Entry - #400042 - SPERMATOGENIC FAILURE, Y-LINKED, 1; SPGFY1 - OMIM

 
ICD+
# 400042

SPERMATOGENIC FAILURE, Y-LINKED, 1; SPGFY1


Alternative titles; symbols

SERTOLI CELL-ONLY SYNDROME, Y-LINKED
SERTOLI CELL-ONLY SYNDROME, TYPE I


Other entities represented in this entry:

SERTOLI CELL-ONLY SYNDROME, TYPE II, INCLUDED
HYPOSPERMATOGENESIS, INCLUDED
INCOMPLETE SERTOLI CELL-ONLY SYNDROME, INCLUDED

Cytogenetic location: Yq11     Genomic coordinates (GRCh38): Y:10,400,001-26,600,000


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number 		Inheritance Phenotype
mapping key
Yq11 Spermatogenic failure, Y-linked, 1 400042 YL 4
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Y-linked
GENITOURINARY
Internal Genitalia (Male)
- Hypospermatogenesis
- Sertoli-cell-only syndrome
- Asthenozoospermia
- Azoospermia
MOLECULAR BASIS
- Caused by mutation in the ubiquitin-specific protease-9, Y chromosome gene (USP9Y, 400005)
▲ Close
Spermatogenic failure - PS258150 - 100 Entries
Location Phenotype Inheritance Phenotype
mapping key 		Phenotype
MIM number 		Gene/Locus Gene/Locus
MIM number
1p34.3 ?Spermatogenic failure 83 AR 3 620354 DNALI1 602135
1p31.1 Spermatogenic failure 2 AR 3 108420 MSH4 602105
1p22.1 ?Spermatogenic failure 21 AR 3 617644 BRDT 602144
1p12 ?Spermatogenic failure 55 AR 3 619380 SPAG17 616554
2p23.3 Spermatogenic failure 80 AR 3 620222 DRC1 615288
2p13.1 Spermatogenic failure 48 AR 3 619108 M1AP 619098
2q11.2 ?Spermatogenic failure 26 AR 3 617961 TSGA10 607166
2q32.1 Spermatogenic failure 34 AR 3 618153 FSIP2 615796
2q33.1 ?Spermatogenic failure 68 AR 3 619805 C2CD6 619776
2q35 ?Spermatogenic failure 54 AR 3 619379 CATIP 619387
2q35 Spermatogenic failure 40 AR 3 618664 CFAP65 614270
3p22.2 Spermatogenic failure 37 AR 3 618429 TTC21A 611430
3p21.1 Spermatogenic failure 18 AR 3 617576 DNAH1 603332
3q13.2 Spermatogenic failure 20 AR 3 617593 CFAP44 617559
3q13.33 Spermatogenic failure 51 AR 3 619177 CFAP91 609910
3q26.31 ?Spermatogenic failure 6 AR 3 102530 SPATA16 609856
4p16.3 ?Spermatogenic failure 62 AR 3 619673 RNF212 612041
4p14 ?Spermatogenic failure 72 AR 3 619867 WDR19 608151
4q12 ?Spermatogenic failure 29 AR 3 618091 SPINK2 605753
4q22.3 Spermatogenic failure 70 AR 3 619828 PDHA2 179061
4q31.22 Spermatogenic failure 42 AR 3 618745 TTC29 618735
5p13.2 Spermatogenic failure 43 AR 3 618751 SPEF2 610172
