Low XIST expression in Sertoli cells of Klinefelter syndrome patients causes high susceptibility of these cells to an extra X chromosome

Abstract

Klinefelter syndrome (KS) is the most common genetic cause of human male infertility. However, the effect of the extra X chromosome on different testicular cell types remains poorly understood. Here, we profiled testicular single-cell transcriptomes from three KS patients and normal karyotype control individuals. Among the different somatic cells, Sertoli cells showed the greatest transcriptome changes in KS patients. Further analysis showed that X-inactive-specific transcript (XIST), a key factor that inactivates one X chromosome in female mammals, was widely expressed in each testicular somatic cell type but not in Sertoli cells. The loss of XIST in Sertoli cells leads to an increased level of X chromosome genes, and further disrupts their transcription pattern and cellular function. This phenomenon was not detected in other somatic cells such as Leydig cells and vascular endothelial cells. These results proposed a new mechanism to explain why testicular atrophy in KS patients is heterogeneous with loss of seminiferous tubules but interstitial hyperplasia. Our study provides a theoretical basis for subsequent research and related treatment of KS by identifying Sertoli cell-specific X chromosome inactivation failure.

Case report: Klinefelter syndrome may protect against the development of spinal and bulbar muscular atrophy

“…In addition, tremor is the first and most frequent symptom in male patients with SBMA, but less frequent in female patients (10). In the current patient, only mild muscle spasms and muscle twitching were observed before the initiation of androgen replacement therapy, which is similar to the symptoms observed in female carriers (8,11). Furthermore, although it was reported that a decrease in serum creatinine levels precedes the onset of motor symptoms by approximately 15 years in male patients with SBMA, no decrease in serum creatinine levels was observed in this patient.…”

“…Therefore, the initiation of testosterone replacement therapy in this patient may have caused an earlier and more severe onset of symptoms by promoting a higher degree of nuclear translocation of the abnormal AR protein bound to testosterone. Although it was reported that excess X chromosome inactivation occurs in the majority of cells in Klinefelter syndrome (11,12), 15%-30% of the genes on the inactivated X chromosome escape inactivation (13). At this time, the extent to which the AR gene is expressed or inactivated in patients with Klinefelter syndrome is unknown.…”