Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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A constitutional de-novo deletion of the long arm of the Y chromosome was detected by standard cytogenetic analysis in a 38-year old male who, except for small testes and cryptozoospermia, was phenotypically normal. The deletion was further characterized by fluorescent in-situ hybridization (FISH) and digital image analysis using contigs of overlapping yeast artificial chromosome (YAC) clones, spanning almost the entire Y chromosome. These results showed that the deletion involved a large interstitial segment on the proximal long arm of the Y chromosome (Yq11.1-->Yq11.22) as well as a more distal portion of the Y chromosome, including the entire heterochromatic region (Yq11.23-->qter). The breakpoints as determined by the YAC probes were defined within the published Vergnaud intervals so that region 6B and 6C was mostly retained. However, the AZFc region harbouring the DAZ locus on distal subinterval 6F was lost in the deletion, making the absence of this region the most probable location for the patient's infertility. The data underline the usefulness of FISH as an alternative technique to conventional banding for the refined detection of chromosome Y deletions/rearrangements.
Mol Hum Reprod 1998 Apr
PMID:Interstitial and terminal deletion of chromosome Y in a male individual with cryptozoospermia. 962 Aug 31

ABSTRACT Antisperm antibodies (ASAs) have been implicated in some instances of infertility. To characterize sperm antigens relevant to immunologic and immunocontraceptive development, SPAG2 (sperm-associated antigen 2) was identified by screening a human testis cDNA library with human sera positive for ASAs. Subsequently, two isoforms, SPAG2-1 and SPAG2-2, were identified in testis and placenta libraries, respectively. In the current study, Southern analysis of human genomic DNA with a probe common to the two SPAG2 isoforms indicated a single SPAG2 gene; therefore, alternative splicing is a likely mechanism for production of variant mRNAs. In situ hybridization of human testis sections demonstrated the expression of SPAG2 in primary spermatocytes, with decreased or arrested expression in postmeiotic cells. Immunofluorescence of Triton X-100-extracted spermatozoa with an anti-SPAG2 peptide antiserum indicate that SPAG2 is an intracellular component of the sperm flagellum. Electron microscopy refined this localization to the outer dense fibers (ODFs), structural filaments associated with the mammalian sperm axoneme. The ODFs have been reported to be composed of keratin-like intermediate filament proteins. However, SPAG2 does not exhibit the molecular characteristics of such proteins, nor does SPAG2 demonstrate sequence homology with previously characterized ODF proteins. Therefore, SPAG2 represents a novel protein of human sperm ODFs. Characterization of SPAG2 will further our understanding of ODF function in normal sperm motility and of flagellar abnormalities that lead to male infertility.
Mol Reprod Dev 1998 Jul
PMID:Expression of the human antigen SPAG2 in the testis and localization to the outer dense fibers in spermatozoa. 962 4

A case is reported in which a high fertilization rate was achieved by conventional in-vitro fertilization (IVF), using spermatozoa from an oligozoospermic man carrying a microdeletion of the long arm of the Y chromosome. The patient presented with idiopathic infertility of 10 years duration; the fertility status of his wife was completely normal. After IVF, five out of eight oocytes retrieved showed normal fertilization and four showed normal embryo cleavage. Four embryos were transferred; however, pregnancy did not result. These results demonstrate that spermatozoa from oligozoospermic patients carrying a Yq microdeletion are fully competent in achieving capacitation, acrosome reaction and fertilizing ability during IVF. Therefore, although definitive conclusions cannot be made from a single case report, we suggest that Yq microdeletion analysis should be considered in oligozoospermic patients undergoing conventional IVF.
Mol Hum Reprod 1998 May
PMID:Case report: high fertilization rate in conventional in-vitro fertilization utilizing spermatozoa from an oligozoospermic subject presenting microdeletions of the Y chromosome long arm. 966 33

