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Rescue of Male Infertility through Correcting a Genetic Mutation Causing Meiotic arrest in Spermatogonial Stem Cells [RNA-seq]

ABSTRACT: Azoospermia patients who carry a monogenetic mutation that causes meiotic arrest may have their biological child through genetic correction in spermatogonial stem cells (SSCs). However, such therapy for infertility has not been experimentally investigated yet. In this study, a mouse model with X-linked TEXT11 mutation (Tex11PM/Y) identified in azoospermia patients exhibited meiotic arrest due to aberrant chromosome segregation. Text11PM/Y SSCs could be isolated and expanded in vitro normally and the mutation was corrected by CRISPR-Cas9, leading to generation of repaired SSC lines. Whole-genome sequencing demonstrated that mutation rate in repaired SSCs are comparable with autonomous mutation in untreated Text11PM/Y SSCs, and no predicted off-target sites are modified. Repaired SSCs could restore spermatogenesis in infertility males and give rise to fertile offspring at a high efficiency. In summary, our study establishes a paradigm for the treatment of male azoospermia by combining in vitro expansion of SSCs and gene therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE158977 | GEO | 2020/10/05

REPOSITORIES: GEO

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Rescue of Male Infertility through Correcting a Genetic Mutation Causing Meiotic arrest in Spermatogonial Stem Cells [WGS]

Project description:Azoospermia patients who carry a monogenetic mutation that causes meiotic arrest may have their biological child through genetic correction in spermatogonial stem cells (SSCs). However, such therapy for infertility has not been experimentally investigated yet. In this study, a mouse model with X-linked TEXT11 mutation (Tex11PM/Y) identified in azoospermia patients exhibited meiotic arrest due to aberrant chromosome segregation. Text11PM/Y SSCs could be isolated and expanded in vitro normally and the mutation was corrected by CRISPR-Cas9, leading to generation of repaired SSC lines. Whole-genome sequencing demonstrated that mutation rate in repaired SSCs are comparable with autonomous mutation in untreated Text11PM/Y SSCs, and no predicted off-target sites are modified. Repaired SSCs could restore spermatogenesis in infertility males and give rise to fertile offspring at a high efficiency. In summary, our study establishes a paradigm for the treatment of male azoospermia by combining in vitro expansion of SSCs and gene therapy.

2020-10-05 | GSE158978 | GEO

Rescue of Male Infertility through Correcting a Genetic Mutation Causing Meiotic arrest in Spermatogonial Stem Cells

Project description:Rescue of Male Infertility through Correcting a Genetic Mutation Causing Meiotic arrest in Spermatogonial Stem Cells

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Rescue of Male Infertility through Correcting a Genetic Mutation Causing Meiotic arrest in Spermatogonial Stem Cells [WGS]

Project description:Rescue of Male Infertility through Correcting a Genetic Mutation Causing Meiotic arrest in Spermatogonial Stem Cells [WGS]

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Rescue of Male Infertility through Correcting a Genetic Mutation Causing Meiotic arrest in Spermatogonial Stem Cells [RNA-seq]

Project description:Rescue of Male Infertility through Correcting a Genetic Mutation Causing Meiotic arrest in Spermatogonial Stem Cells [RNA-seq]

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HnRNPGT knockout disrupts pre-mRNA splicing and arrests sperm development prior to meiotic metaphase

Project description:Human male infertility has long been associated with genetic defects that affect nuclear RNA binding proteins, yet what RNA targets these proteins control or why their absence causes infertility remain poorly defined. Here we find that genetic knockout of the mouse nuclear RNA binding protein gene Hnrnpgt causes azoospermia. Knockout male germ cells arrest during the highly transcriptionally active stage of meiotic prophase with altered meiotic nuclear RNA processing patterns. Hnrnpgt knockout most notably leads to the inclusion of previously unidentified cryptic exons that could otherwise disable gene function and poison the meiotic transcriptome. Hnrnpgt target genes include Esco1 and Kdm4d, which encode proteins that are important for chromosome function, and Hnrnpgt null germ cells have altered centromere clustering and H3K9me3 distribution patterns. Our data reveal a nuclear RNA processing programme that is critical for meiotic metaphase entry.

2019-01-15 | GSE101511 | GEO

Expression profiling of mouse ing2 -/- mice with spermatogenic arrest and infertility

Project description:Expression profiling of mouse ing2 -/- testis vs WT reveals gene expression differences consistent with spermatogenic arrest and infertility. Ing2 is indispensable for male germ cell development in mice. While mice deficient for Ing2 were born and grew without apparent abnormalities, male, but not female, were infertile, consistent with the highest expression of Ing2 in testes in wild-type mice and in humans. Histological and DNA content analyses in Ing2-/- testes revealed a spermatogenesis arrest at meiotic phase and enhanced apoptosis associated with increased p53, resulting in a decline in mature spermatozoa, which became more severe in older age. HDAC1 accumulation and core histone deacetylation at pachytene stage were impaired in Ing2-/- testes, suggesting that the recruitment of HDAC1 by Ing2 plays a critical role in spermatogenesis. This study establishes Ing2 as a novel mammalian regulator of spermatocyte differentiation, which coordinates spermatogenesis stage-specific histone modifications. This study has implications in understanding human male infertility. Testis from WT and Ing2 KO mice at 2-3 months of age where analyzed for differences in gene expression.

