Severe oligozoospermia resulting from deletions of azoospermia factor gene on Y chromosome

Reijo, Renee A.; Alagappan, Raaji; Page, David C.; Patrizio, Pasquale

doi:10.1016/s0140-6736(96)90938-1

Cited by 471 publications

(120 citation statements)

References 15 publications

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“…First, deletions encompassing the DAZ genes cause phenotypes that include low numbers of sperm. Second, analysis of human DAZ exons and introns suggests that they are evolving at the same rate, an observation consistent with neutral genetic drift or positive selection on the DAZ proteins (1,(28)(29)(30). Thus, we speculate that perhaps DAZ has yet to evolve a function essential for completion of spermatogenesis.…”

Section: Discussionsupporting

confidence: 67%

A gene family required for human germ cell development evolved from an ancient meiotic gene conserved in metazoans

Moore

Pera

2001

Proc. Natl. Acad. Sci. U.S.A.

239

313

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The Deleted in AZoospermia (DAZ) genes encode potential RNAbinding proteins that are expressed exclusively in prenatal and postnatal germ cells and are strong candidates for human fertility factors. Here we report the identification of an additional member of the DAZ gene family, which we have called BOULE. With the identification of this gene, it is clear that the human DAZ gene family contains at least three members: DAZ, a Y-chromosome gene cluster that arose 30 -40 million years ago and whose deletion is linked to infertility in men; DAZL, the ''father'' of DAZ, a gene that maps to human chromosome 3 and has homologs required for both female and male germ cell development in other organisms; and BOULE, a gene that we propose is the ''grandfather'' of DAZ and maps to human chromosome 2. Human and mouse BOULE resemble the invertebrate meiotic regulator Boule, the proposed ortholog of DAZ, in sequence and expression pattern and hence likely perform a similar meiotic function. In contrast, the previously identified human DAZ and DAZL are expressed much earlier than BOULE in prenatal germ stem cells and spermatogonia; DAZL also is expressed in female germ cells. These data suggest that homologs of the DAZ gene family can be grouped into two subfamilies (BOULE and DAZL) and that members of the DAZ family evolved from an ancestral meiotic regulator, Boule, to assume distinct, yet overlapping, functions in germ cell development.

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Section: Discussionsupporting

confidence: 67%

A gene family required for human germ cell development evolved from an ancient meiotic gene conserved in metazoans

Moore

Pera

2001

Proc. Natl. Acad. Sci. U.S.A.

239

313

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“…In humans, DAZ (being Y-linked) is expressed only in the testis [20]. Some investigators have proposed that DAZ plays a nonessential role in human spermatogenesis [16].…”

Section: Introductionmentioning

confidence: 99%

“…Some investigators have proposed that DAZ plays a nonessential role in human spermatogenesis [16]. Others have proposed that the DAZ gene is a strong candidate for the azoospermia factor (AZF), inactive or missing DAZ genes could cause azoospermia or oligospermia [12, 20, 21]. The fact that DAZ has a unique role in spermatogenesis [20, 21]suggests that the DAZ genes adopted a new function recently after duplication into the Y chromosome.…”

Section: Introductionmentioning

confidence: 99%

Single-Nucleotide Variant in Multiple Copies of a Deleted in Azoospermia (DAZ) Sequence – a Human Y Chromosome Quantitative Polymorphism

Szmulewicz¹,

Ruiz²,

Reategui³

et al. 2002

Hum Hered

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The evolution of the deleted in azoospermia (DAZ) gene family supports prevalent theories on the origin and development of sex chromosomes and sexual dimorphism. The ancestral DAZL gene in human chromosome 3 is known to be involved in germline development of both males and females. The available phylogenetic data suggest that some time after the divergence of the New World and Old World monkey lineages, the DAZL gene, which is found in all mammals, was copied to the Y chromosome of an ancestor to the Old World monkeys, but not New World monkeys. In modern man, the Y-linked DAZ gene complex is located on the distal part of the q arm. It is thought that after being copied to the Y chromosome, and after the divergence of the human and great ape lineages, the DAZ gene in the former underwent internal rearrangements. This included tandem duplications as well as a T > C transition altering an MboI restriction enzyme site in a duplicated sequence. In this study, we report on the ratios of MboI–/MboI+ variant sequences in individuals from seven worldwide human populations (Basque, Benin, Egypt, Formosa, Kungurtug, Oman and Rwanda) in the DAZ complex. The ratio of PCR MboI– and MboI+ amplicons can be used to characterize individuals and populations. Our results show a nonrandom distribution of MboI–/MboI+ sequence ratios in all populations examined, as well as significant differences in ratios between populations when compared pairwise. The multiple ratios imply that there have been more than one recent reorganization events at this locus. Considering the dynamic nature of this locus and its involvement in male fertility, we investigated the extent and distribution of this polymorphism.