Endometrium is one of the main target tissues of oestrogens. Although homozygous inactivation of oestrogen receptor-alpha leads to infertility in transgenic mice, oestrogen receptor-alpha is detected in endometrium of patients with unexplained infertility. Oestrogen receptor-alpha splicing variants and oestrogen receptor-beta have been studied in oestrogen target tissues, but their expression in endometrium throughout the menstrual cycle and in unexplained infertility is unknown. Using reverse transcription-polymerase chain reaction (RT-PCR), we studied the expression of oestrogen receptor-alpha splicing variants and oestrogen receptor-beta in uterine biopsies from 12 patients with endometriosis and 15 patients with unexplained infertility. A control group included 19 women who had had a previous pregnancy. Our study gave evidence of exon 2, 3, 4 or 7 deleted oestrogen receptor-alpha variants co-existing with the wild-type receptor. We did not find any exon 5 or 6-deleted variants. Exon 4 or 7-deleted variants were detected in all samples. Exon 2 or 3-deleted variants were detected at a similar frequency in fertile women (58 and 68% respectively), endometriotic patients (67 and 83% respectively) and infertile patients (73 and 80% respectively). During the follicular phase, there was a non-significant trend towards a lower frequency of exon-2 deleted variants in the fertile group when compared with the hypofertile group. Oestrogen receptor-beta was detected in all samples. Our preliminary study showed that altered expression of oestrogen receptor-alpha variants and oestrogen receptor-beta may not explain the hypofertility state.
Mol Hum Reprod 1998 Jul
PMID:Expression of oestrogen receptor-alpha splicing variants and oestrogen receptor-beta in endometrium of infertile patients. 970 86

Sperm motility is one of the major determinants of male fertility and is required for successful fertilization. In a previous study, we demonstrated that the occurrence and accumulation of the 4977 bp deletion of mitochondrial DNA (mtDNA) is associated with diminished fertility and motility of human spermatozoa. The possible relationship between multiple deletions of mtDNA and the decline of fertility and motility in human spermatozoa was further explored in 36 subjects including subfertile and infertile males in this study. Using long-range polymerase chain reaction (PCR), we confirmed the 4977 bp deletion and identified two novel deletions of 7345 and 7599 bp of mtDNA in the spermatozoa with poor motility. We used Percoll gradients to fractionate spermatozoa with differing motility, and then screened for two novel large-scale deletions of the mtDNA. The results showed that the ratio of the deleted mtDNA in the spermatozoa with poor motility and diminished fertility were significantly higher than those in the spermatozoa with good motility and fertility. In addition, we found that the frequencies of the three large-scale deletions in the spermatozoa from patients with primary infertility and oligoasthenozoospermia were higher than those of the fertile males. Our findings suggest that mtDNA deletions may play an important role in some pathophysiological conditions of human spermatozoa.
Mol Hum Reprod 1998 Jul
PMID:Multiple deletions of mitochondrial DNA are associated with the decline of motility and fertility of human spermatozoa. 970 88

Human chromosome deletions in Yq11 seem to occur frequently as de novo mutation events in men with idiopathic azoospermia or severe oligozoospermia. However, the molecular extensions of these deletions are variable. They can be large and therefore visible under the microscope or small, not visible under the microscope, and containing the deletion of one or more DNA loci recently mapped in an apparently consecutive order along the Yq11 chromosome region. The results of 20 extensive microdeletion screening programmes have now corroborated the prevalence of the deletion of three non-overlapping DNA regions in proximal, middle and distal Yq11, which were designated earlier as AZFa, AZFb and AZFc. Deletions of single DNA loci were also reported, but as de novo and as polymorphic mutation events. Their clinical significance with regard to the men's infertility should therefore initially be handled with caution. Multiple Y genes expressed in human testis have now been mapped to each AZF region. At least one of them should be functional in human spermatogenesis and, if mutated, cause azoospermia. However, gene-specific mutations leading to the azoospermia phenotype have not yet been found for any of these AZF candidate genes. This might raise the question as to whether an AZF gene really exists in Yq11 or if the azoospermia phenotypes are only observed after deletion of a complete AZF region, after deletion of its complete gene content.
Mol Hum Reprod 1998 Aug
PMID:Human chromosome deletions in Yq11, AZF candidate genes and male infertility: history and update. 973 30

