Browse
Submit Data
Databases
API
Help

Dataset Information

18 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Rescue of male infertility through correcting a genetic mutation causing meiotic arrest in spermatogonial stem cells.

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 an X-linked testis-expressed 11 (TEX11) mutation (Tex11^PM/Y) identified in azoospermia patients exhibited meiotic arrest due to aberrant chromosome segregation. Tex11^PM/Y SSCs could be isolated and expanded in vitro normally, and the mutation was corrected by clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated endonuclease 9 (Cas9), leading to the generation of repaired SSC lines. Whole-genome sequencing demonstrated that the mutation rate in repaired SSCs is comparable with that of autonomous mutation in untreated Tex11^PM/Y SSCs, and no predicted off-target sites are modified. Repaired SSCs could restore spermatogenesis in infertile 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.

SUBMITTER: Wang YH

PROVIDER: S-EPMC8577253 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-10-05 | GSE158979 | GEO

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 [RNA-seq]

2020-10-05 | GSE158977 | 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

| PRJNA667242 | ENA

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]

| PRJNA667245 | ENA

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]

| PRJNA667244 | ENA

XRCC2 mutation causes meiotic arrest, azoospermia and infertility.

Project description:BackgroundMeiotic homologous recombination (HR) plays an essential role in gametogenesis. In most eukaryotes, meiotic HR is mediated by two recombinase systems: ubiquitous RAD51 and meiosis-specific DMC1. In the RAD51-mediated HR system, RAD51 and five RAD51 paralogues are essential for normal RAD51 function, but the role of RAD51 in human meiosis is unclear. The knockout of Rad51 or any Rad51 paralogue in mice exhibits embryonic lethality. We investigated a family with meiotic arrest, azoospermia and infertility but without other abnormalities.MethodsHomozygosity mapping and whole-exome sequencing were performed in a consanguineous family. An animal model carrying a related mutation was created by using a CRISPR/Cas9 system.ResultsWe identified a 1 bp homozygous substitution (c.41T>C/p.Leu14Pro) on a RAD51 paralogue, namely, XRCC2, in the consanguineous family. We did not detect any XRCC2 recessive mutation in a cohort of 127 males with non-obstructive-azoospermia. Knockin mice with Xrcc2-c.T41C/p.Leu14Pro mutation were generated successfully by the CRISPR/Cas9 method. The homozygotes survived and exhibited meiotic arrest, azoospermia, premature ovarian failure and infertility.ConclusionA XRCC2 recessive mutation causing meiotic arrest and infertility in humans was duplicated with knockin mice. Our results revealed a new Mendelian hereditary entity and provided an experimental model of RAD51-HR gene defect in mammalian meiosis.

| S-EPMC6119352 | biostudies-literature

Mutation of Eif4g3, encoding a eukaryotic translation initiation factor, causes male infertility and meiotic arrest of mouse spermatocytes.

Project description:The ENU-induced repro8 mutation was identified in a screen to uncover genes that control mouse gametogenesis. repro8 causes male-limited infertility, with failure of spermatocytes to exit meiotic prophase via the G2/MI transition. The repro8 mutation is in the Eif4g3 gene, encoding eukaryotic translation initiation factor 4, gamma 3. Mutant germ cells appear to execute events of meiotic prophase normally, and many proteins characteristic of the prophase-to-metaphase transition are not obviously depleted. However, activity of CDC2A (CDK1) kinase is dramatically reduced in mutant spermatocytes. Strikingly, HSPA2, a chaperone protein for CDC2A kinase, is absent in mutant spermatocytes in spite of the presence of Hspa2 transcript, consistent with the observation that the repro8 phenotype is markedly similar to the phenotype of the Hspa2 knockout. Thus, EIF4G3 is required for HSPA2 translation in spermatocytes, a finding that provides the first genetic evidence for selective translational control of meiotic exit in mammalian spermatocytes.

| S-EPMC2860251 | biostudies-literature

Heterozygous mutation of eEF1A1b resulted in spermatogenesis arrest and infertility in male tilapia, Oreochromis niloticus.

Project description:Eukaryotic elongation factor 1 alpha (eEF1A) is an essential component of the translational apparatus. In the present study, eEF1A1b was isolated from the Nile tilapia. Real-time PCR and Western blot revealed that eEF1A1b was expressed highly in the testis from 90 dah (days after hatching) onwards. In situ hybridization and immunohistochemistry analyses showed that eEF1A1b was highly expressed in the spermatogonia of the testis. CRISPR/Cas9 mediated mutation of eEF1A1b resulted in spermatogenesis arrest and infertility in the F0 XY fish. Consistently, heterozygous mutation of eEF1A1b (eEF1A1b+/-) resulted in an absence of spermatocytes at 90 dah, very few spermatocytes, spermatids and spermatozoa at 180 dah, and decreased Cyp11b2 and serum 11-ketotestosterone level at both stages. Further examination of the fertilization capacity of the sperm indicated that the eEF1A1b+/- XY fish were infertile due to abnormal spermiogenesis. Transcriptomic analyses of the eEF1A1b+/- testis from 180 dah XY fish revealed that key elements involved in spermatogenesis, steroidogenesis and sperm motility were significantly down-regulated compared with the control XY. Transgenic overexpression of eEF1A1b rescued the spermatogenesis arrest phenotype of the eEF1A1b+/- testis. Taken together, our data suggested that eEF1A1b is crucial for spermatogenesis and male fertility in the Nile tilapia.

| S-EPMC5339811 | biostudies-literature

Variants in RABL2A causing male infertility and ciliopathy.

Project description:Approximately 7% of men worldwide suffer from infertility, with sperm abnormalities being the most common defect. Though genetic causes are thought to underlie a substantial fraction of idiopathic cases, the actual molecular bases are usually undetermined. Because the consequences of most genetic variants in populations are unknown, this complicates genetic diagnosis even after genome sequencing of patients. Some patients with ciliopathies, including primary ciliary dyskinesia and Bardet-Biedl syndrome, also suffer from infertility because cilia and sperm flagella share several characteristics. Here, we identified two deleterious alleles of RABL2A, a gene essential for normal function of cilia and flagella. Our in silico predictions and in vitro assays suggest that both alleles destabilize the protein. We constructed and analyzed mice homozygous for these two single-nucleotide polymorphisms, Rabl2L119F (rs80006029) and Rabl2V158F (rs200121688), and found that they exhibit ciliopathy-associated disorders including male infertility, early growth retardation, excessive weight gain in adulthood, heterotaxia, pre-axial polydactyly, neural tube defects and hydrocephalus. Our study provides a paradigm for triaging candidate infertility variants in the population for in vivo functional validation, using computational, in vitro and in vivo approaches.

| S-EPMC7749704 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data