Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The androgen receptor (AR) is a ligand-dependent X-linked nuclear transcription factor regulating male sexual development and spermatogenesis. The receptor is activated when androgen binds to the C-terminal ligand-binding domain (LBD), triggering a cascade of molecular events, including interactions between the LBD and the N-terminal transactivation domain (TAD), and the recruitment of transcriptional coactivators. A nonconservative asparagine to lysine substitution in AR residue 727 was encountered in a phenotypically normal man with subfertility and depressed spermatogenesis. This N727K mutation, although located in the LBD, did not alter any ligand-binding characteristic of the AR in the patient's fibroblasts or when expressed in heterologous cells. Nonetheless, the mutant AR displayed only half of wild-type transactivation capacity when exposed to physiological or synthetic androgens. This transactivation defect was consistently present when examined with two different reporter systems in three cell lines, using three androgen-driven promoters (including the complex human prostate-specific antigen promoter), confirming the pathogenicity of the mutation. In mammalian two-hybrid assays, N727K disrupted LBD interactions with the AR TAD and with the coactivator, transcription intermediary factor 2 (TIF2). Strikingly, the transactivation defect of the mutant AR can be rectified in vitro with mesterolone, consistent with the ability of this androgen analog to restore sperm production in vivo. Mesterolone, but not the physiological androgen dihydrotestosterone, restored mutant LBD interactions with the TAD and with TIF2, when expressed as fusion proteins in the two-hybrid assay. Our data support an emerging paradigm with respect to AR mutations in the LBD and male infertility: pathogenicity is transmitted through reduced interdomain and coactivator interactions, and androgen analogs that are corrective in vitro may indicate hormonal therapy.
Mol Endocrinol 2000 Aug
PMID:Human androgen receptor mutation disrupts ternary interactions between ligand, receptor domains, and the coactivator TIF2 (transcription intermediary factor 2). 1093 43

Lack of data on the genotype-phenotype relationship in cases of AZF microdeletions is due to the limited number of histological investigations in human male infertility cases. We investigated the possibility of retrospective detection of Yq11 microdeletions by using DNA extracted from diagnostic testicular biopsies. We used histological criteria to select two series of material: 22 biopsies with Sertoli cell-only syndrome and 14 biopsies with maturation arrest at the spermatocyte I stage. Two markers, DFFRY and DAZ, were tested by nested polymerase chain reaction (PCR) in the two series. In the Sertoli cell-only syndrome series, we found four deletions affecting the DFFRY gene (18.2%). In the second series, no deletions were detected. Two conclusions may be considered, although the number of specimens analysed is limited: (i) the frequency of deletions observed in Sertoli cell-only syndrome allows us to suggest that deletion in the AZFa region may be involved in this pathology; and (ii) retrospective studies may yield some additional elements in our search for eventual genotype-phenotype relationships.
Mol Hum Reprod 2000 Sep
PMID:AZFa deletions in Sertoli cell-only syndrome: a retrospective study. 1142 Mar 93

The androgen receptor (AR) gene is located on the X chromosome and contains a polymorphic CAG tract. CAG repeat expansions in the AR have been associated with male infertility and the neuromuscular disease, spinal bulbar muscular atrophy (SBMA). Based on Mendelian inheritance patterns, moderate CAG expansions in infertile men treated by intracytoplasmic sperm injection (ICSI) would be vertically transmitted to female offspring. Should further elongation of the repeat region occur in the male germline, it is conceivable that longer expansions could also be transmitted by ICSI and may lead to an increased incidence of male infertility and SBMA in succeeding generations. To determine the degree of stability of the paternal AR CAG tract following ICSI, we compared the CAG repeat number in the AR alleles of 92 men presenting for ICSI and their 99 ICSI-conceived daughters. CAG repeat lengths in the AR alleles were determined by fluorescent polymerase chain reaction and Genescan analysis of amplification products separated on DNA sequencing gels. In the vast majority of cases (95 out of 99), we found that the AR CAG tracts ranging in size from 15-28 repeats exhibited stable inheritance in female offspring. However, in the remaining father-daughter pairs, there was a discordance in the expected inheritance pattern with evidence for both CAG expansion (20-->24; 22-->23) and contraction (26-->18 or 22) of the paternal AR allele. The detection of a low frequency of CAG mutation in paternal AR alleles following ICSI would be consistent with gonadal mosaicism originating from meiotic DNA replication errors. These findings in a typical group of infertile men undergoing ICSI for a variety of indications tend to alleviate concerns that ICSI may promote the transmission of AR alleles with expanded CAG tracts and suggest that the risk of SBMA in second generation sons would be extremely low.
Mol Hum Reprod 2000 Sep
PMID:CAG trinucleotide repeats in the androgen receptor gene of infertile men exhibit stable inheritance in female offspring conceived after ICSI. 1095 60