A cDNA encoding for a sperm antigen, designated NZ-2, was cloned and sequenced from human testis cDNA-lambda gt11 expression library by using antibodies to human sperm surface antigens belonging to 14-18 kD molecular regions. These sperm antigens are involved in binding to zona pellucida of the human oocyte. Computer generated translation analysis of 963-bp cDNA yielded an open reading frame (ORF) of 163 amino acids (aa) with first ATG, Met start codon at nucleotide (nt) 335 and the stop codon TAA at nt 824. The NZ-2 cDNA has 335-bp 5' and 139-bp 3' noncoding regions. The translated protein has a calculated molecular weight of approximately 19 kD, and has two casein kinase II (CK-2) sites at aa 94-97 and 149-152, respectively. Extensive computer search in the GenBank, National Biomedical Research Foundation (NBRF), and Swiss database indicates it to be a novel protein, having 99.5% nt sequence similarity, except for the first 40-bp, only with the human bacterial artificial chromosome (BAC) containing cloned human sperm DNA, at position 76935-76009. The in vitro translated product of T3 RNA polymerase by using NZ-2 cDNA digested with XhoI yielded a protein band of approximately 20 kD, indicating it to be sense strand. The in vitro translated product of T7 RNA polymerase by using NZ-2 cDNA digested with NotI did not yield any protein band, indicating it to be antisense strand. The approximately 20 kD protein was recognized specifically by the antisperm IgG, not by the control IgG in the Western blot procedure. Neither antisperm IgG nor control IgG recognized any protein band in the in vitro translation products of the antisense strand. The human genomic DNAs from three different cells/tissues namely, sperm, kidney, and testis when cut by HindIII, and then hybridized with the NZ-2 cDNA probe in the Southern blot procedure, showed restriction fragment length polymorphism (RFLP). The recombinant human sperm NZ-2 antigen may find applications in the development of a contraceptive vaccine, and diagnosis and treatment of infertility in humans.
Mol Reprod Dev 1998 Oct
PMID:Cloning and sequencing of cDNA encoding for a human sperm antigen involved in fertilization. 974 Mar 25

Targeted disruption of cpg-1, a gene encoding the G protein Gi alpha subunit, CPG-1, in the chestnut blight fungus, Cryphonectria parasitica, results in reduced mycelial growth, reduced orange pigmentation, loss of virulence, loss of asexual sporulation, and female infertility. We report the development of a complementation system for cpg-1 null mutants and its use to evaluate the in vivo consequences of mutating conserved putative CPG-1 myristoylation (G2) and palmitoylation (C3) sites. Independent mutations of the two putative acylation sites differentially altered complex fungal biological processes, including virulence, and modified CPG-1 membrane association. Results of combined Northern (RNA) and Western (immunoblot) analysis also indicated a role for lipid modification in post-transcriptional regulation of CPG-1 accumulation.
Mol Plant Microbe Interact 1998 Nov
PMID:Mutagenesis of putative acylation sites alters function, localization, and accumulation of a Gi alpha subunit of the chestnut blight fungus Cryphonectria parasitica. 980

