Next Article in Journal
Integrated Quantitative Neuro-Transcriptome Analysis of Several Brain Areas in Human Trisomy 21
Next Article in Special Issue
Rare and Common Variants Uncover the Role of the Atria in Coarctation of the Aorta
Previous Article in Journal
A 6.5kb Intergenic Structural Variation Exacerbates the Fitness Cost of P450-Based Metabolic Resistance in the Major African Malaria Vector Anopheles funestus
Previous Article in Special Issue
The Genetic Architecture of a Congenital Heart Defect Is Related to Its Fitness Cost
Article

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

1
Supercomputer Education and Research Centre, Indian Institute of Science, Bangalore 560012, India
2
Department of Developmental Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15201, USA
3
Department of Biomedical Informatics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15206, USA
4
Intelligent Systems Program, School of Computing and Information, University of Pittsburgh, Pittsburgh, PA 15260, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Lars Allan Larsen
Genes 2022, 13(4), 627; https://doi.org/10.3390/genes13040627
Received: 27 January 2022 / Revised: 8 March 2022 / Accepted: 8 March 2022 / Published: 1 April 2022
(This article belongs to the Special Issue Genetics and Epigenetics of Human Congenital Heart Disease)
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. View Full-Text
Keywords: protein–protein interactions; interactome; congenital heart disease; developmental disorder; hypoplastic left heart syndrome; web application protein–protein interactions; interactome; congenital heart disease; developmental disorder; hypoplastic left heart syndrome; web application
Show Figures

Figure 1

MDPI and ACS Style

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. https://doi.org/10.3390/genes13040627

AMA Style

Karunakaran KB, Gabriel GC, Balakrishnan N, Lo CW, Ganapathiraju MK. Novel Protein–Protein Interactions Highlighting the Crosstalk between Hypoplastic Left Heart Syndrome, Ciliopathies and Neurodevelopmental Delays. Genes. 2022; 13(4):627. https://doi.org/10.3390/genes13040627

Chicago/Turabian Style

Karunakaran, Kalyani B., George C. Gabriel, Narayanaswamy Balakrishnan, Cecilia W. Lo, and Madhavi K. Ganapathiraju. 2022. "Novel Protein–Protein Interactions Highlighting the Crosstalk between Hypoplastic Left Heart Syndrome, Ciliopathies and Neurodevelopmental Delays" Genes 13, no. 4: 627. https://doi.org/10.3390/genes13040627

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop