Human Y Chromosome Azoospermia Factors (AZF) Mapped to Different Subregions in Yq11
TL;DR: The presence of not one but three spermatogenesis loci in Yq11 is proposed and that each locus is active during a different phase of male germ cell development.
Abstract: In a large collaborative screening project, 370 men with idiopathic azoospermia or severe oligozoospermia wereanalysed for deletions of 76 DNA loci in Yq11. In 12 individuals, we observed de novo microdeletions involvingseveral DNA loci, while an additional patient had an inherited deletion. They were mapped to three differentsubregions in Yq11. One subregion coincides to the AZF region defined recently in distal Yq11. The second andthird subregion were mapped proximal to it, in proximal and middle Yq11, respectively. The different deletionsobserved were not overlapping but the extension of the deleted Y DNA in each subregion was similar in eachpatient analysed. In testis tissue sections, disruption of spermatogenesis was shown to be at the same phasewhen the microdeletion occurred in the same Yq11 subregion but at a different phase when the microdeletionoccurred in a different Yq11 subregion. Therefore, we propose the presence of not one but three spermatogenesisloci in Yq11 and that each locus is active during a different phase of male germ cell development. As the mostsevere phenotype after deletion of each locus is azoospermia, we designated them as: AZFa, AZFb and AZFc.Their probable phase of function in human spermatogenesis and candidate genes involved will be discussed. INTRODUCTIONGenes for male germ cell development are present on the Ychromosome in different species groups (1–3). In men, theposition of a spermatogenesis locus was mapped in theeuchromatic part of the long Y arm (Yq11). It was called‘azoospermia factor’ (AZF), as the first six men observed withterminal deletions in Yq were azoospermic (4). Mature spermcells were not detectable in their seminal fluid. In all cases, the Ydeletions included the large heterochromatin block of the long Yarm (Yq12) and an undefined amount of the adjacent euchromatin(Yq11). Subsequently, the presence of AZF in Yq11 wasconfirmed by numerous studies at both cytogenetic (5) andmolecular level (6–8). However, the genetic complexity of AZFcould not be revealed by these analyses.This first became possible by the detection of sterile patientswith small interstitial deletions (i.e. microdeletions) in Yq11. Ina study with 13 sterile men suffering from idiopathic azoospermiatwo different microdeletions in Yq11 were observed (9). Theywere mapped to two non overlapping positions in Yq11 interval6 (10). However, further studies of Yq11 microdeletionsassociated to the phenotype of male sterility, only confirmed theposition of an AZF locus in distal Yq11 (11,12). The mostextensive study was performed by Reijo et al. (13) on 89 sterile
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TL;DR: In this article, the authors examined various conditions of the multiplex PCR, using a large number of primer pairs, and proposed a protocol for developing a multiple-x PCR assay and suggest ways to overcome commonly encountered problems.
Abstract: By simultaneously amplifying more than one locus in the same reaction, multiplex PCR is becoming a rapid and convenient screening assay in both the clinical and the research laboratory. While numerous papers and manuals discuss in detail conditions influencing the quality of PCR in general, relatively little has been published about the important experimental factors and the common difficulties frequently encountered with multiplex PCR. We have examined various conditions of the multiplex PCR, using a large number of primer pairs. Especially important for a successful multiplex PCR assay are the relative concentrations of the primers at the various loci, the concentration of the PCR buffer, the cycling temperatures and the balance between the magnesium chloride and deoxynucleotide concentrations. Based on our experience, we propose a protocol for developing a multiplex PCR assay and suggest ways to overcome commonly encountered problems.
1,013 citations
TL;DR: These EAU guidelines are a short comprehensive overview of the updated guidelines of male infertility as recently published by the EAU and are also available in the National Guideline Clearinghouse ( www.guideline.gov/).
802 citations
Cites background from "Human Y Chromosome Azoospermia Fact..."
...AZF deletions are divided into AZFa, AZFb, and AZFc regions [28,29] and represent the most frequent molecular genetic cause of azoospermia and severe oligozoospermia....
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TL;DR: A systematic search of the nonrecombining region of the human Y chromosome (NRY) identified 12 novel genes or families, 10 with full-length complementary DNA sequences, which may account for infertility among men with Y deletions.
Abstract: A systematic search of the nonrecombining region of the human Y chromosome (NRY) identified 12 novel genes or families, 10 with full-length complementary DNA sequences. All 12 genes, and six of eight NRY genes or families previously isolated by less systematic means, fell into two classes. Genes in the first group were expressed in many organs; these housekeeping genes have X homologs that escape X inactivation. The second group, consisting of Y-chromosomal gene families expressed specifically in testes, may account for infertility among men with Y deletions. The coherence of the NRY's gene content contrasts with the apparently haphazard content of most eukaryotic chromosomes.
771 citations
710 citations
TL;DR: The factors responsible for Y chromosome deletions in spermatozoa remain unresolved but may be one facet of a central reproductive problem: controlling the amount of oxidative stress experienced by germ cells during their differentiation and maturation in the male reproductive tract.
Abstract: Recent advances in understanding of male infertility have implicated two major causative factors, oxidative stress and Y chromosome deletions. A major cause of oxidative stress appears to be the high rate of reactive oxygen species generation associated with the retention of excess residual cytoplasm in the sperm midpiece. Other possible causes include the redox cycling of xenobiotics, and antioxidant depletion or apoptosis. Oxidative stress induces peroxidative damage in the sperm plasma membrane and DNA damage in both the mitochondrial and nuclear genomes. Nuclear DNA damage in the germ line of the father may be associated with pathology in the offspring, including childhood cancer and infertility. Gene deletions on the non-recombining region of the Y chromosome account for the infertility observed in about 15% of patients with azoospermia and 5-10% of subjects with severe oligozoospermia. The Y chromosome is particularly susceptible to gene deletions because of the inability of the haploid genome to deploy recombination repair in retrieving lost genetic information. Aberrant recombination, defective chromatin packaging, abortive apoptosis and oxidative stress may all be involved in the aetiology of DNA damage in the germ line. The factors responsible for Y chromosome deletions in spermatozoa remain unresolved but may be one facet of a central reproductive problem: controlling the amount of oxidative stress experienced by germ cells during their differentiation and maturation in the male reproductive tract.
699 citations
Cites background from "Human Y Chromosome Azoospermia Fact..."
...Vogt et al. (1996) observed that Y chromosome microdeletions follow a certain deletion pattern, with three recurrently deleted nonoverlapping subregions in proximal, middle and distal Yq11, designated AZFa, AZFb and AZFc, respectively....
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References
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TL;DR: De la Chapelle dysplasia, also known as atelosteogenesis type II, is a lethal form of neonatal dwarfism in which gross limb shortening is associated with a characteristic triangular configuration of the radius and ulna.
Abstract: de la Chapelle dysplasia, also known as atelosteogenesis type II, is a lethal form of neonatal dwarfism in which gross limb shortening is associated with a characteristic triangular configuration of the radius and ulna. Inheritance is autosomal recessive.
3,241 citations
TL;DR: The region contains a single–copy gene, DAZ (Deleted in AZoospermia), which is transcribed in the adult testis and appears to encode an RNA binding protein, and the possibility that DAZ is AZF should now be explored.
Abstract: We have detected deletions of portions of the Y chromosome long arm in 12 of 89 men with azoospermia (no sperm in semen). No Y deletions were detected in their male relatives or in 90 other fertile males. The 12 deletions overlap, defining a region likely to contain one or more genes required for spermatogenesis (the Azoospermia Factor, AZF). Deletion of the AZF region is associated with highly variable testicular defects, ranging from complete absence of germ cells to spermatogenic arrest with occasional production of condensed spermatids. We find no evidence of YRRM genes, recently proposed as AZF candidates, in the AZF region. The region contains a single–copy gene, DAZ (Deleted in AZoospermia), which is transcribed in the adult testis and appears to encode an RNA binding protein. The possibility that DAZ is AZF should now be explored.