Various endocrine and neuronal functions are governed by the cAMP-dependent signaling pathway. In eukaryotes, transcriptional regulation upon stimulation of the adenylyl cyclase signaling pathway is mediated by a family of cAMP-responsive nuclear factors. This family consists of a large number of members which may act as activators or repressors. These factors contain the basic domain/leucine zipper motifs and bind as dimers to cAMP-response elements (CRE). The function of CRE-binding proteins (CREBs) is modulated by phosphorylation by several kinases. Direct activation of gene expression by CREBs requires phosphorylation by the cAMP-dependent protein kinase A to the serine-133 residue. The gene CREM encodes various transcription factors which play key physiological and developmental roles within the hypothalamic-pituitary-gonadal axis. We have previously shown that the transcriptional activator CREMtau is highly expressed in postmeiotic cells. Spermiogenesis is a complex process by which postmeiotic male germ cells differentiate into mature spermatozoa. This process involves remarkable structural and biochemical changes which are under the hormonal control of the hypothalamic-pituitary axis. We have addressed the specific role of CREM in spermiogenesis using CREM-mutant mice generated by homologous recombination. Analysis of the seminiferous epithelium from mutant male mice reveals that spermatogenesis stops at the first step of spermiogenesis. Late spermatids are completely absent while there is a significant increase in apoptotic germ cells. A series of postmeiotic germ cell-specific genes are not expressed. Mutant male mice completely lack spermatozoa. This phenotype is reminiscent of cases of human infertility.
J Mol Med (Berl)
PMID:Regulating the balance between differentiation and apoptosis: role of CREM in the male germ cells. 984 51

The biosynthesis of estrogens is catalyzed by an enzyme known as aromatase (aromatase cytochrome P450; P450 arom; the product of the CYP19 gene). In recent years a number of patients have been described suffering from aromatase deficiency due to mutations in the CYP19 gene, resulting in the synthesis of a non-functional gene product and a resulting failure to synthesize estrogens. Males with this condition have sustained linear growth into adulthood resulting from failure of epiphyseal closure. Osteopenia and reduced bone mineral density and bone age are also characteristic. Lack of circulating estrogens is accompanied by elevated testosterone and gonadotropins. One of the men had macroorchidism with testicular volumes in excess of 25 ml (Morishima et al. J. Clin. Endocrinol. Metab. 80, 3689, 1995). Semen analysis was not performed on this patient, but it is of note that the one patient described with estrogen insensitivity due to a mutation in the estrogen receptor had a normal sperm count, although motility was decreased (Smith et al., New England J. Med. 331. 1056, 1994). By contrast, the other man with aromatase deficiency had testicular volumes of only 8 ml per testes, and was infertile. Sperm analysis revealed a count of 1 million/ml with 100% immotile sperm (Carani et al. New England J. Med. 337, 91, 1997). However, his clinical picture is confused by the fact that another male sibling has azoospermia, but has no CYP19 mutation, suggesting that the infertility problem may be due to a second genetic condition in this consanguineous family. Recently mice have been generated in which the aromatase (CYP19) gene and the gene encoding the estrogen receptor-alpha have been inactivated by targeted disruption (ArKO and ERKO mice, respectively). Male ERKO mice are infertile with atrophy of the testes and seminiferous tubule dysmorphogenesis resulting in decreased spermatogenesis and inacive sperm. By contrast the ArKO mice are initially fertile and sire litters of normal size ad frequency, however with advancing age the number of litters sired decreases relative to those of wild type litter ates. In contrast to the ERKO mice, light microscopic analysis of the testes of the ArKO mice reveals no gross morphological abnormalties and the testes are of normal size. Following recent observations that the estrogen receptor-beta isoform is highly expressed in seminiferous epthelium, spermatids and spermatocytes, it is conceivable that the relatively high levels of estrogens present in the ERKO mice can act through the ER-beta to cause infertility by a direct action on the testes. In this context it is well known that administration of high levels of estrogen to men results in infertility. It is apparent that studies of human and mouse models with disruptions of aromatase and the estrogen receptor have as yet failed to clarify the role of estrogens in male fertility and testicular function. Development of an ER-beta knockout mouse, or else a double, or even triple, knockout model, may be required in order to resolve these issues.
Mol Cell Endocrinol 1998 Oct 25
PMID:Genetic mutations resulting in estrogen insufficiency in the male. 992 99


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