6p21.33 Spermatogenic failure 74 AR 3 619937 MSH5 603382
6p21.31 Spermatogenic failure 90 AR 3 620744 ARMC12 620377
6p21.31 Spermatogenic failure 3 AD, AR 3 606766 SLC26A8 608480
6p21.2 Spermatogenic failure 46 AR 3 619095 DNAH8 603337
6q15 ?Spermatogenic failure 85 AR 3 620490 SPACA1 612739
6q21 Spermatogenic failure 38 AR 3 618433 ARMC2 618424
6q21 Spermatogenic failure 89 AR 3 620705 AK9 615358
6q25.3 Spermatogenic failure 57 AR 3 619528 PNLDC1 619529
7p12.2 ?Spermatogenic failure 66 AR 3 619799 ZPBP 608498
7q11.23 Spermatogenic failure 77 AR 3 620103 FKBP6 604839
7q21.13 Spermatogenic failure 24 AR 3 617959 CFAP69 617949
7q22.1 Spermatogenic failure 61 AR 3 619672 STAG3 608489
7q36.1 Spermatogenic failure 50 AR 3 619145 XRCC2 600375
8p12 Spermatogenic failure 25 AR 3 617960 TEX15 605795
8p11.23 Spermatogenic failure 79 AR 3 620196 KCNU1 615215
8q22.2 Spermatogenic failure 64 AR 3 619696 FBXO43 609110
9p21.2 Spermatogenic failure 58 AR 3 619585 IFT74 608040
9q31.3 Spermatogenic failure 86 AR 3 620499 ACTL7A 604303
9q31.3 Spermatogenic failure 75 AR 3 619949 SHOC1 618038
9q33.3 Spermatogenic failure 8 AD 3 613957 NR5A1 184757
9q34.3 Spermatogenic failure 32 AD 3 618115 SOHLH1 610224
10q22.2 ?Spermatogenic failure 41 AR 3 618670 CFAP70 618661
10q25.1 Spermatogenic failure 19 AR 3 617592 CFAP43 617558
10q25.1 Spermatogenic failure 49 AR 3 619144 CFAP58 619129
10q26.11 Spermatogenic failure 12 AD 3 615413 NANOS1 608226
10q26.3 ?Spermatogenic failure 15 AR 3 616950 SYCE1 611486
11p15.4 Spermatogenic failure 65 AR 3 619712 DHND1 617277
11p14.1 Spermatogenic failure 76 AR 3 620084 CCDC34 612324
11q13.1 Spermatogenic failure 7 AR 3 612997 CATSPER1 606389
12p13.32 Spermatogenic failure 82 AR 3 620353 AKAP3 604689
12p12.3 Spermatogenic failure 17 AR 3 617214 PLCZ1 608075
12q14.2 Spermatogenic failure 9 AR 3 613958 DPY19L2 613893
12q23.2 Pregnancy loss, recurrent, 4 AD 3 270960 SYCP3 604759
12q23.2 Spermatogenic failure 4 AD 3 270960 SYCP3 604759
12q24.31 Spermatogenic failure 33 AR 3 618152 WDR66 618146
12q24.31 ?Spermatogenic failure 67 AR 3 619803 CCDC62 613481
12q24.31 Spermatogenic failure 56 AR 3 619515 DNAH10 605884
13q32.1 Spermatogenic failure 47 AR 3 619102 DZIP1 608671
14q13.2 Spermatogenic failure 36 AD 3 618420 PPP2R3C 615902
14q21.2 Spermatogenic failure 28 AR 3 618086 FANCM 609644
