Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 28 January 2022 / Approved: 1 February 2022 / Online: 1 February 2022 (16:00:59 CET)

A peer-reviewed article of this Preprint also exists.

Karunakaran, K.B.; Gabriel, G.C.; Balakrishnan, N.; Lo, C.W.; Ganapathiraju, M.K. Novel Protein–Protein Interactions Highlighting the Crosstalk between Hypoplastic Left Heart Syndrome, Ciliopathies and Neurodevelopmental Delays. Genes 2022, 13, 627. Karunakaran, K.B.; Gabriel, G.C.; Balakrishnan, N.; Lo, C.W.; Ganapathiraju, M.K. Novel Protein–Protein Interactions Highlighting the Crosstalk between Hypoplastic Left Heart Syndrome, Ciliopathies and Neurodevelopmental Delays. Genes 2022, 13, 627.

Journal reference: Genes 2022, 13, 627
DOI: 10.3390/genes13040627

Abstract

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) affecting 1 in 5,000 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 (http://severus.dbmi.pitt.edu/wiki-HLHS). 364 genes including 73 novel interactors were differentially regulated in tissues/iPSC-derived cardiomyocytes of HLHS patients. Novel PPIs facilitated the identification of TOR signaling and endoplasmic reticulum stress modules. 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 respectively enriched for genes involved in intellectual disability and/or developmental delay, and neuronal death pathways. This supported the increased burden of ciliopathy variants and prevalence of neurological abnormalities observed among HLHS patients with developmental delay and microcephaly respectively.

Keywords

protein-protein interactions; interactome; congenital heart disease; developmental disorder; hypoplastic left heart syndrome; web application

Subject

BIOLOGY, Other

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