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Query: UNIPROT:P06889 (Mol)
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The DAZ (Deleted in AZoospermia) and DAZLA (DAZ-like autosomal) genes may be determinants of male infertility. The DAZ gene on the long arm of the human Y chromosome is a strong candidate for the 'azoospermia factor' (AZF). Its role in spermatogenesis is supported by its exclusive expression in testis, its deletion in a high percentage of males with azoospermia or severe oligospermia, and its homology with a Drosophila male infertility gene boule. No DAZ homologous sequences have been found on the mouse Y chromosome. Instead, a Dazla gene was isolated from mouse chromosome 17 and has been considered to be a murine homologue of DAZ. However, the homology between human DAZ and mouse Dazla is not strong, and Dazla contains only one of the seven DAZ repeats found in DAZ. We report the isolation of the human DAZLA gene by screening a human testis cDNA library with a DAZ cDNA clone. DAZLA encodes only one DAZ repeat and shares high homology with the mouse Dazla, indicating that these two genes are homologues. Using a panel of rodent-human somatic cell lines and fluorescence in situ hybridization, the DAZLA gene was mapped to 3p24, a region not known to share homology with mouse chromosome 17. The DAZLA gene may be involved in some familial cases of autosomal recessive male infertility.
Hum Mol Genet 1996 Dec
PMID:The human autosomal gene DAZLA: testis specificity and a candidate for male infertility. 896 56

Microdeletions linked to deletion intervals 5 and 6 of the Y chromosome have been associated with male factor infertility. Members from at least two gene families lie in the region containing azoospermia factor (AZF), namely YRRM and DAZ. With the advent of intracytoplasmic sperm injection (ICSI), it is possible for men with severe male factor infertility to produce a child. The genetic consequences of such a procedure have been questioned. This report describes the first study of a population (32 couples) of infertile fathers and their sons born after ICSI. The objectives were firstly to determine the incidence and map location of Y chromosome microdeletions and to compare the frequencies with other population studies involving severe male factor infertility, and secondly to formulate a working hypothesis concerning developmental aetiology of Y chromosome microdeletions. The incidence of microdeletions in the ICSI population was shown to be 9.4% (within the range 9-18% reported for populations of severe male factor infertility patients). Microdeletions in two out of three affected father/son pairs mapped in the region between AZFb and AZFc and the third involved a large microdeletion in AZFb and AZFc. Of three affected father/son pairs, microdeletions were detected in the blood of one infertile propositus father and three babies. Assuming that the gonomes of the ICSI-derived babies are direct reflections of those of their fathers germ lines, it is possible that two of three infertile fathers were mosaic for intact Y and microdeleted Y chromosomes. In such cases, the developmental aetiology of the microdeletion may be due to a de-novo microdeletion arising as a post-zygotic mitotic error in the infertile propositus father, thus producing a mosaic individual who may or may not transmit the deletion to his ICSI-derived sons depending on the extent of primordial germ cell mosaicism. In one of three affected fathers, the microdeletion detected in his blood was also detected in his ICSI-derived son. In this case the de-novo event giving rise to the microdeletion may have occurred due to a post- (or pre-) meiotic error in the germ line of this father's normally fertile father (i.e. the ICSI-derived baby's grandfather).
Mol Hum Reprod 1996 Dec
PMID:The incidence and possible relevance of Y-linked microdeletions in babies born after intracytoplasmic sperm injection and their infertile fathers. 923 38

Two types of plasminogen activators (PA), tissue type (tPA) and urokinase type (uPA), were identified in the seminal plasma of both the human and the rhesus monkey. We studied the possible relationship between PA activities in the seminal plasma and the sperm counts and motility and demonstrated that: (i) PA activity in human seminal plasma from infertile patients was associated with immotile spermatozoa; (ii) the treatment of fertile men with testosterone enanthate (TE) to induce azoospermia was accompanied by an increase in seminal PA activity; (iii) when monomer T4 (isolated from multiglycosides of Tripterygium wilforddi) was administered to fertile male rhesus monkeys to induce azoospermia, PA activities in seminal plasma increased considerably; and (iv) immunocytochemistry studies showed that both uPA and PAI-1 antigens were localized on the surface of human spermatozoa, indicating that human spermatozoa were capable of binding uPA and PAI-1 through their receptors or forming a complex. These data demonstrate that seminal PA activity may be related to azoospermia, and possibly, to the fertilizing capability of spermatozoa in primates.
Mol Hum Reprod 1996 Feb
PMID:Preliminary studies on the role of plasminogen activator in seminal plasma of human and rhesus monkey. 923 65

