Spermatogenic Failure, Y-Linked, 1
A number sign (#) is used with this entry because Sertoli cell-only (SCO) syndrome has been found to be associated with interstitial deletions in the 'azoospermia factor' (AZF) region on the long arm of the Y chromosome, particularly deletions of the AZFa region, which includes the ubiquitin-specific protease 9 gene (USP9Y; 400005), the DEAD/H box 3 gene (DBY; 400010), and the ubiquitously transcribed tetratricopeptide repeat gene (UTY; 400009).
DescriptionIn the evaluation of male infertility, the Sertoli cell-only (SCO) syndrome is diagnosed on testicular biopsy when either no germ cells are visible in any seminiferous tubules (SCO type I) or germ cells are present in a minority of tubules (SCO type II). It is believed that the latter variant arises from a failure to complete differentiation and maturation of spermatocytes and spermatids, leading to degeneration of germ cells within most tubules (Sargent et al., 1999).
Another, possibly X-linked, form of Sertoli cell-only syndrome has also been reported (305700).
Heterogeneity of Spermatogenic Failure
See 415000 for a general discussion of the AZF region of the Y chromosome and Y-linked nonobstructive spermatogenic failure.
For a discussion of phenotypic and genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).
Molecular GeneticsJohnson et al. (1989) screened 6 azoospermic men with normal karyotypes and biopsy-proven germ cell aplasia (SCO) using hybridization probes specific for molecular deletions in distal Yq11 and identified 1 individual with absence of the 50f2/C band. No deletions were detected with pFP105/B and 2 more proximal Yq11 probes.
Vogt et al. (1996) analyzed testis biopsies in patients with deletions in different regions of Yq11. A patient with a deletion in proximal Yq11 had SCO syndrome type I. Vogt et al. (1996) reported that in 3 patients with a microdeletion in middle Yq11 testicular histology revealed spermatogenic arrest at the spermatocyte stage. Populations of spermatogonia and spermatocytes were normal in tubules. No postmeiotic germ cells could be detected, which indicated that disruption of spermatogenesis occurred before or during meiosis at the spermatocyte stage. Results of studies in 5 patients with microdeletions in distal Yq11 suggested a postmeiotic spermatid or sperm maturation defect. Because microdeletions were found in 3 different Yq11 subregions that led to spermatogenesis disruption at different phases of the process, Vogt et al. (1996) proposed the presence of 3 spermatogenesis loci in Yq11, which they designated AZFa, AZFb, and AZFc. They proposed in addition that each locus is active during a different phase of male germ cell development.
Brown et al. (1998) found that 3 azoospermic male patients had deletion of the USP9Y gene. Two patients had a testicular phenotype that resembled Sertoli cell-only type I, and the third (patient 'SAYER') had diminished spermatogenesis, with a testicular biopsy that revealed small to moderate numbers of mature spermatozoa and occasional tubules with only spermatids, spermatocytes, or spermatogonia (see 400005.0002). In all 3 patients, the deletions extended from close to the 3-prime end into the gene, removing the entire coding sequence of USP9Y.
Foresta et al. (1998) performed PCR testing for a set of 29 Y-specific STSs in 18 azoospermic men with SCO type I on testicular fine needle aspiration cytology (FNAC) and in 20 fertile men with normal spermatogenesis on FNAC. Yq microdeletions were found in 10 (55.5%) of the 18 patients with SCO but not in fertile controls or the fathers or brothers of 6 of the 10 patients with microdeletions. Microdeletion analysis revealed 2 homogeneous regions with a high incidence of deletion; the smallest was common to all patients and appeared to encompass the final portion of AZFa to proximal AZFb. Foresta et al. (1998) concluded that a large percentage of idiopathic SCO syndrome may be genetically determined and that there is a Y-related region that seems to possess 1 or more genes essential for spermatogenesis.
Sun et al. (1999) reported a patient (WHT2996) with a deletion of the entire AZFa region who had no testicular germ cells.
Sargent et al. (1999) refined the deletion breakpoints in 4 patients with AZFa male infertility. All patients had USP9Y and an anonymous EST, AZFaT1, deleted in their entirety, and 3 patients also had DBY (400010) deleted. The 3 patients with AZFaT1, USP9Y, and DBY deleted showed a severe Sertoli cell-only type I phenotype, whereas the patient who had retained DBY (SAYER, originally reported by Brown et al., 1998) showed a milder oligozoospermic phenotype (see 400005.0002). RT-PCR analysis of mouse testis RNA showed that Dby is expressed primarily in somatic cells, while Usp9y is expressed specifically in testis in a germ cell-dependent fashion.
Foresta et al. (2000) reported a complete sequence map of the AZFa region, the genomic structure of AZFa genes, and their deletion analysis in 173 infertile men with well-defined spermatogenic alterations. Deletions were found in 9 patients: DBY alone was deleted in 6, USP9Y alone in 1 (see 400005.0002), and there was 1 each with USP9Y-DBY or DBY-UTY missing. No patients solely lacked UTY (400009). There was no clear correlation between the size and location of the deletions and the testicular phenotype; patients lacking DBY exhibited either complete Sertoli cell-only syndrome or severe hypospermatogenesis (SCO syndrome type II). Expression analysis of AZFa genes and their X-chromosome homologs revealed ubiquitous expression for all except DBY; a shorter DBY transcript was expressed only in testis. The authors suggested that DBY plays a key role in the spermatogenic process.
