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Single-cell analysis of pathology in Klinefelter syndrome and idiopathic male infertility

ABSTRACT: Single-cell analysis of pathology in Klinefelter syndrome and idiopathic male infertility

PROVIDER: PRJNA715093 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13986982.fastq.gz	Fastqsanger.gz
	SRR13986983.fastq.gz	Fastqsanger.gz
	SRR13986984.fastq.gz	Fastqsanger.gz
	SRR13986985.fastq.gz	Fastqsanger.gz
	SRR13986986.fastq.gz	Fastqsanger.gz

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Single-cell analysis of pathology in Klinefelter syndrome and idiopathic male infertility

Project description:Klinefelter syndrome (KS), also known as 47,XXY, is characterized by a distinct set of physiological abnormalities, commonly including infertility. The molecular basis for Klinefelter-related infertility is still unclear, largely due to the cellular complexity of the testis and the intricate endocrine and paracrine signaling that regulates spermatogenesis. Here, we demonstrate an analysis framework for dissecting human testis pathology that uses comparative analysis of single-cell RNA-sequencing data from the biopsies of 13 human donors. By comparing donors from a range of ages and forms of infertility, we generate gene expression signatures that characterize normal testicular function and distinguish clinically distinct forms of male infertility. Unexpectedly, we identified a subpopulation of Sertoli cells within multiple cases of KS that lack transcription from the XIST locus, with the consequence of increased X-linked gene expression compared to all other KS cell populations. By systematic assessment of known signaling pathways, we identify 72 pathways potentially active in testis, dozens of which appear upregulated in KS. Altogether our data support a model of pathogenic changes in interstitial cells cascading from loss of X-inactivation in pubertal Sertoli cells, and nominate testicular GNRH1 as a dosage-sensitive factor secreted by Sertoli cells that may contribute to the process. Our findings demonstrate the value of comparative patient analysis in mapping genetic mechanisms of disease, and identify an epigenetic phenomenon in KS Sertoli cells that may prove important for understanding causes of infertility and sex chromosome evolution.

2021-09-26 | GSE169062 | GEO

Identification of a damaging variant rs35033974 associated with idiopathic male infertility through degradation of TEX101 protein and its transient interactome

Project description:Human TEX101 is a testis-specific cell membrane protein expressed exclusively in male germ cells and a validated biomarker of male infertility. TEX101 was suggested to function as a cell surface chaperone of numerous proteins involved in sperm migration and sperm-egg interaction. However, the precise functional roles of human TEX101 in spermatogenesis and fertilization are unknown. Here, we show that a common homozygous variant rs35033974 of TEX101 (G99V) with ~1% frequency in the general population may be associated with idiopathic male infertility. Spermatozoa from patients with homozygous rs35033974 exhibited near-complete degradation of variant G99V TEX101 protein and concomitant degradation of its interactome, as revealed by proteomic measurements. Substantially reduced levels of numerous testis-specific membrane proteins involved in sperm migration and sperm-oocyte fusion (including LY6K, IZUMO3 and ADAM29) were confirmed in spermatozoa of men with homozygous G99V variant. These men were previously diagnosed with idiopathic male infertility or oligospermia and failed the treatment by intrauterine insemination. Collectively, these data may facilitate diagnostics of idiopathic male infertility, provides a rational for selection of male infertility treatments and validate TEX101 and its interactome as targets to develop non-hormonal male contraceptives.

2024-11-02 | MSV000096278 | MassIVE

Identification of a damaging variant rs35033974 associated with idiopathic male infertility through degradation of TEX101 protein and its transient interactome

2018-11-21 | PXD008333 | Pride

Klinefelter syndrome comorbidities induced by increased X gene dosages and altered protein interactome activity

Project description:Klinefelter syndrome (KS) is the most common male chromosomal abnormality (47,XXY). Males with KS suffers from numerous comorbidities. Gene expression data integrated with other data types can increase the knowledge and clinically handling of KS males. Gene expression microarray from eight human Klinefelter syndrome patients (47,XXY) and eight human controls. The age of the Klinefelter syndrome patients varied, which was corrected for in the pre-processing as described in the paper and also in the 'normalization data transformation protocol' of this submission.

2017-03-23 | E-MTAB-4922 | biostudies-arrayexpress

Decreased miRNA expression in Klinefelter syndrome

Project description:Decreased miRNA expression in Klinefelter syndrome

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Gene expression data from whole blood of Klinefelter Syndrome patients compared to male and female controls

Project description:Patients with Klinefelter Syndrome have the karyotype 47,XXY. These men are suffering from hypergonadotropic hypogonadism and are infertile. It is debated whether the different hormonal constitution observed in these patients or different gene expression With the Microarray analysis we could identify genes on the X-chromosomes that are upregulated in KS-patietns compared to healthy male controls. But also autosomal genes were found to be differentially regulated.

2015-01-07 | GSE42331 | GEO

Biallelic variants in CFAP61 cause multiple morphological abnormalities of the flagella and idiopathic male infertility

Project description:Biallelic variants in CFAP61 cause multiple morphological abnormalities of the flagella and idiopathic male infertility

| PRJEB48973 | ENA

Single-cell sequencing reveals the relationship between phenotypes and genotypes of Klinefelter syndrome

Project description:One of the most common congenital disorders of male infertility is Klinefelter syndrome. Because of its extreme heterogeneity in clinical and genetic presentation, the relationship between transcriptome and the clinical phenotype and the associated co-morbidities seen in KS has not been fully clarified yet. We reported here a 47 XXY karyotype Chinese male (KS) with infertility and analyzed the differences in gene expression patterns of peripheral blood mononuclear cells (PBMCs) from a Chinese male and a female control with normal karyotype by single-cell sequencing. We analyzed a total of 24,439 cells and divided them into 5 immune cell types (including B cell, T cell, macrophage cell, dendritic cell, and natural killer cell) according to the marker genes. Using unsupervised dimensionality reduction and clustering algorithms, we identified molecularly distinct subpopulations of cells between KS and both controls. Gene ontology enrichment analyses yielded terms associated with well-known comorbidities seen in KS as well as an affected immune system, type I diabetes mellitus. Based on our data, we point towards several candidate genes, which may be implicated in the phenotype of KS. Overall, our analysis showed a comprehensive map of the cell types of the PBMCs of KS patient at the single-cell level, which will contribute to preventing comorbidity and improving the life quality of KS patients.

2019-08-27 | GSE136353 | GEO

Epigenetic Transgenerational Inheritance of Testis Pathology and Sertoli Cell Epimutations: Generational Origins of Male Infertility

Project description:Epigenetic Transgenerational Inheritance of Testis Pathology and Sertoli Cell Epimutations: Generational Origins of Male Infertility

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Fam170a deficiency causes male infertility

Project description:Fam170a deficiency causes male infertility

| PRJNA1180445 | ENA