Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.
Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.
Nat Commun. 2024 Aug 21;15(1):7154. doi: 10.1038/s41467-024-51328-3.
Roberts syndrome (RBS) is an autosomal recessive disorder with profound growth deficiency and limb reduction caused by ESCO2 loss-of-function variants. Here, we elucidate the pathogenesis of limb reduction in an Esco2;Prrx1-Cre mouse model using bulk- and single-cell-RNA-seq and gene co-expression network analyses during embryogenesis. Our results reveal morphological and vascular defects culminating in hemorrhage of mutant limbs at E12.5. Underlying this abnormal developmental progression is a pre-apoptotic, mesenchymal cell population specific to mutant limb buds enriched for p53-related signaling beginning at E9.5. We then characterize these p53-related processes of cell cycle arrest, DNA damage, cell death, and the inflammatory leukotriene signaling pathway in vivo. In utero treatment with pifithrin-α, a p53 inhibitor, rescued the hemorrhage in mutant limbs. Lastly, significant enrichments were identified among genes associated with RBS, thalidomide embryopathy, and other genetic limb reduction disorders, suggesting a common vascular etiology among these conditions.
罗伯茨综合征（RBS）是一种常染色体隐性遗传病，由 ESCO2 功能丧失变异引起严重的生长发育不良和肢体减少。在这里，我们使用胚胎发生期间的 bulk 和单细胞 RNA-seq 以及基因共表达网络分析，阐明了 Esco2;Prrx1-Cre 小鼠模型中肢体减少的发病机制。我们的结果揭示了形态和血管缺陷，最终导致 E12.5 时突变肢体出血。这种异常发育进展的基础是一种凋亡前的、间质细胞群体，其特异性在于突变的肢芽中富含与 p53 相关的信号，从 E9.5 开始富集。然后，我们在体内对这些与细胞周期停滞、DNA 损伤、细胞死亡和炎症白三烯信号通路相关的 p53 相关过程进行了表征。在子宫内用 pifithrin-α（一种 p53 抑制剂）治疗可挽救突变肢体的出血。最后，与 RBS、沙利度胺胚胎病和其他遗传性肢体减少疾病相关的基因之间存在显著富集，这表明这些疾病之间存在共同的血管病因。
