Astro Veronica, Fiacco Elisabetta, Cardona-Londoño Kelly Johanna, De Toma Ilario, Alzahrani Hams Saeed, Alama Jumana, Kokandi Amal, Hamoda Taha Abo-Almagd Abdel-Meguid, Felemban Majed, Adamo Antonio
Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.
Sequentia Biotech SL, Barcelona, Spain.
Endocr Connect. 2023 Apr 26;12(5). doi: 10.1530/EC-22-0515. Print 2023 May 1.
The transcriptional landscape of Klinefelter syndromeduring early embryogenesis remains elusive. This study aimed to evaluate the impact of X chromosome overdosage in 47,XXY males induced pluripotent stem cells (iPSCs) obtained from patients with different genomic backgrounds and ethnicities.
We derived and characterized 15 iPSC lines from four Saudi 47,XXY KS patients and one Saudi 46,XY male. We performed a comparative transcriptional analysis using the Saudi KS-iPSCs and a cohort of European and North American KS-iPSCs.
We identified a panel of X-linked and autosomal genes commonly dysregulated in Saudi and European/North American KS-iPSCs vs 46,XY controls. Our findings demonstrate that seven PAR1 and nine non-PAR escape genes are consistently dysregulated and mostly display comparable transcriptional levels in both groups. Finally, we focused on genes commonly dysregulated in both iPSC cohorts and identified several gene-ontology categories highly relevant to KS physiopathology, including aberrant cardiac muscle contractility, skeletal muscle defects, abnormal synaptic transmission, and behavioral alterations.
Our results indicate that a transcriptomic signature of X chromosome overdosage in KS is potentially attributable to a subset of X-linked genes sensitive to sex chromosome dosage and escaping X inactivation, regardless of the geographical area of origin, ethnicity, and genetic makeup.
克氏综合征早期胚胎发育过程中的转录图谱仍不清楚。本研究旨在评估从具有不同基因组背景和种族的患者获得的47,XXY男性诱导多能干细胞（iPSC）中X染色体剂量过多的影响。
我们从四名沙特47,XXY克氏综合征患者和一名沙特46,XY男性中获得并鉴定了15条iPSC系。我们使用沙特克氏综合征-iPSC以及一组欧洲和北美克氏综合征-iPSC进行了比较转录分析。
我们鉴定出一组在沙特和欧洲/北美克氏综合征-iPSC与46,XY对照中普遍失调的X连锁和常染色体基因。我们的研究结果表明，7个PAR1和9个非PAR逃逸基因持续失调，且在两组中大多显示出相当的转录水平。最后，我们关注两个iPSC队列中普遍失调的基因，并确定了几个与克氏综合征生理病理学高度相关的基因本体类别，包括异常的心肌收缩力、骨骼肌缺陷、异常的突触传递和行为改变。
我们的结果表明，克氏综合征中X染色体剂量过多的转录组特征可能归因于对性染色体剂量敏感且逃避X失活的X连锁基因子集，而与起源的地理区域、种族和基因组成无关。
