Klinefelter syndrome comorbidities induced by increased X gene dosages and altered protein interactome activity
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Kirstine Belling
PROVIDER: E-MTAB-4922 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Klinefelter syndrome (KS) is the most prevalent aneuploidy in males and is characterized by an extra copy of the X chromosome,while the non-mosaic form of KS with 47,XXY karyotype is the most frequent (80-90%), less common non-disjunction events during the early mitotic division of the zygote result in mosaic forms of KS (47,XXY/46,XY). Here, using a paradigmatic cohort of KS-inducible pluripotent stem cells (iPSCs) carrying 47,XXY karyotypes we present the first iPSC-based disease-modeling study performed on KS patients from Saudi Arabia. We profiled the transcriptome of these Saudi KS-iPSCs, virtually characterized by subduedcgenetic backgrounds. Moreover, we performed a comparative transcriptomic analysis to assess the aberrant gene expression profile due to X dosage imbalance in four Saudi and five European and North American 47,XXY patients-derived iPSCs from our previously published study on KS and high-grade sex chromosome aneuploidies (SCAs). We identified a transcriptomic signature including ten PAR1 genes and thirteen non-PAR escape genes consistently upregulated in KS compared to 46,XY controls in both groups, as well as 193 consistenty disregulated autosomal genes. Our results indicate that the global transcriptional impact of X chromosome overdosage in KS is largely attributable to X-linked genes escaping X inactivation, regardless of the geographical area of origin, ethnicity, and genetic background.
2023-08-02 | GSE220268 | GEO
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
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
Project description:We have evaluated the transcriptome of different testicular cell types, including germ cells, at single cell level in a testicular biopsy of a man with Klinefelter syndrome (XXY karyotype)
2019-08-30 | GSE130151 | GEO
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
Project description:Objective: Klinefelter Syndrome (KS) is the most common sexual chromosome abnormality (47,XXY) and represents the first genetic cause of male infertility. The mechanisms leading to KS testis degeneration are still unclear and no therapy is so far available for affected patients. The present study is aimed to unravel information about molecules playing a key role in the disruption of the spermatogenesis. Design: Gene expression profiles analysis of KS azoospermic testis versus normal testis, could provide useful information about the molecular basis of the alteration of the spermatogenesis. Materials and Methods: Transcriptome analysis was performed carrying out gene expression profile by a whole genome microarray approach on testis biopsies obtained from 6 azoospermic non-mosaic KS men and from 3 controls, for a total of 12 experiments. T-test and False Discovery Rate were used to evaluate differentially expressed genes. Identified transcripts were analysed by Ingenuity Pathways Analysis software to disclose genes biological functions. Results: Data analysis revealed the differentially up- and down-expression, in KS testis versus the control ones, of 656 and 247 genes related to Endocrine system development and function, Lipid metabolism, Reproductive disease, Free radical scavenging, and Cell death. Conclusions: Take together these data show the presence of several genes involved in testis microenvironment deregulation leading to the spermatogenesis failure. This information, associated with an early diagnosis could help to unravel possible therapeutic targets for testis failure prevention and limitation. Gene expression profile of 6 azoospermic KS testicular biopsies versus 3 pooled control testicular biposies form patients with normal spermatogenesis. A total of 12 experiments was carried out including biological and technical replicates.
2014-06-15 | E-GEOD-54023 | biostudies-arrayexpress
Project description:Klinefelter syndrome (KS) is the most prevalent aneuploidy in males and is characterized by one or more supernumerary X chromosomes. Here, using a paradigmatic cohort of KS-inducible pluripotent stem cells (iPSCs) carrying 49-XXXXY, 48-XXXY, and 47-XXY karyotypes, we identified genes within the pseudoautosomal region 1 (PAR1) region as the most susceptible to dosage-dependent transcriptional dysregulation and therefore potentially responsible for the progressively worsening phenotype in higher grade X aneuploidies. By contrast, biallelically expressed non-PAR escape genes displayed high interclonal and interpatient variability in iPSCs and differentiated derivatives, suggesting that these genes could be associated with variable KS traits. By interrogating KS-iPSCs at single-cell resolution, we showed that PAR1 and non-PAR escape genes were not only resilient to X-inactive specific transcript (XIST)-mediated inactivation but also that their transcriptional regulation was disjointed from the absolute XIST expression level. Finally, we explored the transcriptional effects of X chromosome overdosage on autosomes and identified the transcription factor nuclear respiratory factor 1 as the master regulator of zinc finger protein X-linked. Our findings provided the first evidence of an X-dosage-sensitive autosomal transcription factor regulating an X-linked gene in low- and high-grade X aneuploidies.
