Division of Human Genetics, The Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, USA.
Kirby Center for Molecular Ophthalmology and Center for Advanced Retinal and Ocular Therapeutics (CAROT), Scheie Eye Institute, The University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA.
Sci Rep. 2018 Jan 18;8(1):1056. doi: 10.1038/s41598-018-19173-9.
Cornelia de Lange syndrome (CdLS) is a complex disorder with multiple structural and developmental defects caused by mutations in structural and regulatory proteins involved in the cohesin complex. NIPBL, a cohesin regulatory protein, has been identified as a critical protein responsible for the orchestration of transcriptomic regulatory networks necessary for embryonic development. Mutations in NIPBL are responsible for the majority of cases of CdLS. Through RNA-sequencing of human induced pluripotent stem cells and in vitro-derived cardiomyocytes, we identified hundreds of mRNAs, pseudogenes, and non-coding RNAs with altered expression in NIPBL patient-derived cells. We demonstrate that NIPBL haploinsufficiency leads to upregulation of gene sets identified in functions related to nucleosome, chromatin assembly, RNA modification and downregulation of Wnt signaling, cholesterol biosynthesis and vesicular transport in iPSC and cardiomyocytes. Mutations in NIPBL result in the dysregulation of many genes responsible for normal heart development likely resulting in the variety of structural cardiac defects observed in the CdLS population.
康氏综合征（CdLS）是一种复杂的疾病，由参与黏合复合物的结构和调节蛋白的突变引起多种结构和发育缺陷。黏合复合物调节蛋白 NIPBL 已被确定为负责协调转录组调控网络的关键蛋白，该网络对于胚胎发育是必需的。NIPBL 的突变负责大多数 CdLS 病例。通过对人类诱导多能干细胞和体外衍生的心肌细胞进行 RNA 测序，我们在 NIPBL 患者来源的细胞中鉴定出数百个 mRNA、假基因和非编码 RNA 的表达发生改变。我们证明 NIPBL 杂合不足导致与核小体、染色质组装、RNA 修饰相关的功能以及 Wnt 信号、胆固醇生物合成和囊泡运输的基因集上调，在 iPSC 和心肌细胞中。NIPBL 突变导致许多负责正常心脏发育的基因失调，可能导致 CdLS 人群中观察到的各种结构性心脏缺陷。