Many studies have shown that congenital absence of the vas deferens (CAVD) is a genital cystic fibrosis transmembrane conductance regulator (CFTR)-mediated phenotype, with a broad spectrum of abnormalities causing male infertility. The genotype of these patients includes mutations in the CFTR gene, e.g. DeltaDeltaF508, R117H and the T5 allele; all of which are commonly found in CAVD. In this study we have screened the entirety of CFTR gene in 47 males with anomalies of the vas deferens: 37 cases of congenital bilateral absence of the vas deferens, three cases of congenital unilateral absence of the vas deferens and seven cases of obstructive azoospermia with hypoplastic vas deferens. Among the 94 chromosomes studied, 65 mutations, of which three are novel (2789+2insA, L1227S, 4428insGA), were identified. The majority of patients (63.8%) had two detectable CFTR gene mutations. Furthermore, high frequencies of the DeltaDeltaF508 mutation (44.7%), the T5 allele (36.2%) and R117H mutation (19.1%) were observed.
Mol Hum Reprod 2000 Dec
PMID:Molecular screening of the CFTR gene in men with anomalies of the vas deferens: identification of three novel mutations. 1110 88

Using an enzyme-linked immunosorbent assay (ELISA), sera (n = 15) and seminal plasma (n = 30) from antisperm antibody-positive immunoinfertile men (n = 45) and from fertile men (n = 45), were tested for the immunoreactivity with the synthetic YLP(12) sperm peptide. Of the 15 immunoinfertile sera tested, 46% were positive for immunoglobulin (Ig)M, 73% for IgG, and 40% for IgA. Of the 30 samples of immunoinfertile seminal plasma tested, 10% were positive for IgM, 20% for IgG, and 43% for IgA. None of the sera or seminal plasma from fertile men showed a positive reaction. There was no significant correlation between the sperm immobilization technique (SIT) or tray agglutination technique (TAT) titres or percentage binding in immunobead binding technique (IBT) and the antibody reactivity for any class in the ELISA. The YLP(12) peptide conjugated to bovine serum albumin-Sepharose 4B beads pulled out IgG antibodies from the serum of the immunoinfertile, but not the fertile, men. The beads pulled out IgA antibodies from the immunoinfertile, but not the fertile, seminal plasma. The immuno-affinity purified antipeptide antibodies reacted with a specific band of 72 +/- 5 kDa in the human testis and with a specific band of approximately 50 +/- 5 kDa in the human sperm extracts. The YLP(12) peptide may have applications in the specific diagnosis and treatment of male infertility and in contraceptive vaccine development.
Mol Hum Reprod 2001 Jan
PMID:Presence of antibodies to sperm YLP(12) synthetic peptide in sera and seminal plasma of immunoinfertile men. 1113 56

It is believed that one cause of sperm dysfunction might arise through multiple mitochondrial DNA deletions (Delta mtDNA) resulting in the formation of an incomplete electron transport chain. This study investigates the incidence of multiple Delta mtDNA in human spermatozoa prepared on Percoll gradients. Firstly, we investigated for the presence of two frequently analysed Delta mtDNA, the 4977 and 7.4 kb deletions, using conventional polymerase chain reaction (PCR). These two deletions are characteristically flanked by direct repeats. We further analysed the incidence of one other deletion, the 15 bp deletion in the cytochrome c oxidase subunit III (COX III) of complex IV to determine whether other deletions flanked by direct repeats could be equally predictive. The incidence of these three deletions was not clearly associated with the diagnostic categorization of male infertility. However, the use of long PCR showed that samples harbouring high numbers of Delta mtDNA were associated with the diagnostic categorization of male infertility. We propose that these deletions could arise through a free radical-driven event occurring at the spermatogonial cell stage resulting in the replication of Delta mtDNA molecules at the expense of wild-type molecules. These anomalies in ejaculated sperm mtDNA could account for reproductive failure in some men.
Mol Hum Reprod 2001 Jan
PMID:Men with oligoasthenoteratozoospermia harbour higher numbers of multiple mitochondrial DNA deletions in their spermatozoa, but individual deletions are not indicative of overall aetiology. 1113 67

In our program's 13 years of experience, more than 9000 embryos have been cryopreserved in gonadotropin-stimulated IVF cycles. Over 1500 thaw and transfer cycles have yielded a pregnancy rate of approximately 25%. Different ovarian stimulation regimens (various preparations of FSH. alone or in combination with hMG, with or without concomitant use of a GnRH agonist) did not influence embryo survival or pregnancy rate. Likewise, the application of oocyte/embryo micromanipulation techniques for assisted fertilization (ICSI for male infertility) or assisted hatching (performed selectively) did not have an impact on pregnancy results. Survival and transfer rates of embryos cryopreserved at pronuclear or cleaving stage did not differ significantly. However, implantation and pregnancy rates were higher with pronuclear embryo freezing (day-2 transfers) when compared to embryos frozen at the cleavage stage (day-3 transfers). This may be the result of patient selection and transfer policies. Similar implantation and pregnancy results were achieved in natural and estrogen progesterone supplemented transfer cycles. Initial experience with pronuclear freezing followed by transfer at the blastocyst stage appears to offer a very successful alternative for selected patients.
Mol Cell Endocrinol 2000 Nov 27
PMID:Impact of different clinical variables on pregnancy outcome following embryo cryopreservation. 1115 58

