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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]

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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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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.

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