Integration and reanalysis of transcriptomics and methylomics data derived from blood and testis tissue of men with 47,XXY Klinefelter syndrome indicates the primary involvement of Sertoli cells in the testicular pathogenesis

Abstract

Klinefelter syndrome (KS; 47,XXY) is the most common sex chromosomal anomaly and causes a multitude of symptoms. Often the most noticeable symptom is infertility caused by azoospermia with testicular histology showing hyalinization of tubules, germ cells loss, and Leydig cell hyperplasia. The germ cell loss begins early in life leading to partial hyalinization of the testis at puberty, but the mechanistic drivers behind this remain poorly understood. In this systematic review, we summarize the current knowledge on developmental changes in the cellularity of KS gonads supplemented by a comparative analysis of the fetal and adult gonadal transcriptome, and blood transcriptome and methylome of men with KS. We identified a high fraction of upregulated genes that escape X‐chromosome inactivation, thus supporting previous hypotheses that these are the main drivers of the testicular phenotype in KS. Enrichment analysis showed overrepresentation of genes from the X‐ and Y‐chromosome and testicular transcription factors. Furthermore, by re‐evaluation of recent single cell RNA‐sequencing data originating from adult KS testis, we found novel evidence that the Sertoli cell is the most affected cell type. Our results are consistent with disturbed cross‐talk between somatic and germ cells in the KS testis, and with X‐escapee genes acting as mediators.

Comparative single-cell analysis of biopsies clarifies pathogenic mechanisms in Klinefelter syndrome

“…Emerging single-cell RNA-seq (scRNA-seq) methods have enabled the quantitative characterization of cell populations within the testis and can clearly contribute new insights into the pathologic mechanisms of KS. Pioneering scRNA-seq studies of KS have emerged in the past year, hinting at a special role for the Sertoli cell in KS pathology, [17][18][19] but insights have been limited by the small number of donors and suitable analysis tools. An scRNAseq framework is needed to delineate the role of the X chromosome in KS and separate expression changes that are general responses to spermatogenic impairment versus causes of KS-specific pathology.…”

Transcriptomic differences between fibrotic and non-fibrotic testicular tissue reveal possible key players in Klinefelter syndrome-related testicular fibrosis

“…Winge et al recently compared all published studies concerning differentially expressed analyses and revealed an overlap of only eight transcripts which were up-regulated in at least two studies on testis tissue, while no down-regulated genes overlapped between the studies 60 . Of these eight genes, only one was found differentially expressed in our analysis of fibrotic versus non-fibrotic tissue, e.g.…”

Mediastinal germ cell tumors: many questions and perhaps an answer

“…Next, why is the risk approximately 70-fold increased in males with Klinefelter syndrome (24)? People with sex-chromosome constitution that results in Klinefelter syndrome, usually XXY, have disturbed spermatogonial niches, such that at puberty virtually no germ cells remain (25), and probably also no GCNIS cells are retained. This deficiency would explain why these individuals are infertile and hardly develop testicular type II GCTs.…”