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

Details

• Personal Author:
  Balakrishnan N ; Gabriel GC ; Ganapathiraju MK ; Karunakaran KB ; Lo CW
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Cardiovascular Diseases Cardiovascular System Genetics Occupational Health Safety
• Keywords:
  Author Keywords: Protein-protein Interactions; Interactome; Congenital Heart Disease; Developmental Disorder; Hypoplastic Left Heart Syndrome; Web Application Proteins; Congenital Effects; Genes; Genetic Disorders; Heart Disease; Genetics; Developmental Disorders;
• DOI:
  https://doi.org/10.3390/genes13040627
• ISSN:
  2073-4425
• Document Type:
  Text
• Funding:
  Cooperative Agreement
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; Pennsylvania
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  13
• Issue:
  4
• NIOSHTIC Number:
  nn:20065397
• Citation:
  Genes 2022 Apr; 13(4):627
• Contact Point Address:
  Madhavi K. Ganapathiraju, Department of Biomedical Informatics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15206, USA
• Email:
  avi@pitt.edu
• Federal Fiscal Year:
  2022
• Performing Organization:
  University of Pittsburgh at Pittsburgh
• Peer Reviewed:
  True
• Start Date:
  20060901
• Source Full Name:
  Genes
• End Date:
  20260831
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:dafcd12abf7f968a9f030d8ecb80e7da977727588b921450baa61b8f303e533eb89105b38f84d9577ef9bf9de2f2af24249a9d58eb6468fd5c574a679c1c6567
• Download URL:
  https://stacks.cdc.gov/view/cdc/248929/cdc_248929_DS1.pdf
• File Type:
  [PDF - 3.60 MB ]