2022-02-03 | GSE152001 | GEO
Project description:Detection of genomic rearrangements from a single cell instead of a population of cells is an emerging research technique with important applications in the study of human fertility, constitutional chromosomal disorders, and tumor progression. Here, we develop a method to improve the detection of single-cell genome-wide copy number variation. At this study, 7 amplified single cell DNA samples derived from EBV-line [47,XY,+21], [46,XY,der(20),t(18;20)(p11.21;p13)], [46,XX,del(18)(p11.21->pter)], [46,X,der(X),t(X;14)(q21.1;q12.2)] were analyzed by Agilent 244K array CGH. For these single cell Agilent 244K array CGH analyses: non-amplified genomic DNA extracted from the blood of a Klinefelter patient (XXY) was used as a reference sample. As a validation, the corresponding non-amplified genomic DNA samples were analyzed by 250K Nsp I SNP arrays (platform GPL3718). Non-amplified genomic DNA extracted from the blood of a Klinefelter patient (XXY) was used as a reference sample for BAC array CGH
2011-08-23 | E-GEOD-27892 | biostudies-arrayexpress
Project description:Objective: Klinefelter Syndrome (KS) is the most common sexual chromosome abnormality (47,XXY; 46,XY/47XXY) and represents the first genetic cause of male infertility. The mechanisms leading to KS testis degeneration are still unclear and no therapy is so far available for affected patients. The present study is aimed to unravel information about molecules playing a key role in the disruption of the spermatogenesis in mosaic oligospermic KS patients. Design: Gene expression profiles analysis of KS mosaic oligospermic testis versus normal testis, could provide useful information about the molecular basis of the alteration of the spermatogenesis. Materials and Methods: Transcriptome analysis was performed carrying out gene expression profile by a whole genome microarray approach on testis biopsies obtained from 3 oligopermic mosaic KS men and from 3 controls, for a total of 6 experiments. T-test and False Discovery Rate were used to evaluate differentially expressed genes. Identified transcripts were analysed by Ingenuity Pathways Analysis software to disclose genes biological functions. Results: Data analysis revealed the differentially up- and down-expression, in mosaic KS testis versus the control ones, of respectively 303 and 747 genes related to Endocrine system disorders, Lipid metabolism, Reproductive disease, cell and organ morphology, and cell death. Conclusions: Taken together these data show the presence of several de-regulated genes involved in mosaic KS testis failure. Data show the defects in sperm production and development and defects within the somatic component of the testis. This information, associated with an early diagnosis could help to unravel possible therapeutic targets for testis failure prevention and limitation.
2016-10-01 | GSE83989 | GEO
Project description:Objective: Klinefelter Syndrome (KS) is the most common sexual chromosome abnormality (47,XXY) and represents the first genetic cause of male infertility. The mechanisms leading to KS testis degeneration are still unclear and no therapy is so far available for affected patients. The present study is aimed to unravel information about molecules playing a key role in the disruption of the spermatogenesis. Design: Gene expression profiles analysis of KS azoospermic testis versus normal testis, could provide useful information about the molecular basis of the alteration of the spermatogenesis. Materials and Methods: Transcriptome analysis was performed carrying out gene expression profile by a whole genome microarray approach on testis biopsies obtained from 6 azoospermic non-mosaic KS men and from 3 controls, for a total of 12 experiments. T-test and False Discovery Rate were used to evaluate differentially expressed genes. Identified transcripts were analysed by Ingenuity Pathways Analysis software to disclose genes biological functions. Results: Data analysis revealed the differentially up- and down-expression, in KS testis versus the control ones, of 656 and 247 genes related to Endocrine system development and function, Lipid metabolism, Reproductive disease, Free radical scavenging, and Cell death. Conclusions: Take together these data show the presence of several genes involved in testis microenvironment deregulation leading to the spermatogenesis failure. This information, associated with an early diagnosis could help to unravel possible therapeutic targets for testis failure prevention and limitation.
2014-06-15 | GSE54023 | GEO