1,133 citations
"Human Y Chromosome Azoospermia Fact..." refers background in this paper
...Corresponding lengths of PCR amplification products are: RBM1/RBM2: 800 bp; DAZ: 1300 bp; SPGY1: 460 bp. Individuals with Yq11 anomalies used for creation of the interval map were described earlier (10), with the exception of H17, H21, H34, H35, H36, H79, H87, B314, B316 and B324....
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...Another 3% had balanced autosomal translocations [45,XY,- der(13;14)(q10;q10) or 45,XY,der (14;21)(q10;q10), respectively]....
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...DAZ contains seven tandem repeats of a 72-nucleotide unit (13), SPGY1 contains at least 12 tandem repeats of a 72-nucleotide unit with the same consensus sequence as the DAZ repeat unit....
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...Candidate genes for expression of AZFc are DAZ (13) and SPGY1 (32) isolated as cDNA clones....
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...by also observing divergent histological phenotypes in patients with deletion of AZFc in distal Yq11 (13)....
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TL;DR: It is suggested that on the distal portion of the nonfluorescent segment of the long arm of the Y, factors are located controlling spermatogenesis.
Abstract: A deletion of the Y chromosome at the distal portion of band q11 was found in 6 men with normal male habitus but with azoospermia. Five of them were found during a survey of 1170 subfertile males while the sixth was karyotyped because of slight bone abnormalities. These findings, together with a review of the literature, suggest that on the distal portion of the nonfluorescent segment of the long arm of the Y, factors are located controlling spermatogenesis.
926 citations
TL;DR: The isolation and characterization of a gene family located within a deletion in Y chromosome interval 6 is reported, suggesting a possible role in RNA processing or translational control during early spermatogenesis.
512 citations
"Human Y Chromosome Azoospermia Fact..." refers methods in this paper
...The only exception was locus RBM1/C (formerly YRRM/C; 12) in Yq11 interval D18....
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...These figures coincide with the polymorphic deletion frequency of the RBM2 (formerly YRRM2; 12) gene copy observed in Caucasians (21)....
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...The genomic DNA loci of the RBM (formerly YRRM; 12) gene family were coined RBM1/A-I, because they were analysed with the probe RBM1 (pMK5) kindly provided by H. J. Cooke....
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...In this patient group, we observed, additionally, deletions of the following DNA loci: DY7/C, DYS75, RBF8, DYS21, DYS65 and YRRM1/E analysed by blot experiments (data not shown)....
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...The genomic fragments of the RBM [formerly YRRM (12)] gene family in Yq11 were coined RBM1/A, B2, C, E, F because they were analysed with the RBM1 cDNA probe 5 Human Molecular Genetics, 1996, Vol. 5, No. 7936 Figure 2....
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TL;DR: A deletion map of the human Y chromosome was constructed by testing 96 individuals with partial Y chromosomes for the presence or absence of many DNA loci, and should be useful in identifying Y chromosomal genes, in exploring the origin of chromosomal disorders, and in tracing the evolution of the Y chromosome.
Abstract: A deletion map of the human Y chromosome was constructed by testing 96 individuals with partial Y chromosomes for the presence or absence of many DNA loci. The individuals studied included XX males, XY females, and persons in whom chromosome banding had revealed translocated, deleted, isodicentric, or ring Y chromosomes. Most of the 132 Y chromosomal loci mapped were sequence-tagged sites, detected by means of the polymerase chain reaction. These studies resolved the euchromatic region (short arm, centromere, and proximal long arm) of the Y chromosome into 43 ordered intervals, all defined by naturally occurring chromosomal breakpoints and averaging less than 800 kilobases in length. This deletion map should be useful in identifying Y chromosomal genes, in exploring the origin of chromosomal disorders, and in tracing the evolution of the Y chromosome.
492 citations
"Human Y Chromosome Azoospermia Fact..." refers methods in this paper
...Origin and preparation of DNA probes and STS primer pairs were described in detail previously (16, 19 ,30)....
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...Most primers used were selected from the pool of sY sequences published by Vollrath et al. ( 19 )....
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