Novel Protein-Protein Interactions Highlighting the Crosstalk between Hypoplastic Left Heart Syndrome, Ciliopathies and Neurodevelopmental Delays.
Novel Protein-Protein Interactions Highlighting the Crosstalk between Hypoplastic Left Heart Syndrome, Ciliopathies and Neurodevelopmental Delays.
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左心发育不良综合征 (HLHS) 是一种严重的先天性心脏病 (CHD)，影响五千分之一的新生儿。我们构建了从大规模小鼠诱变筛选中鉴定出的 74 个 HLHS 相关基因的相互作用组，并使用我们的高精度蛋白质相互作用预测 (HiPPIP) 模型用 408 个新型蛋白质相互作用 (PPI) 对其进行了扩充。交互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 来源的心肌细胞中，总共 364 个基因（包括 73 个新型相互作用因子）受到差异性调节。新型 PPI 有助于识别 TOR 信号传导和内质网应激模块。我们发现 60.5% 的相互作用组由管家基因组成，这些基因可能含有大效应突变并驱动 HLHS 病因，但传播有限。糖尿病、阿尔茨海默病和肝癌相关基因与 HLHS 基因的网络邻近性提示了它们与 HLHS 共病的机制基础。相互作用组基因显示出心外异常部位（胎盘、肝脏和大脑）的组织特异性。 HLHS相互作用组与纤毛病和小头畸形相关基因的相互作用组有显着的重叠，共享基因分别富含与智力障碍和/或发育迟缓以及神经元死亡途径相关的基因。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负担增加和神经系统异常患病率分别增加。
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.
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发育不全左心综合征的产前头部生长和白质损伤。
影响因子：
3.6
作者：
Hinton RB;Andelfinger G;Sekar P;Hinton AC;Gendron RL;Michelfelder EC;Robitaille Y;Benson DW
通讯作者：
Benson DW
影响因子：
3.7
作者：
Cerami E;Demir E;Schultz N;Taylor BS;Sander C
通讯作者：
Sander C
影响因子：
14.9
作者：
Harris, MA;Clark, J;White, R
通讯作者：
White, R
DOI：
10.1126/science.1262110
发表时间：
2015-05-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
GTEx Consortium
通讯作者：
GTEx Consortium
影响因子：
4.6
作者：
Karunakaran KB;Chaparala S;Lo CW;Ganapathiraju MK
通讯作者：
Ganapathiraju MK