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

• Published in: Genes Vol. 13; no. 4; p. 627
• Main Authors: Karunakaran, Kalyani B, Gabriel, George C, Balakrishnan, Narayanaswamy, Lo, Cecilia W, Ganapathiraju, Madhavi K
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.04.2022; MDPI
• Subjects: Alzheimer's disease; Animals; Cardiomyocytes; Ciliopathies - metabolism; Congenital diseases; Coronary artery disease; Coronary vessels; Diabetes mellitus; Endoplasmic reticulum; Etiology; Gene expression; Genomes; Genomics; Heart; Heart diseases; Humans; Hypoplastic Left Heart Syndrome - genetics; Hypoplastic Left Heart Syndrome - metabolism; Induced Pluripotent Stem Cells - metabolism; Infant, Newborn; Intellectual disabilities; Liver diseases; Mice; Microcephaly - genetics; Microcephaly - metabolism; Microencephaly; Mortality; Mutagenesis; Mutation; Myocytes, Cardiac - metabolism; Neonates; Nervous System Malformations; Neurodegenerative diseases; Protein interaction; Proteins; Pulmonary arteries; Transcription factors; protein–protein interactions; congenital heart disease; interactome; hypoplastic left heart syndrome; web application; developmental disorder
• ISSN: 2073-4425; 2073-4425
• 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.