Intracytoplasmic sperm injection (ICSI) has been applied successfully in the treatment of male infertility in humans and in fertilization research in mice. However, the technique has had limited success in producing offspring in other species including the rabbit. The aim of this research was to test the in vitro and in vivo developmental of rabbit oocytes after ICSI. Sperm used for ICSI were collected from mature Dutch Belted buck and washed 2-3 times with PBS +0.1% polyvinyl alcohol (PVA) and then mixed with 10% polyvinyl pyrrolidone (PVP) prior to microinjection. Oocytes were collected from superovulated does 14-15 hr after hCG injection and were fertilized by microinjection of a single sperm into the ooplasm of each oocyte without additional activation treatment. After ICSI, the presumed zygotes were either cultured in KSOM +0.3% BSA for 4 days or transferred into oviducts of recipient does at the pronuclear or 2-cell stage. A high percentage of fertilization (78%, n = 114) and blastocyst development (39%) was obtained after ICSI. Control oocytes, receiving a sham injection, exhibited a lower activation rate (31%, n = 51) and were unable to develop to the blastocyst stage, suggesting that the blastocysts developed following ICSI were derived from successful fertilization rather than parthenogenetic development. A total of 113 embryos were transferred to six recipient does. Two recipients became pregnant and delivered seven live young. Our results demonstrated that rabbit oocytes can be successfully fertilized and activated by ICSI and can result in the birth of live offspring.
Mol Reprod Dev 2001 May
PMID:Full term development of rabbit oocytes fertilized by intracytoplasmic sperm injection. 1133 45

Impaired ciliary and flagellar functions resulting in male infertility and recurrent respiratory tract infections are found in patients suffering from primary ciliary dyskinesia (PCD). In most cases, axonemal defects are present, i.e. PCD patients often lack inner and/or outer dynein arms in their sperm tails and cilia, supporting the hypothesis that mutations in dynein genes may cause PCD. However, to date it is unclear whether mutations in dynein heavy chain genes are responsible for impaired flagellar and ciliary motility in mammals. To elucidate the role of the mouse dynein heavy chain 7 (MDHC7) gene, which encodes a component of the inner dynein arm, we have generated mice lacking this dynein heavy chain isoform. Both MDHC7(+/-) and MDHC7(-/-) mice are viable and show no malformations; however, homozygous males produce no offspring. In comparison to MDHC7(+/-) and wild-type mice the spermatozoa of MDHC7(-/-) mice revealed a dramatic reduced straight line velocity and progressive movement, resulting in the inability of MDHC7-deficient sperm to move from the uterus into the oviduct. Additionally, we measured the beat frequency of tracheal cilia and observed a decrease in the beat frequency of approximately 50% in MDHC7(-/-) mice. The reduction in both ciliary and flagellar motility is not correlated with any gross defects in the axonemal structure. The phenotype of MDHC7(-/-) mice is similar to that observed in some patients suffering from PCD, and our data strongly suggest that in some patients this disease could be due to mutations in the homologous human gene DNAH1 (HDHC7).
Hum Mol Genet 2001 May 15
PMID:Disruption of an inner arm dynein heavy chain gene results in asthenozoospermia and reduced ciliary beat frequency. 1137 5

It is believed that the transition proteins (Tnp1 and Tnp2) participate in the removal of the nucleohistones and in the initial condensation of the spermatid nucleus. Later in spermatogenesis, Tnp1 and Tnp2 are replaced by the protamines 1 and 2. In an effort to elucidate the physiological role of Tnp2, we have disrupted its locus by homologous recombination. Breeding of the Tnp2(-/-) males on different genetic backgrounds revealed normal fertility on the mixed background C57BL/6Jx129/Sv, but total infertility on the inbred 129/Sv background. Light and electron microscopy showed that the germ cells were capable of undergoing chromatin condensation, although many spermatozoa exhibited head abnormalities with acrosomes not attached to the nuclear envelope. Furthermore, migration of Tnp2(-/-) spermatozoa from the uterus into the oviduct was reduced. These results suggest that male infertility of the Tnp2(-/-) mice is a result of sperm head abnormalities and reduced sperm motility. The increased level of the Tnp1 transcript in testes of the Tnp2-deficient mice raises the possibility that a deficiency created through the disruption of the Tnp2 gene can be compensated for by recruitment of the Tnp1.
Mol Hum Reprod 2001 Jun
PMID:Teratozoospermia in mice lacking the transition protein 2 (Tnp2). 1138 7


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