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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twenty-eight X-linked, recessive mutations of Drosophila melanogaster conferring enhanced sensitivity to the monofunctional alkylating agent, methyl methanesulfonate, have been recoered and assigned to five complementation groups. These groups can be distinguished on the basis of map location and variations in the pattern of mutagen sensitivity. Allelism of members of one complementation group with the previously described meiotic mutant, mei-41, (Baker and Carpenter, 1972) as well as the frequent appearance of female infertility with mutagen sensitivity suggests associated defects in meiotic chromosome behavior or early embryogenesis. Examination of the mutagen sensitivity of double mutants has led to the formulation of a working model of DNA repair for this organism. Studies of a similar nature (Boyd et al., 1976) have identified five additional X chromosome complementation groups, suggesting that the genome of Drosophila melanogaster may contain many loci involved with mutagen sensitivity. The continued isolation and characterization of conditional mutants of this type promises future insights into the mechanisms of DNA replication, DNA repair and recombination in this complex higher eucaryote.
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PMID:Mutagen sensitivity of Drosophila melanogaster. III. X-linked loci governing sensitivity to methyl methanesulfonate. 18 78

Abnormal embryo development represents the major cause of implantation failures and accounts for the low rate of human infertility in vivo or in vitro. Chromosome abnormalities are widely involved in this process. Indeed, 28.4% of oocytes carry a chromosome aberration, i.e. 25.6% aneuploidy and 2.8% structural anomalies. Fertilisation abnormalities (possibly increased by in vitro procedures) were recorded: 7 to 28% of oocytes from fertilisation failure showed a sperm premature chromosome condensation probably resulting from ooplasmic immaturity. Moreover, 1.6% and 3.8% of inseminated oocytes had either a single or 3 pronuclei demonstrating parthenogenesis or triploidy, respectively. In vitro developmental capacities of embryos depends on the degree of ploidy. Parthenogenetic embryos display a fairly normal development until implantation. Triploid zygotes show an original way of division: half of them divide first into 3 cells and then into 6 cells (via a tripolar spindle) whereas diploid zygotes divide into 2 and then 4 cells. As a consequence of either meiotic or mitotic non disjunctions or fertilisation anomalies, 25 to 71% preimplantation embryos carry a chromosome disorder. As an outgrowth of in vitro fertilisation and embryo transfer, detection of genetic and metabolic defects prior to implantation might be possible in the future. So far, 6 girls have been born in couples at risk of transmitting X-linked disease. This technic will increase the efficiency of IVF and avoid the trauma of repeated abortions.
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PMID:Cytogenetic analysis of oocytes and embryos. 130 24

Recent advances in micromanipulation and biopsy of gametes and embryos have made it possible to develop new approaches for early genetic diagnosis and prevention of genetic disease and for treatment of severe male-factor infertility. Preimplantation diagnosis of a number of X-linked and autosomal recessive disorders has been performed, using polar body sampling and blastomere biopsy, coupled with polymerase chain reaction. Blastocyst biopsy has also been performed in human embryos; however, there has been no clinical application so far. Existing data have not shown any detrimental effect of micromanipulation and biopsy involved in the preimplantation development of the human embryo. The existing experience on micromanipulation of gametes (zona-opening procedures, subzonal sperm insertion, and sperm microinjection into the ooplasm) has also demonstrated the clinical usefulness in assisted fertilization, suggesting a possible selective application of various micromanipulation techniques and their combinations in male infertility.
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PMID:Micromanipulation of gametes and embryos in preimplantation genetic diagnosis and assisted fertilization. 139 44