Overall, approximately 11% of men attending infertility clinics suffer unexplained oligo- or azoospermia. Cytogenetic observations of loss of the distal portion of the Y chromosome long arm (Yq) were found to be associated with disrupted spermatogenesis. The existence of a gene locus involved in the regulation of spermatogenesis, the azoospermia factor (AZF), was thus postulated. It is suggested that microdeletions, or mutations, at the AZF locus could result in impaired spermatogenesis in chromosomally normal men. In order to test this hypothesis we have carried out Y chromosome genetic screening of 100 oligo- or azoospermic 46XY patients. We have also assessed phenotype/genotype relationships in those patients whose infertility has an underlying genetic aetiology. Patients were screened by polymerase chain reaction (PCR) with a set of Y chromosome-specific sequence tagged sites (STS) for submicroscopic deletions of their Y chromosome. Our results show that as many as 8% of cases of unexplained male infertility may have an underlying genetic aetiology related to microdeletions in two specific regions of the Y chromosome. Positive results from such a screen will be important when deciding the suitability of a patient for assisted conception schemes such as intracytoplasmic sperm injection.
Mol Hum Reprod 1996 Oct
PMID:Polymerase chain reaction screening for Y chromosome microdeletions: a first step towards the diagnosis of genetically-determined spermatogenic failure in men. 923 96

Sequenced-tagged site (STS) analysis of the Y chromosome long arm (Yq) of azoospermic males has identified a minimum common deleted region of several hundred kilobases in approximately 13% of cases. A candidate azoospermia gene, DAZ (deleted in azoospermia), has been isolated from this region. DAZ has also been shown to be absent in severely oligozoospermic males albeit at a much lower frequency. These data, although highly suggestive, do not constitute formal proof that DAZ actually plays a role in azoospermia, as no small intragenic deletions, rearrangements or point mutations in the gene have been found. In this study we report the screening of DNA from 168 azoospermic/oligospermic males for the presence of the DAZ gene. Deletions involving DAZ were detected in five out of 43 (11.6%) azoospermic males whereas none were found in the remaining 125 oligospermic patients. We present the genomic structure of the 5' end of the DAZ gene together with its sequence analysis in 30 non-obstructed azoospermic males. No mutations in DAZ were found in any of the patients sequenced. These data provide no formal proof that DAZ is AZF. Thus the possibility is still valid that another gene(s) mapping to the deletion interval may be responsible for, or contribute to, the observed phenotypes. Alternatively, if DAZ is AZF, they suggest that the most frequent cause of gene inactivation is via large deletions possibly mobilized by Y chromosome repetitive sequences.
Mol Hum Reprod 1997 Jan
PMID:Absence of DAZ gene mutations in cases of non-obstructed azoospermia. 923 8

We evaluated the frequency of chromosomal aberrations and microdeletions of the Y chromosome in a sample of 204 patients included in an intracytoplasmic sperm injection (ICSI) programme. The prevalence of Y chromosome deletions in males with severely or only moderately reduced sparm counts is mainly unknown, so that patients were chosen with sperm counts ranging from mild oligozoospermia to azoospermia. While six out of 158 (3.8%) patients showed constitutional chromosomal aberrations, only two out of 204 (0.98%) patients were diagnosed with a microdeletion of Yq11. One had a terminal deletion in subinterval 6 of Yq11.23 which included the DAZ gene and a corresponding sperm count < 0.1 x 10(6) spermatozoa/ml. The second patient had an isolated deletion of marker Y6PH54c, a more proximal site in subinterval 5 on Yq11.23, but repeatedly showed sperm counts of 3-8 x 10(8) spermatozoa/ml. Thus, of the 158 patients who underwent a combined cytogenetic and Y-microdeletion screening, eight patients (5.1%) showed chromosomal abnormalities, either at the cytogenatic (n = 6) or the molecular level (n = 2). In conclusion, although rare in number, microdeletions of the Y chromosome can also be observed in patients with moderately reduced sperm counts. A more proximal site of the deletion breakpoint does not necessarily imply a more severe impairment of spermatogenesis than a distal deletion site. In our sample, the overall frequency of constitutional chromosomal aberrations exceeded the incidence of microdeletions of the Y chromosome even in patients with idiopathic azoo- or severe oligozoospermia.
Mol Hum Reprod 1997 Aug
PMID:Combined cytogenetic and Y chromosome microdeletion screening in males undergoing intracytoplasmic sperm injection. 929 54

