Supercomputer Education and Research Centre, Indian Institute of Science, Bangalore 560012, India.
Department of Developmental Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15201, USA.
Genes (Basel). 2022 Apr 1;13(4):627. doi: 10.3390/genes13040627.
Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) affecting 1 in 5000 newborns. We constructed the interactome of 74 HLHS-associated genes identified from a large-scale mouse mutagenesis screen, augmenting it with 408 novel protein-protein interactions (PPIs) using our High-Precision Protein-Protein Interaction Prediction (HiPPIP) model. The interactome is available on a webserver with advanced search capabilities. A total of 364 genes including 73 novel interactors were differentially regulated in tissue/iPSC-derived cardiomyocytes of HLHS patients. Novel PPIs facilitated the identification of TOR signaling and endoplasmic reticulum stress modules. We found that 60.5% of the interactome consisted of housekeeping genes that may harbor large-effect mutations and drive HLHS etiology but show limited transmission. Network proximity of diabetes, Alzheimer's disease, and liver carcinoma-associated genes to HLHS genes suggested a mechanistic basis for their comorbidity with HLHS. Interactome genes showed tissue-specificity for sites of extracardiac anomalies (placenta, liver and brain). The HLHS interactome shared significant overlaps with the interactomes of ciliopathy- and microcephaly-associated genes, with the shared genes enriched for genes involved in intellectual disability and/or developmental delay, and neuronal death pathways, respectively. This supported the increased burden of ciliopathy variants and prevalence of neurological abnormalities observed among HLHS patients with developmental delay and microcephaly, respectively.
左心发育不全综合征（HLHS）是一种严重的先天性心脏病（CHD），影响每 5000 名新生儿中的 1 名。我们从大规模的小鼠诱变筛选中鉴定出 74 个与 HLHS 相关的基因，并使用我们的高精度蛋白质-蛋白质相互作用预测（HiPPIP）模型，将其与 408 个新的蛋白质-蛋白质相互作用（PPIs）进行了扩充。互作组可在具有高级搜索功能的网络服务器上使用。在 HLHS 患者的组织/iPSC 衍生的心肌细胞中，共有 364 个基因（包括 73 个新的相互作用蛋白）发生了差异调控。新的 PPIs 有助于鉴定 TOR 信号和内质网应激模块。我们发现，互作组中 60.5%的基因是管家基因，这些基因可能包含大效应突变，并驱动 HLHS 的发病机制，但表现出有限的传递。与 HLHS 基因接近的糖尿病、阿尔茨海默病和肝癌相关基因表明了它们与 HLHS 共病的机制基础。互作组基因在胎盘、肝脏和大脑等心脏外异常部位具有组织特异性。HLHS 互作组与纤毛病和小头畸形相关基因的互作组有显著重叠，共享基因富集了涉及智力障碍和/或发育迟缓以及神经元死亡途径的基因。这支持了在发育迟缓和小头畸形的 HLHS 患者中观察到的纤毛病变异和神经异常的增加负担。
