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

Karunakaran, K B and Gabriel, G C and Balakrishnan, N and Lo, C W and Ganapathiraju, M K (2022) Novel Protein–Protein Interactions Highlighting the Crosstalk between Hypoplastic Left Heart Syndrome, Ciliopathies and Neurodevelopmental Delays. In: Genes, 13 (4).

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Abstract

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 interac-tome 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 neu-ronal 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. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Item Type:	Journal Article
Publication:	Genes
Publisher:	MDPI
Additional Information:	The copyright for this article belongs to MDPI
Department/Centre:	Division of Interdisciplinary Sciences > Supercomputer Education & Research Centre
Date Deposited:	19 May 2022 11:51
Last Modified:	19 May 2022 11:51
URI:	https://eprints.iisc.ac.in/id/eprint/71935

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