14q21.2 ?Spermatogenic failure 63 AR 3 619689 RPL10L 619655
14q23.1 Spermatogenic failure 52 AR 3 619202 C14orf39 617307
14q32.2 ?Spermatogenic failure 27 AR 3 617965 AK7 615364
14q32.33 ?Spermatogenic failure 30 AR 3 618110 TDRD9 617963
15q21.1 ?Spermatogenic failure 59 AR 3 619645 TERB2 617131
16p13.3 Spermatogenic failure 22 AR 3 617706 MEIOB 617670
16p13.3 Spermatogenic failure 10 AD 3 614822 SEPT12 611562
16q22.1 Spermatogenic failure 60 AR 3 619646 TERB1 617332
16q22.2 Spermatogenic failure 31 AR 3 618112 PMFBP1 618085
17p13.2 ?Spermatogenic failure 14 AR 3 615842 ZMYND15 614312
17p13.1 Spermatogenic failure 45 AR 3 619094 DNAH2 603333
17p12 Spermatogenic failure 81 AR 3 620277 TEKT3 612683
17p12 Spermatogenic failure 71 AR 3 619831 ZSWIM7 614535
17q21.2 Spermatogenic failure 11 AD 3 615081 KLHL10 608778
17q22 Spermatogenic failure 23 AR 3 617707 TEX14 605792
17q24.1 Spermatogenic failure 44 AR 3 619044 CEP112 618980
17q25.1 Spermatogenic failure 35 AR 3 618341 QRICH2 618304
17q25.3 Spermatogenic failure 39 AR 3 618643 DNAH17 610063
18q11.2 ?Spermatogenic failure 13 AR 3 615841 TAF4B 601689
19p13.2 Spermatogenic failure 53 AR 3 619258 ACTL9 619251
19p13.11 Spermatogenic failure 78 AR 3 620170 IQCN 620160
19q13.2 Spermatogenic failure 69 AR 3 619826 GGN 609966
19q13.33 Spermatogenic failure 88 AR 3 620547 KASH5 618125
19q13.43 Spermatogenic failure 5 AR 3 243060 AURKC 603495
20p11.23 Spermatogenic failure 84 AR 3 620409 CFAP61 620381
20q11.21 Spermatogenic failure 16 AR 3 617187 SUN5 613942
20q13.33 Spermatogenic failure 1 AD 3 258150 SYCP2 604105
22q13.33 ?Spermatogenic failure 73 AR 3 619878 MOV10L1 605794
22q13.33 ?Spermatogenic failure 87 AR 3 620500 ACR 102480
Xp21.1 Spermatogenic failure, X-linked 3 XLR 3 301059 CFAP47 301057
Xp11.23 Spermatogenic failure, X-linked, 5 XL 3 301099 SSX1 312820
Xq13.1 Spermatogenic failure, X-linked 2 XLR 3 309120 TEX11 300311
Xq13.1 Spermatogenic failure, X-linked, 4 XL 3 301077 GCNA 300369
Xq26.2 Spermatogenic failure, X-linked, 6 XL 3 301101 USP26 300309
Xq26.3 ?Spermatogenic failure, X-linked, 7 XLR 3 301106 CT55 301105
Yq11 Spermatogenic failure, Y-linked, 1 YL 4 400042 DELYq11 400042
Yq11.221 Spermatogenic failure, Y-linked, 2 YL 3 415000 USP9Y 400005
Not Mapped Spermatogenic failure, X-linked 1 XL 305700 SPGFX1 305700
▲ Close