Kamp et al. (2000) mapped the breakpoints of AZFa microdeletions in 6 men with Sertoli cell-only syndrome. The proximal breakpoints were identified in a long retroviral sequence block (HERV15yq1) at the 5-prime end of the DYS11 DNA locus on Yq11, interval D3. The distal breakpoints were found in a homologous HERV15 sequence block mapped to the Yq11 interval D6, i.e., in the distal part of the AZFa region (HERV15yq2). Compared with the HERV15yq1 sequence, HERV15yq2 is marked by a deletion of a HERV15 sequence domain at its 5-prime end and insertion of a Line-1 3-prime untranslated region sequence block (L1PA4) of similar length at its 3-prime end. For all 6 AZFa patients it was possible to bridge both retroviral sequence blocks by PCR, which normally span a distance of 781 kb in proximal Yq11 in fertile men. The AZFa breakpoint-fusion regions in the 6 patients were located in their recombined HERV15yq1-HERV15yq2 sequence blocks in either 1 of 2 long identical sequence domains (ID1 and ID2). The authors hypothesized that intrachromosomal recombination events between the 2 homologous retroviral sequence blocks in proximal Yq11 are probably responsible for most of the AZFa microdeletions observed in men with SCO syndrome.
Moro et al. (2000) reported a partial deletion of the 'deleted in azoospermia' (DAZ; 400003) cluster in the AZFc region which removed all but 1 of the DAZ copies. This deletion was found in a patient affected with severe oligozoospermia who had a testicular phenotype characterized by a great quantitative reduction of germ cells (SCO type II). The absence of this deletion in the fertile brother of the patient suggested that this de novo mutation indeed caused the spermatogenic failure.
Deletions of the azoospermia factors on the Y chromosome long arm may involve germ cell-specific genes or ubiquitously expressed genes. Foresta et al. (2001) hypothesized that microdeletions involving genes specifically expressed in germ cells should not alter Sertoli cell function. To examine this, they evaluated the testicular hormonal function in infertile patients affected by severe testiculopathies (including SCO and hypospermatogenesis, but no cases of maturation arrest) with and without Yq microdeletions, with particular emphasis on Sertoli cell function. They studied 102 well-characterized infertile patients; 27 had Yq microdeletions, 24 of which involved the DAZ gene cluster, and 75 were classified as idiopathic cases. Patients with Yq microdeletions had lower FSH (see 136530) and higher inhibin B (see 147290) plasma concentrations compared to patients without microdeletions, suggesting that Sertoli cell function in Yq-deleted men is only partially altered. Furthermore, patients with deletions involving germ cell-specific genes had higher concentrations of inhibin B compared to patients with deletions of ubiquitously expressed genes. The authors inferred that a specific alteration of germ cells only partially influences Sertoli cell function. The hormonal status of patients without deletions suggested that in such cases the cause of the spermatogenic defect may have damaged both Sertoli and germ cells. Inhibin B production in patients with Yq deletions was about 70% higher than in nondeleted patients, and the functional relationship between FSH and inhibin B was normally preserved.
Kamp et al. (2001) developed a rapid screening protocol for deletion analysis of the complete AZFa sequence based on the deletion pattern of 4 new sequence tagged sites: 2 flanking HERV15yq1 and 2 flanking HERV15yq2, the proximal and distal sequence blocks, respectively, that define complete AZFa deletions (see Kamp et al., 2000). Using this protocol in 100 men with a histologic diagnosis of complete germ cell aplasia (SCO syndrome), Kamp et al. (2001) identified 9 (9%) who had complete AZFa deletions. Based on their experience with more than 1,000 azoospermic or severely oligozoospermic males, Kamp et al. (2001) concluded that deletion of the complete AZFa sequence is always associated with a uniform SCO pattern on testicular biopsy.
Frydelund-Larsen et al. (2002) analyzed the serum concentrations of reproductive hormones in infertile patients with AZFc microdeletions and compared these to concentrations in a matched group of infertile patients without Yq microdeletions and to those in a group of fertile control individuals. In contrast to the study of Foresta et al. (2001), they found low serum inhibin B and elevated FSH levels in the majority of 16 patients with AZFc microdeletions compared with fertile control subjects. Their data supported the view that in patients with AZF microdeletions the serum concentration of inhibin B depends upon the functional interaction between Sertoli cells and spermatocytes and/or spermatids. Bilateral testicular biopsies in 10 of the AZFc-deleted patients revealed a variable histologic pattern of severe testiculopathy: 2 patients had bilateral spermatocytic arrest and 1 had bilateral SCO syndrome; the remainder had a combination of both, and some cases showed signs of testicular atrophy. Frydelund-Larsen et al. (2002) suggested that the variable histologic picture might be related to a progressive nature of the testicular defect caused by deletion of the AZFc region.
Using BAC clones, Ferlin et al. (2003) assembled a complete map of AZFb, which was estimated to extend over 3.2-Mb, with repeated sequences representing only 12% of the region. Among 700 infertile men with spermatogenic failure, 4 unrelated subjects (2 with a Sertoli cell-only phenotype and 2 with severe hypospermatogenesis) were found to have partial AZFb deletions and apparently identical breakpoints.
In a 42-year-old man who underwent spermatologic and genetic analysis as part of an infertility analysis after his partner had a miscarriage, Luddi et al. (2009) identified a 513,594-bp deletion in the AZFa region of the Y chromosome, with breakpoints located approximately 320,521 bp upstream and 33,465 bp downstream of the USP9Y gene (400005.0002). Spermatologic analysis revealed that total progressive motility was slightly reduced (mild asthenozoospermia), but all other sperm characteristics were within the normal range. His father and brother, who did not undergo spermatologic analysis, were also found to carry the deletion. The authors concluded that USP9Y is not essential for normal sperm production and fertility in humans.
HistoryThe Sertoli cell-only syndrome was first described by Del Castillo et al. (1947).