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

Kalyani B Karunakaran1, George C Gabriel2, Narayanaswamy Balakrishnan1

  • 1Supercomputer Education and Research Centre, Indian Institute of Science, Bangalore 560012, India.

Genes
|April 23, 2022
PubMed

Insights

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect. This study maps HLHS genes and their interactions, revealing novel pathways and links to other diseases like Alzheimer's and diabetes.

Area of Science:

  • Genetics and Genomics
  • Cardiovascular Biology
  • Systems Biology

Background:

  • Hypoplastic left heart syndrome (HLHS) is a critical congenital heart defect affecting approximately 1 in 5000 newborns.
  • Understanding the genetic and molecular underpinnings of HLHS is crucial for developing effective diagnostic and therapeutic strategies.

Purpose of the Study:

  • To construct a comprehensive interactome for genes associated with HLHS.
  • To identify novel protein-protein interactions (PPIs) and molecular pathways involved in HLHS pathogenesis.
  • To explore potential genetic links between HLHS and other complex diseases and extracardiac anomalies.

Main Methods:

  • Construction of the HLHS gene interactome using data from mouse mutagenesis screens.
  • Augmentation of the interactome with novel PPIs predicted by the High-Precision Protein-Protein Interaction Prediction (HiPPIP) model.
  • Differential gene expression analysis in HLHS patient tissues and iPSC-derived cardiomyocytes.
  • Network analysis to identify signaling modules and shared genetic factors with other diseases.

Main Results:

  • A web-accessible HLHS interactome was created, incorporating 74 known and 408 novel PPIs.
  • 364 genes, including 73 novel interactors, were differentially regulated in HLHS patient samples.
  • Identification of TOR signaling and endoplasmic reticulum stress as key pathways.
  • Significant network proximity was observed between HLHS genes and those associated with diabetes, Alzheimer's disease, and liver carcinoma.
  • HLHS interactome genes showed tissue-specificity relevant to extracardiac anomalies and shared overlaps with ciliopathy and microcephaly interactomes.

Conclusions:

  • The constructed HLHS interactome provides a valuable resource for understanding HLHS etiology.
  • Novel PPIs and identified pathways offer new targets for research and potential therapeutic interventions.
  • Genetic links suggest shared mechanisms between HLHS and other complex diseases, as well as ciliopathies and neurological abnormalities.

Keywords:
congenital heart diseasedevelopmental disorderhypoplastic left heart syndromeinteractomeprotein–protein interactionsweb application

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