▼ TEXT

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).

▼ Description

In 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 Genetics

Johnson 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.


▼ History

The Sertoli cell-only syndrome was first described by Del Castillo et al. (1947).


▼ REFERENCES

  1. Brown, G. M., Furlong, R. A., Sargent, C. A., Erickson, R. P., Longepied, G., Mitchell, M., Jones, M. H., Hargreave, T. B., Cooke, H. J., Affara, N. A. 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. Molec. Genet. 7: 97-107, 1998. [PubMed: 9384609, related citations] [Full Text]

  2. Del Castillo, E. B., Trabucco, A., De La Balze, F. A. Syndrome produced by absence of the germinal epithelium without impairment of the Sertoli or Leydig cells. J. Clin. Endocr. 7: 493-502, 1947. [PubMed: 20260948, related citations] [Full Text]

  3. Ferlin, A., Moro, E., Rossi, A., Dallapiccola, B., Foresta, C. The human Y chromosome's azoospermia factor b (AZFb) region: sequence, structure, and deletion analysis in infertile men. J. Med. Genet. 40: 18-24, 2003. [PubMed: 12525536, related citations] [Full Text]

  4. Foresta, C., Bettella, A., Moro, E., Roverato, A., Merico, M., Ferlin, A. Sertoli cell function in infertile patients with and without microdeletions of the azoospermia factors on the Y chromosome long arm. J. Clin. Endocr. Metab. 86: 2414-2419, 2001. [PubMed: 11397833, related citations] [Full Text]

  5. Foresta, C., Ferlin, A., Garolla, A., Moro, E., Pistorello, M., Barbaux, S., Rossato, M. High frequency of well-defined Y-chromosome deletions in idiopathic Sertoli cell-only syndrome. Hum. Reprod. 13: 302-307, 1998. [PubMed: 9557827, related citations] [Full Text]

  6. Foresta, C., Ferlin, A., Moro, E. Deletion and expression analysis of AZFa genes on the human Y chromosome revealed a major role for DBY in male infertility. Hum. Molec. Genet. 9: 1161-1169, 2000. [PubMed: 10767340, related citations] [Full Text]

  7. Frydelund-Larsen, L., Krausz, C., Leffers, H., Andersson, A. M., Carlsen, E., Bangsboell, S., McElreavey, K., Skakkebaek, N. E., Rajpert-De Meyts, E. Inhibin B: a marker for the functional state of the seminiferous epithelium in patients with azoospermia factor c microdeletions. J. Clin. Endocr. Metab. 87: 5618-5624, 2002. [PubMed: 12466362, related citations] [Full Text]

  8. Johnson, M. D., Tho, S. P. T., Behzadian, A., McDonough, P. G. Molecular scanning of Yq11 (interval 6) in men with Sertoli-cell-only syndrome. Am. J. Obstet. Gynec. 161: 1732-1737, 1989. [PubMed: 2603934, related citations] [Full Text]

  9. Kamp, C., Hirschmann, P., Voss, H., Huellen, K., Vogt, P. H. Two long homologous retroviral sequence blocks in proximal Yq11 cause AZFa microdeletions as a result of intrachromosomal recombination events. Hum. Molec. Genet. 9: 2563-2572, 2000. [PubMed: 11030762, related citations] [Full Text]

  10. Kamp, C., Huellen, K., Fernandes, S., Sousa, M., Schlegel, P. N., Mielnik, A., Kleiman, S., Yavetz, H., Krause, W., Kupker, W., Johannisson, R., Schulze, W., Weidner, W., Barros, A., Vogt, P. H. High deletion frequency of the complete AZFa sequence in men with Sertoli-cell-only syndrome. Molec. Hum. Reprod. 7: 987-994, 2001. [PubMed: 11574668, related citations] [Full Text]

  11. Luddi, A., Margollicci, M., Gambera, L., Serafini, F., Cioni, M., De Leo, V., Balestri, P., Piomboni, P. Spermatogenesis in a man with complete deletion of USP9Y. New Eng. J. Med. 360: 881-885, 2009. [PubMed: 19246359, related citations] [Full Text]

  12. Moro, E., Ferlin, A., Yen, P. H., Franchi, P. G., Palka, G., Foresta, C. Male infertility caused by a de novo partial deletion of the DAZ cluster on the Y chromosome. J. Clin. Endocr. Metab. 85: 4069-4073, 2000. [PubMed: 11095434, related citations] [Full Text]

  13. 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. The critical region of overlap defining the AZFa male infertility interval of proximal Yq contains three transcribed sequences. J. Med. Genet. 36: 670-677, 1999. [PubMed: 10507722, related citations]

  14. Sun, C., Skaletsky, H., Birren, B., Devon, K., Tang, Z., Silber, S., Oates, R., Page, D. C. An azoospermic man with a de novo point mutation in the Y-chromosomal gene USP9Y. Nature Genet. 23: 429-432, 1999. [PubMed: 10581029, related citations] [Full Text]

