Novel Protein–Protein Interactions Highlighting the Crosstalk between Hypoplastic Left Heart Syndrome, Ciliopathies and Neurodevelopmental Delays

Genes

Madhavi K. Ganapathiraju¹  Cecilia W. Lo²  George C. Gabriel²  Narayanaswamy Balakrishnan³  Kalyani B. Karunakaran³ 

[1] Department of Biomedical Informatics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15206, USA;Department of Developmental Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15201, USA;Supercomputer Education and Research Centre, Indian Institute of Science, Bangalore 560012, India;

关键词: protein–protein interactions;    interactome;    congenital heart disease;    developmental disorder;    hypoplastic left heart syndrome;    web application;   

DOI  :  10.3390/genes13040627

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown