The association of abnormal spermatogenesis in men with Y chromosome deletions suggests that genes important for spermatogenesis have been removed from these individuals. Recently, genes encoding two putative RNAbinding proteins (RBM and DAZ͞SPGY) have been mapped to two different regions of the human Y chromosome. Both of these genes encode proteins that contain a single RNA recognition motif and a (different) internally repeating sequence. Y-linked RBM homologues are found in all mammalian species. We have raised an antiserum to RBM and used it to show that RBM is a nuclear protein expressed in fetal, prepubertal, and adult male germ cells. The distribution of RBM protein in the adult correlates with the pattern of transcriptional activity in spermatogenesis, suggesting that RBM is involved in the nuclear metabolism of newly synthesized RNA. RBM sequences are found on both arms of the Y chromosome making genotype-phenotype correlations difficult for this gene family. To address the location of the functional genes and the consequences of their deletion, we examined a panel of men with Y chromosome deletions and known testicular pathologies using this antiserum. This approach enabled us to map a region of the Y chromosome essential for RBM expression. In the absence of detectable RBM expression we see stages of germ cell development up to early meiosis, but not past this point into the haploid phase of spermatogenesis.
The ability of human spermatozoa to exhibit sperm-oocyte fusion in response to the ionophore, A23187, was examined in relation to the capacity of these cells to generate reactive oxygen species. In 70 fertile control donors, there was an overwhelming pattern of high levels of sperm-oocyte fusion associated with low levels of reactive oxygen species production. By contrast, 88% of the 74 oligozoospermic patients exhibited less than 25% oocyte penetration in response to A23187 and 58% exhibited no penetration whatsoever. Of the 40 oligozoospermic patients who failed to respond to A23187, nine had low levels of reactive oxygen species production in association with impaired liquefaction of seminal plasma. Of the remainder, 17 (55%) exhibited defective sperm function together with elevated production of reactive oxygen species. These observations, which are the first to describe a biochemical defect in the spermatozoa of oligozoospermic patients, may carry significant implications for the etiology and treatment of this condition.
SUMMARYNumerous reports have ascribed immunosuppressive activity to human seminal plasma and there is growing agreement ihat much of this activity can be accounted for by the very high levels of E series prostaglandins present (up to 300 /iM 19-hydroxy prostaglandin E). However not all suppressive activity is due to prostaglandin since several reports have appeared of high molecular weight active substances and we have found that stripped seminal plasma is slill effective in inhibiting the mitogeninduced proliferation of lymphocytes. In this sludy such immunosuppressive activity has been separated by molecular size I'ractionation and the activity has been lound to be particulate and corresponded to the previously reported prostascmes. These are trilaminar to multilaminar vesicles (150 nm diameter) which are secreted by the prostate. Pure preparations of proslasomes inhibited mitogen-induccd lymphoproliferation in a dose-dependont manner with a concentration of prostasomes equivalent to 4{Y'A< of thai seen in seminal fluid giving 69'y,, suppression of thymidine incorporation. The suppressive activity survived boiling and therefore was unlikely ui be due to enzymatic action associated with these organelles. Interaction with Ihe accessory cells, involved in full development ofthe lymphoproliferation induced by mitogen, was indicated and ihis possibility was supported by lhe demonstration ofa direcl effect of prostasomes on macrophage function using a mouse macrophage cell line. The proslasomes in semen may play a complementary role to the prostaglandins in neutralizing the immune defences of the female reproductive tract. This combination would allow the alloantigenie spermatozoa the best chance of achieving fertilization, but at Ihc same time leave the recipient open to any infeetion present in the semen.
DFFRY (the Y-linked homologue of the DFFRX Drosophila fat-facets related X gene) maps to proximal Yq11.2 within the interval defining the AZFa spermatogenic phenotype. The complete coding region of DFFRY has been sequenced and shows 89% identity to the X-linked gene at the nucleotide level. In common with DFFRX , the potential amino acid sequence contains the conserved Cys and His domains characteristic of ubiquitin C-terminal hydrolases. The human DFFRY mRNA is expressed in a wide range of adult and embryonic tissues, including testis, whereas the homologous mouse Dffry gene is expressed specifically in the testis. Analysis of three azoospermic male patients has shown that DFFRY is deleted from the Y chromosome in these individuals. Two patients have a testicular phenotype which resembles Sertoli cell-only syndrome, and the third diminished spermatogenesis. In all three patients, the deletions extend from close to the 3' end into the gene, removing the entire coding sequence of DFFRY. The mouse Dffry gene maps to the Sxrb deletion interval on the short arm of the mouse Y chromosome and its expression in mouse testis can first be detected between 7.5 and 10.5 days after birth when type A and B spermatogonia and pre-leptotene and leptotene spermatocytes are present.
Alfuzosin (10 mg) once daily significantly improved the rate of successful TWOC in patients with AUR related to BPH, even in elderly patients and those with a large drained volume who were at increased risk for TWOC failure. This should contribute to decrease the morbidity and mortality associated with emergency surgery and avoid the discomfort and potential morbidity associated with an in situ catheter.
For males with idiopathic sterility, a molecular screen specific for small lesions (microdeletions) in interval 6 of the Y chromosome was set up using 29 Y-DNA probes. A "de novo" microdeletion in Y interval 6 was detected in 2 out of 19 "chromosomally normal" sterile males. The first microdeletion includes the Y-DNA probes pY6HP35 and 12f3; the second microdeletion includes the Y-DNA probes pY6HP52, 49f, FR15-II and the subinterval "C" of probe 50f2. A probe of the pY6H sequence family is present in both deletions. Sequences of this family cross-hybridize to dhMiF1, a DNA sequence of a fertility gene structure on the Y chromosome of Drosophila hydei. It was possible to map the position of the Y-deletion of one patient to the distal part of Yq11.22 or the proximal part of Yq11.23, and the deletion of the second patient to the distal part of Yq11.23. These microdeletions probably do not overlap. Since AZF, a human spermatogenesis gene, has been mapped to Y interval 6, we postulate that the microdeletions detected in this chromosome region affect the functional DNA structure of the AZF gene. If this holds true, it is possible that the AZF locus, cytogenetically mapped to distal Yq11, contains two spermatogenesis genes (AZFa and AZFb) or a large gene structure comparable to the Y fertility genes of Drosophila.
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