2010-11-19 | E-GEOD-18610 | biostudies-arrayexpress

Expression profiling of mouse ing2 -/- mice with spermatogenic arrest and infertility

2010-11-19 | GSE18610 | GEO

Genome Rearrangements and Pervasive Meiotic Drive Cause Hybrid Infertility in Fission Yeast

Project description:Hybrid sterility is one of the earliest postzygotic isolating mechanisms to evolve between two recently diverged species. Uncovering the mechanisms of hybrid sterilitynot only provides insight into the origins of species but also potentially revealsnovel causes of intra-species infertility.Here we identify causes underlying hybrid infertilityofSchizosaccharomyces pombeand S. kambucha, two fission yeast species that are 99.5% identical at the nucleotide level.These yeasts mate to form viable diploids that efficiently complete meiosis. However,S. kambucha/S. pombe hybrids generate few viable gametes, most of which are either aneuploid or diploid.We find that chromosomal rearrangements and related recombination defectsare major causes of hybrid infertility. Surprisingly, using experiments in which we eliminate meiotic recombination, we find thatrecombination defects cannot completely explain the hybrid infertility. Instead, we find that a significant fraction of hybrid infertility is caused by the action of at least three distinct meiotic drive alleles, one on each S. kambucha chromosome,that M-bM-^@M-^\cheatM-bM-^@M-^] to be transmitted to more than half (up to 90%) of viable gametes.Two of these driving lociare linked by a chromosomal translocation and thus constitute a novel type of paired meiotic drive complex. We find that all three S. kambuchadrive loci independently contribute to hybrid infertility by causing nonrandom spore death. This study reveals how quickly multiple barriers to fertility can arise.In addition, it provides further support for models in which genetic conflicts, such as those caused by meiotic drive alleles, can drive speciation. Meiotic DNA double-strand break analysis of Schizosaccharomyces kambucha by immunoprecipitating accumulated Rec12-FLAG covalently linked to DNA (without exogenous crosslinking agent used) following nitrogen starvation .

2014-05-15 | E-GEOD-57039 | biostudies-arrayexpress

NLRP14 deficiency contributes to female infertility and early embryo arrest

Project description:Oocyte maturation is vital to attain full competence required fertilization and embryogenesis. As a maternal effect factor, NLRP14 is preferentially expressed in mammalian oocytes and early embryos. Yet the role and molecular mechanism of NLRP14 in oocyte maturation and early embryogenesis is largely unknown. Whether NLRP14 deficiency accounts for human infertility with oocyte and embryo defects remains to be elucidated. Here, NLRP14 is identified essential for establishment of competent oocytes that can sustain early embryo development. Maternal deficiency of Nlrp14 results in sterility characterized by oocyte maturation defects and early embryo arrest. Nlrp14 ablation leads to compromised oocyte quality and developmental competence due to impaired oocyte cytoplasmic and nuclear maturation. Mechanistically, NLRP14 interacts with UHRF1 in oocyte cytoplasm to protect it from proteasome-dependent degradation, and perturbs maternal mRNA zygotic-decay and zygotic genome activation during maternal-zygotic transition. Furthermore, compound heterozygous pathogenic variants in NLRP14 gene are identified in infertile women with early embryonic arrest, which interrupt the NLRP14-UHRF1 interaction or UHRF1 protein expression. Our data uncover a vital role of NLRP14 as a new cytoplasmic-specific modulator of UHRF1 in oocyte meiotic maturation and early embryogenesis, which should provide new insights into risk prediction and genetic diagnosis for female infertility.

2024-06-01 | GSE234001 | GEO

X-linked CNV burden and male infertility

Project description:Male factor infertility affects about 7% of men in the general population and it can be related to a number of different etiologic factors, including genetic anomalies. Both sex chromosomes are enriched in genes prevalently or exclusively expressed in the testis. Nevertheless only the Y chromosome-linked Copy Number Variants (CNVs) and Y-linked genes have been demonstrated as important contributors to impaired sperm production in humans Data on the potential role of X-linked gene products in spermatogenesis derives mainly from model organisms. X-linked genes seem to be expressed both in pre-meiotic and post-meiotic germ cells in the mouse testis and interestingly those expressed in the post-meiotic cells belong to multicopy gene families. The apparent paucity of X-linked factors in male infertility is most likely related to the scarcity of studies, which focused only on a total of seven genes. No pathogenic mutations causing infertility have, thus far, been described in these genes, with the exception of AR gene In order to advance in the understanding of the role of X-linked CNVs and genes in male infertility, we applied an innovative approach based on high resolution X chromosome specific CGH array. Given that such a detailed analysis of the X chromosome has not been published so far and the testicular function of subjects included in the Genomic Variant Database is unknown (except for 24 X-linked CNVs reported in the recent paper by Tuttelmann), our is the first study providing a detailed analysis of X-linked losses and gains in several hundreds of subjects with known sperm parameters.

2012-10-01 | GSE37948 | GEO

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