The DAZLA (DAZ Like Autosomal) gene on human chromosome 3 shares a high degree of homology with the DAZ (Deleted in AZoospermia) gene family on the Y chromosome, a gene family frequently deleted in males with azoospermia or severe oligospermia. The involvement of both DAZ and DAZLA in spermatogenesis is suggested by their testis-specific expression and their homology with a Drosophila male infertility gene, boule. Whereas male infertility resulting from deletion of the DAZ genes on the Y chromosome occurs sporadically, that due to a defective DAZLA gene is expected to be inheritable. The fraction of males with idiopathic azoospermia or oligospermia that harbour mutations in the DAZLA gene remains unknown. As a prerequisite for mutation screening, the genomic structure of the DAZLA gene was elucidated and found to consist of 11 exons spanning 19 kh. The exon/intron boundaries are conserved between DAZ and DAZLA. The 5' end of both genes are hypomethylated in spermatozoa but not in leukocytes or placenta, consistent with the expression pattern of the genes. The genomic structure of DAZLA paves the way for mutation detection in families with autosomal recessive male infertility.
Mol Hum Reprod 1997 Aug
PMID:A putative human male infertility gene DAZLA: genomic structure and methylation status. 929 55

We describe a 28 year old male with a pseudodicentric Y chromosome who suffered from azoospermia attributed to maturation arrest of the primary spermatocyte, as diagnosed by testicular biopsy. Chromosome analysis, using G, Q and C banding techniques, revealed an abnormal karyotype of 45,X[7]/46,X,psu dic (Y)(pter-->q11.2::q11.2-->pter)[33]. Polymerase chain reaction (PCR) DNA analysis did not detect the absence of DAZ and RBM1 which are candidates for azoospermic factor (AZF) genes. Therefore, it is suggested that the maturation arrest of the primary spermatocyte in this patient was caused either by a pairing dysfunction between the X and Y chromosomes during meiosis or by deletions in the autosomal or the Y chromosomal spermatogenesis controlling genes, excluding DAZ and RBM1.
Mol Hum Reprod 1997 Aug
PMID:Dicentric Y chromosome in an azoospermic male. 929 56

Complex chromosomal rearrangements are very rare events in the human population. According to our knowledge on the consequences of simple reciprocal translocations for male fertility, translocations involving three or more chromosomes are thought to lead to severe reproductive impairments in terms of meiotic disturbance or chromosomal imbalance of gametes. We report the case of a 48 year old man whose sperm count revealed either oligozoospermia (<10(3) spermatozoa/ml) or azoospermia. He was referred to the laboratory for in-vitro fertilization after intracytoplasmic sperm injection. Cytogenetic investigations showed a complex chromosomal rearrangement involving firstly a translocation between the short arm of chromosome 7 and the long arm of chromosome 13 and secondly a translocation between the short arm of the same chromosome 13 and the short arm of chromosome 9. Diagnosis was ascertained by fluorescence in-situ hybridization and staining of the nucleolar organizer regions. Theoretical study of the translocated chromosomes predicted a 'chain' configuration of the hexavalent at the pachytene stage of meiosis. In all, 32 modes of segregation were considered and only one resulted either in a normal or a balanced gamete karyotype. Genetic counselling and choice of appropriate artificial reproduction technique are discussed.
Mol Hum Reprod 1997 Oct
PMID:Assisted reproductive technology and complex chromosomal rearrangements: the limits of ICSI. 939 62

A total of 50 men were selected from all patients attending an infertility clinic on the basis of oligozoospermia or azoospermia with concentrations of luteinizing hormone >6 IU/l and testosterone >30 nmol/l. Six of these men responded to written invitation and DNA was extracted from blood leukocytes. Individual exons of the androgen receptor gene were amplified by polymerase chain reaction and screened for the presence of mutations by denaturing gradient gel electrophoresis. The glutamine rich portion of exon 1 was sequenced directly. All of the coding sequence of the gene was examined except the glycine rich portion of exon 1 in all patients. No mutations or deletions were identified. Androgen receptor gene mutations do not appear to be present in infertile men with biochemical disturbances compatible with androgen resistance. It is therefore unlikely that such mutations are a major factor in the pathogenesis of oligozoospermia/azoospermia and infertility.
Mol Hum Reprod 1997 Nov
PMID:Preliminary investigations on androgen receptor gene mutations in infertile men. 943 18


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