A family is described in which gynecomastia and undervirilization in five men (four of whom have fathered children) were inherited in a manner compatible with an X-linked defect. Three members from whom blood could be obtained had supranormal serum testosterone and normal LH and FSH levels. One man had severe oligospermia with decreased motility, and one had normal sperm density and motility. In fibroblasts cultured from genital skin biopsies from two of the men, the levels of androgen receptor and affinity of binding of receptor to dihydrotestosterone were normal. However, androgen binding in fibroblast monolayers was thermolabile, up-regulation of receptor levels did not occur after prolonged incubation of monolayers with dihydrotestosterone or methyltrienolone, and dissociation rates at 37 C were increased with the synthetic androgen mibolerone. In addition, in cytosol preparations the androgen receptor protein was unstable. This disorder probably represents the most subtle functional abnormality of androgen receptor characterized to date, since it is compatible with normal male phenotypic development and in some affected men with fertility. It follows that infertility is not an invariable feature of androgen resistance as we previously suggested.
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PMID:A mutation of the androgen receptor associated with partial androgen resistance, familial gynecomastia, and fertility. 334 54

Despite the absence of phenotypic manifestations in alternating generations characteristic of X-linked disorders, a thesis is presented that a major type of Kinsey grades 5 and 6 male homosexuality is determined by a gene in the Xq28 region. A total of 133 families in 78 kinshps of male and female homosexual probands, in addition to 116 families (including those of 40 famous homosexuals) from the literature, revealed an unbalanced secondary sex ratio in the maternal generation of male, but not of female, homosexuals. On the maternal side, in this study, the ratio of all uncles to all aunts of 90 males homosexuals was 132/209, chi 2 = 8.52, p = 0.004. On the maternal side for the total of all sources, the ratio of uncles to aunts of male homosexuals was 241/367, chi 2 = 13.20; p < 0.0001. The male/female ratio of the total number of maternal sibships bearing homosexuals (310/628: 0.491) was a measure of fetal wastage of the mothers' male sibs; 49%. This ratio was very close to that of the total number of children born to fathers affected with any one of nine Xq28-linked male semilethal conditions (255/508: ratio 0.556); for the difference between the two populations chi 2 = 0.859, p = 0.354. The male/female ratio of the total number of children born to female carriers of any one of these same conditions (1,232/1,062: ratio 1.16), chi 2 = 13.8 p < or = 0.0001, is close to that of the total number of children in homosexual sibships: 511/413, chi 2 = 10.4, p = 0.005. Between the number of children born to Xq28 mothers and to those born of mothers of homosexuals chi 2 = 0.581, p = 0.446. One may readily surmise that the maternal influence so often related to homosexuality may lie in the mother being a genetic carrier, with traits thereto associated. In this study, 65% of the mothers of homosexuals had no or only one live-born brother. Additional support for a genetic hypothesis is found in the occurrence of multiple instances--almost exclusively among maternal relatives--of infertility, spontaneous abortions, miscarriages, stillbirths, remaining single past age 30, and suicide. Of 109 male and 43 female homosexual index cases in the present series there were 6 instances of brother/sister homosexual sibships.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Homosexuality, type 1: an Xq28 phenomenon. 779 4

Light- and electron-microscopic analyses of chromosomal pairing and recombination in F1 and first-backcross generation mice of the C57BL/6J x Mus spretus cross revealed a variety of meiotic irregularities that could contribute to meiocyte loss and infertility. Pachytene anomalies included univalency, partially paired bivalents, homolog-length inequalities, nonhomologous pairing, and associations of asynapsed autosomal segments with the X chromosome. These phenomena were most prevalent in F1 males, which are invariably sterile. Although F1 females were qualitatively fertile, breeding data indicated significant reproductive impairment. Molecular analyses of X-linked and pseudoautosomal loci in sterile and fertile backcross males revealed that the failure of X-Y pairing and recombination is correlated with heterozygosity within the pseudoautosomal regions of the X and Y chromosomes. In addition to impairing fertility, the synaptic disturbances (such as localized asynapsis and nonhomologous pairing) observed in F1 individuals can potentially alter recombinational patterns, thereby contributing to the genetic-map distortion observed with this interspecific cross. Together, the cytogenetic and reproductive data suggest that sex-related differences in the gametogenic process, quantitative differences in the incidence of synaptic irregularities in female and male meiosis, and phenomena associated with the X and Y chromosomes comprise the etiological basis of the sex-biased F1 sterility. The differential gender-related effects of these cytogenetic phenomena may constitute the underlying basis of Haldane's rule in mammals.
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PMID:Meiotic abnormalities in hybrid mice of the C57BL/6J x Mus spretus cross suggest a cytogenetic basis for Haldane's rule of hybrid sterility. 850 Mar 53

