Rare mutations in the complement regulatory gene CSMD1 are associated with male and female infertility
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA563627 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10059806.fastq.gz | Fastqsanger.gz | |||
| SRR10059806_1.fastq.gz | Fastqsanger.gz | |||
| SRR10059806_2.fastq.gz | Fastqsanger.gz | |||
| SRR10059807.fastq.gz | Fastqsanger.gz | |||
| SRR10059807_1.fastq.gz | Fastqsanger.gz |
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Project description:Infertility in men and women is a common and complex genetic trait with shared biological bases between the sexes. We performed a series of rare variant analyses across 73,185 women and men to identify genes that contribute to primary gonadal dysfunction and identified CSMD1 as a strong candidate in both sexes. CSMD1 is a complement regulatory protein on chromosome 8p23. In order to interpret and support our genetic findings, we performed detailed transcriptomic and protein-based experiments which found CSMD1 enriched at the germ-cell/somatic-cell interface in both male and female gonads. We then performed a battery of tests on Csmd1 knockout mice. Knockout males show increased rates of infertility, and present testes with severe histological degeneration and significantly increased deposition of complement C3 protein. Knockout females show significant reduction in ovarian quality and breeding success, as well as impaired branching of the mammary glands. Furthermore, double knockout of Csmd1 and C3 leads to an unexpected and non-additive reduction in breeding success, suggesting that CSMD1 and the complement pathway play an important role in the normal postnatal development of the gonads in both sexes.
2019-09-04 | GSE136769 | GEO
Project description:Infertility in men and women is a complex genetic trait with shared biological bases between the sexes. Here, we perform a series of rare variant analyses across 73,185 women and men to identify genes that contribute to primary gonadal dysfunction. We report CSMD1, a complement regulatory protein on chromosome 8p23, as a strong candidate locus in both sexes. We show that CSMD1 is enriched at the germ-cell/somatic-cell interface in both male and female gonads. Csmd1-knockout males show increased rates of infertility with significantly increased complement C3 protein deposition in the testes, accompanied by severe histological degeneration. Knockout females show significant reduction in ovarian quality and breeding success, as well as mammary branching impairment. Double knockout of Csmd1 and C3 causes non-additive reduction in breeding success, suggesting that CSMD1 and the complement pathway play an important role in the normal postnatal development of the gonads in both sexes.
| S-EPMC6789153 | biostudies-literature
Project description:we performed lentiviral CRISPR interference (CRISPRi) by recruiting dCas9 fused with the KRAB domain to the CSMD1 enhancer (fam3) in the neuronal precursor cell line – Lund human mesencephalic (LUHMES). Given that the expression of CSMD1 was not detectable in LUHMES cells we differentiated these cells into neurons. Differentiated neurons with CRISPRi of CSMD1 enhancer showed significantly higher expression of CSMD1 than control.
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Project description:CSMD1 gene, mapping to human chromosomal region 8p23, encodes a transmembrane protein with an extracellular region containing 14 CUB and 28 sushi domains, a transmembrane domain and a cytoplasmic domain with a putative tyrosine phosphorylation site.The loss of CSMD1 has been found to be associated with enhanced cell proliferation, migration and poor prognosis in head and neck squamous cell carcinoma (HNSCCs), lung squamous cell carcinoma (SCCs), melanoma, and breast cancer, suggesting its role as a tumor suppresser.However, its role in hypertrophic scar has not been uncovered. So we decided using fibroblasts to see its transcriptomes changing after CSMD1 knockdown.
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Project description:The escalating issue of infertility has become a global concern. Female infertility is primarily attributed to the decrease in both the quantity and quality of oocytes with advancing age, which is a significant factor in female infertility. The present study aims to explore the proteomic profile of exosomes obtained from human follicular fluid to identify the protein signature associated with aging and unsuccessful in vitro fertilization (IVF) outcomes. Despite the lack of significant differences in the morphology and particle size of follicular fluid exosomes between the two groups, the proteomic analysis demonstrated a distinct pattern of differentially expressed proteins. B cell activation, pathogen invasion, and disrupted metabolic processes were found to be significantly higher in the aging group, indicating the involvement of these pathways in aging-associated infertility. Moreover, the PI3K-AKT signaling pathway, which is linked to follicle maturation, was identified as the most influential signaling pathway in the aging group. In vivo experiments corroborated the weakened role of exosomes derived from the aging group in follicle maturation. Finally, the study employed a random forest machine learning algorithm, which further suggested that hydrolase activity might play a crucial role in determining the final IVF outcome. The expression of key differentially expressed proteins was validated. This study provides novel insights into the aging-associated protein signature of follicular fluid exosomes and their potential role in infertility. The findings imply that the aging-related protein signature in exosomes could serve to improve the diagnosis and treatment of infertility.
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Project description:This is RNA-seq from LUHMES cells and differentiated neurons with and without CSMD1 enhancer CRISPRi
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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.
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