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“…Men with deletions encompassing the Y-chromosome DAZ gene cluster have defects in spermatogenesis that are detected initially in the stem cell population. These men frequently lack all germ cells, including the spermatogonial stem cells, and only somatic cells are present in testicular tissue (1)(2)(3). In addition, expression of the DAZ gene and its ancestral, autosomal homolog, DAZL, only occurs in germ cells; DAZ is expressed in males, and DAZL is expressed in males and females (4,5).…”

mentioning

confidence: 99%

Human Pumilio-2 is expressed in embryonic stem cells and germ cells and interacts with DAZ (Deleted in AZoospermia) and DAZ-Like proteins

Moore

Jaruzelska

Fox

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

207

215

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Early in development, a part of the embryo is set aside to become the germ cell lineage that will ultimately differentiate to form sperm and eggs and transmit genetic information to the next generation. Men with deletions encompassing the Y-chromosome DAZ genes have few or no germ cells but are otherwise healthy, indicating they harbor specific defects in formation or maintenance of germ cells. A DAZ homolog, DAZL (DAZ-Like), is found in diverse organisms, including humans and is required for germ cell development in males and͞or females. We identified proteins that interact with DAZ proteins to better understand their function in human germ cells. Here, we show that PUM2, a human homolog of Pumilio, a protein required to maintain germ line stem cells in Drosophila and Caenorhabditis elegans, forms a stable complex with DAZ through the same functional domain required for RNA binding, protein-protein interactions and rescue of Pumilio mutations in flies. We also show that PUM2 is expressed predominantly in human embryonic stem cells and germ cells and colocalizes with DAZ and DAZL in germ cells. These data implicate PUM2 as a component of conserved cellular machinery that may be required for germ cell development.A ll stem cells have potential to differentiate or proliferate mitotically. These potentials must be balanced for the stem cell population to be maintained. If differentiation exceeds proliferation, the stem cell population is not maintained. Evidence in humans suggests that the DAZ genes function early in the germ line stem cells. Men with deletions encompassing the Y-chromosome DAZ gene cluster have defects in spermatogenesis that are detected initially in the stem cell population. These men frequently lack all germ cells, including the spermatogonial stem cells, and only somatic cells are present in testicular tissue (1-3). In addition, expression of the DAZ gene and its ancestral, autosomal homolog, DAZL, only occurs in germ cells; DAZ is expressed in males, and DAZL is expressed in males and females (4, 5). Evidence from model organisms also suggests the DAZ genes function in germ cell maintenance. The Xenopus homolog of DAZ, Xdazl, is expressed in a region of the early oocyte that contains the germ plasm that is required for formation and maintenance of the germ cell lineage (6, 7). Inhibition of Xdazl leads to loss of the primordial germ cells (6, 7). Finally, the DAZ homolog in mice, Dazl, is most abundantly expressed in premeiotic germ cells; disruption of this gene causes depletion of germ cells beginning prenatally (8-10). DAZ and DAZL homologs may function interchangeably as suggested by the observation that a human DAZ transgene can partially rescue a mouse Dazl mutation (11). To shed light on how DAZ genes might function in human germ cells, we sought to identify proteins that interact with DAZ proteins. Materials and MethodsTwo-Hybrid Screening of DAZ-Interacting Proteins. The yeast two-hybrid system was used to identify proteins that interact with a DAZ:GAL4 DNA-binding domain fusion prot...

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Severe oligozoospermia resulting from deletions of azoospermia factor gene on Y chromosome

Cited by 471 publications

References 15 publications

A gene family required for human germ cell development evolved from an ancient meiotic gene conserved in metazoans

A gene family required for human germ cell development evolved from an ancient meiotic gene conserved in metazoans

Single-Nucleotide Variant in Multiple Copies of a Deleted in Azoospermia (DAZ) Sequence – a Human Y Chromosome Quantitative Polymorphism

Human Pumilio-2 is expressed in embryonic stem cells and germ cells and interacts with DAZ (Deleted in AZoospermia) and DAZ-Like proteins

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