5 (Abstract).  Back to cited text no. 35    
36.Mark A Jobbing, C Tyler-Smith. New uses for new haplotypes the human Y chromosome disease and selection. TIG 2000; 16(8): 356-362.  Back to cited text no. 36    
37.Noemie Sant, Phillippe Terriou, Andre Navarro, Nicolaslevy, MJ Mitchell. The human Y chromosome genes BPY2, CDYI and DAZ are not essential for sustained fertility. Mol Hum Reprod 2000; 6(9): 789-793.  Back to cited text no. 37    
38.Chan PT, Schlegel PN. Non-obstructive azoospermia. Curr Opin Urol 2000; 10(6): 617-624.  Back to cited text no. 38    
39.Csilla Krausz, Lluis Quintana-Murci, Ken McElreavey. Prognostic value of Y deletion analysis. Hum Reprod 2000: 15(7): 1431-1434.  Back to cited text no. 39    
40.Picton HM, Kim SS, Gowden RG. Cryopreservation of gonadal tissues and cells. Br Med Bull 2000; 56(3): 603-615.  Back to cited text no. 40    


  [Figure - 1]

  [Table - 1], [Table - 2]


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