Genes on the long arm of Y (Yq), particularly within interval 6, are believed to play a critical role in human spermatogenesis. Cytogenetically detectable deletions of this region are associated with azoospermia in men, but are relatively uncommon. It has been hypothesized that microdeletions of Yq may account for a significant proportion of men with infertility. The objective of this study was to validate a sequence-tagged site (STS)-mapping strategy for the detection of Yq microdeletions and to use this method to determine the proportion of men with idiopathic azoospermia or severe oligozoospermia who carry microdeletions in Yq. STS mapping of a sufficiently large sample of infertile men should also help further localize the putative gene(s) involved in the pathogenesis of male infertility. Genomic DNA was extracted from peripheral leukocytes of 16 normal fertile men, 7 normal fertile women, 60 infertile men (50 of whom had azoospermia and 10 of whom had severe oligozoospermia with no other recognizable cause of infertility), and 15 patients with the X-linked disorder, ichthyosis. PCR primers were synthesized for 26 STSs that span Yq interval 6. None of the 16 normal men of known fertility had microdeletions. Seven normal fertile women failed to amplify any of the 26 STSs, providing evidence of their Y specificity. No microdeletions were detected in any of the 15 patients with ichthyosis. Of the 60 infertile men typed with 26 STSs, 11 (18%; 10 azoospermic and 1 oligozoospermic) failed to amplify 1 or more STS. Interestingly, 4 of the 11 patients had microdeletions in a region that is outside the Yq region from which the DAZ (deleted in azoospermia gene region) gene was cloned. In an additional 3 patients, microdeletions were present both inside and outside the DAZ region. In 3 subjects, the microdeletions were verified by Southern analysis using labeled PCR products corresponding to the deleted STSs as probes. These data suggest a high prevalence (18%) of Yq microdeletions in men with idiopathic azoospermia/severe oligospermia. The physical locations of these microdeletions provide further support for the concept that a gene(s) on Yq deletion interval 6 plays an important role in spermatogenesis. The presence of deletions that do not overlap with the DAZ region suggests that genes other than the DAZ gene may also be implicated in the pathogenesis of some subsets of male infertility.
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PMID:Substantial prevalence of microdeletions of the Y-chromosome in infertile men with idiopathic azoospermia and oligozoospermia detected using a sequence-tagged site-based mapping strategy. 863 31

Male sexual differentiation and development proceed under direct control of androgens. Androgen action is mediated by the intracellular androgen receptor, which belongs to the superfamily of ligand-dependent transcription factors. In the X-linked androgen insensitivity syndrome, defects in the androgen receptor gene have prevented the normal development of both internal and external male structures in 46, XY individuals. The complete form of androgen insensitivity syndrome is characterized by 46, XY karyotype, external female phenotype, intra-abdominal testes, absence of uterus and ovaries, blindly ending vagina, and gynecomastia. There is also a group of disorders of androgen action that result from partial impairment of androgen receptor function. Clinical indications can be abnormal sexual development of individuals with a predominant male phenotype with severe hypospadias and micropenis or of individuals with a predominantly female phenotype with cliteromegaly, ambiguous genitalia, and gynecomastia. Complete or gross deletions of the androgen receptor gene have not been frequently found in persons with the complete androgen insensitivity syndrome, whereas point mutations at several different sites in exons 2-8 encoding the DNA- and androgen-binding domain have been reported in both partial and complete forms of androgen insensitivity, with a relatively high number of mutations in two clusters in exons 5 and 7. The number of mutations in exon 1 is extremely low, and no mutations have been reported in the hinge region, located between the DNA-binding domain and the ligand-binding domain. The X-linked condition of spinal and bulbar muscle atrophy (Kennedy's disease) is characterized by a progressive motor neuron degeneration associated with signs of androgen insensitivity and infertility. The molecular cause of spinal and bulbar muscle atrophy is an expanded length (> 40 residues) of one of the polyglutamine stretches in the N-terminal domain of the androgen receptor.
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PMID:Molecular basis of androgen insensitivity. 873 95