  15. Vogt, P. H., Edelmann, A., Kirsch, S., Henegariu, O., Hirschmann, P., Kiesewetter, F., Kohn, F. M., Schill, W. B., Farah, S., Ramos, C., Hartmann, M., Hartschuh, W., Meschede, D., Behre, H. M., Castel, A., Nieschlag, E., Weidner, W., Grone, H.-J., Jung, A., Engel, W., Haidl, G. Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum. Molec. Genet. 5: 933-943, 1996. [PubMed: 8817327, related citations] [Full Text]


Contributors:
Marla J. F. O'Neill - updated : 5/11/2011
Marla J. F. O'Neill - updated : 3/3/2009
Marla J. F. O'Neill - updated : 6/29/2007
Marla J. F. O'Neill - updated : 1/14/2005
Creation Date:
Marla J. F. O'Neill : 12/10/2004
Edit History:
carol : 06/02/2022
terry : 12/09/2011
carol : 5/11/2011
alopez : 3/4/2009
terry : 3/3/2009
carol : 6/29/2007
carol : 2/10/2005
terry : 1/14/2005
carol : 12/14/2004
carol : 12/14/2004
carol : 12/10/2004
carol : 12/10/2004

# 400042

SPERMATOGENIC FAILURE, Y-LINKED, 1; SPGFY1


Alternative titles; symbols

SERTOLI CELL-ONLY SYNDROME, Y-LINKED
SERTOLI CELL-ONLY SYNDROME, TYPE I


Other entities represented in this entry:

SERTOLI CELL-ONLY SYNDROME, TYPE II, INCLUDED
HYPOSPERMATOGENESIS, INCLUDED
INCOMPLETE SERTOLI CELL-ONLY SYNDROME, INCLUDED

ORPHA: 1646;   DO: 0070186;  


Cytogenetic location: Yq11     Genomic coordinates (GRCh38): Y:10,400,001-26,600,000


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number 		Inheritance Phenotype
mapping key
Yq11 Spermatogenic failure, Y-linked, 1 400042 Y-linked 4

TEXT

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).

Description

In 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 Genetics

Johnson 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.


History

The Sertoli cell-only syndrome was first described by Del Castillo et al. (1947).


REFERENCES

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  2. Del Castillo, E. B., Trabucco, A., De La Balze, F. A. Syndrome produced by absence of the germinal epithelium without impairment of the Sertoli or Leydig cells. J. Clin. Endocr. 7: 493-502, 1947. [PubMed: 20260948] [Full Text: https://doi.org/10.1210/jcem-7-7-493]

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  8. Johnson, M. D., Tho, S. P. T., Behzadian, A., McDonough, P. G. Molecular scanning of Yq11 (interval 6) in men with Sertoli-cell-only syndrome. Am. J. Obstet. Gynec. 161: 1732-1737, 1989. [PubMed: 2603934] [Full Text: https://doi.org/10.1016/0002-9378(89)90959-9]

  9. Kamp, C., Hirschmann, P., Voss, H., Huellen, K., Vogt, P. H. Two long homologous retroviral sequence blocks in proximal Yq11 cause AZFa microdeletions as a result of intrachromosomal recombination events. Hum. Molec. Genet. 9: 2563-2572, 2000. [PubMed: 11030762] [Full Text: https://doi.org/10.1093/hmg/9.17.2563]

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Contributors:
Marla J. F. O'Neill - updated : 5/11/2011
Marla J. F. O'Neill - updated : 3/3/2009
Marla J. F. O'Neill - updated : 6/29/2007
Marla J. F. O'Neill - updated : 1/14/2005

Creation Date:
Marla J. F. O'Neill : 12/10/2004

Edit History:
carol : 06/02/2022
terry : 12/09/2011
carol : 5/11/2011
alopez : 3/4/2009
terry : 3/3/2009
carol : 6/29/2007
carol : 2/10/2005
terry : 1/14/2005
carol : 12/14/2004
carol : 12/14/2004
carol : 12/10/2004
carol : 12/10/2004



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OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2024 Johns Hopkins University.

NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2024 Johns Hopkins University.
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