We use triple colour fluorescent in-situ hybridization (FISH) to sex human embryos for preimplantation diagnosis of X-linked disease, to analyse chromosome numbers in embryos donated for research purposes and as a diagnostic tool for patients undergoing infertility treatment, especially in cases where abnormal embryo development occurs. We have reported on the use of FISH in a case where all embryos showed accelerated cleavage. Here we report on the use of triple colour FISH in a case where five out of seven oocytes were multi-nucleated when examined for pronuclei. The embryos were spread whole using HCl/Tween 20 and triple colour FISH performed with probes for chromosomes X, Y and 1 in a 2 h procedure. Two embryos were normal for the probes used, and three showed abnormalities, including one 4-cell embryo where all nuclei were X,X,X,Y,1,1,1,1. FISH indicated that fertilization had occurred, but that the majority of embryos were abnormal confirming that such embryos should not be considered for transfer. In these cases, or where there is recurrent in-vitro fertilization failure or spontaneous abortions, embryos in future cycles can be examined using FISH to ascertain the level of chromosome abnormality which may aid future infertility treatment.
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PMID:The use of fluorescent in-situ hybridization (FISH) for the analysis of in-vitro fertilization embryos: a diagnostic tool for the infertile couple. 882 54

Kennedy's disease (spinal and bulbar muscular atrophy) is an X-linked form of motor neuron disease that affects adult men. The syndrome is characterized by progressive atrophy of the limb muscles, pelvic and shoulder girdles and dysphagia and dysarthria, and is caused by the degeneration of spinal and bulbar motor neurons. Kennedy's disease is caused by a trinucleotide repeat expansion of a CAG repeat in exon A of the androgen receptor gene, and is one of a group of neurological diseases caused by trinucleotide repeat expansions in different genes. The mutation in Kennedy's disease involves an increased number of glutamine residues in the amino-terminal domain of the receptor. Point mutations and deletions in the androgen receptor gene cause androgen insensitivity syndrome, however subjects with Kennedy's disease have normal virilization, although progressive gynaecomastia, testicular atrophy and infertility may occur. Androgen receptors are expressed widely in the normal brain, and in the anterior horn cells of the spinal cord; however, their role in neuronal tissue is not known, nor is it known how the androgen receptor gene mutation causes neuronal degeneration. Kennedy's disease is likely to be a 'gain of function' abnormality, so that the presence of the receptor with an increased number of glutamines is toxic to motor neurons. It is possible that the mutation alters interaction of the receptor with other neuronal transcription factors, or neuronotoxicity may occur because of a non-specific effect caused by the presence of a protein with a large homoglutamine domain. Studies of patients with Kennedy's disease have shown that expression of androgen receptor mRNA and protein in spinal cord may be decreased, as can be the affinity of the mutant receptor for androgen. In vitro studies have shown impaired transcription activation ability of the mutant androgen receptor. The age at onset of Kennedy's disease may correlate with the size of the CAG repeat, however there is a large degree of variability of age at onset between subjects with the same number of repeats. Further study of the effect of the Kennedy's disease mutation on androgen receptor function in motor neurons will allow us to increase our understanding of the pathogenesis of this disease.
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PMID:Spinal and bulbar muscular atrophy: androgen receptor dysfunction caused by a trinucleotide repeat expansion. 886 71


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