Transcription factor protein interactomes reveal genetic determinants in heart disease

Barbara Gonzalez-Teran, Maureen Pittman, Franco Felix, Reuben Thomas, Desmond Richmond-Buccola, Ruth Hüttenhain, Krishna Choudhary, Elisabetta Moroni, Mauro W. Costa, Yu Huang, Arun Padmanabhan, Michael Alexanian, Clara Youngna Lee, Bonnie E.J. Maven, Kaitlen Samse-Knapp, Sarah U. Morton, Michael McGregor, Casey A. Gifford, J. G. Seidman, Christine E. SeidmanBruce D. Gelb, Giorgio Colombo, Bruce R. Conklin, Brian L. Black, Benoit G. Bruneau, Nevan J. Krogan, Katherine S. Pollard, Deepak Srivastava

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Congenital heart disease (CHD) is present in 1% of live births, yet identification of causal mutations remains challenging. We hypothesized that genetic determinants for CHDs may lie in the protein interactomes of transcription factors whose mutations cause CHDs. Defining the interactomes of two transcription factors haplo-insufficient in CHD, GATA4 and TBX5, within human cardiac progenitors, and integrating the results with nearly 9,000 exomes from proband-parent trios revealed an enrichment of de novo missense variants associated with CHD within the interactomes. Scoring variants of interactome members based on residue, gene, and proband features identified likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied and co-activated cardiac developmental genes, and the identified GLYR1 missense variant disrupted interaction with GATA4, impairing in vitro and in vivo function in mice. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating genetic variants in heart disease.

Original languageEnglish
Pages (from-to)794-814.e30
JournalCell
Volume185
Issue number5
DOIs
StatePublished - 3 Mar 2022

Keywords

  • GATA4
  • GLYR1
  • NPAC
  • TBX5
  • congenital heart disease
  • de novo variants
  • disease variants
  • genetics
  • protein interactome networks

Fingerprint

Dive into the research topics of 'Transcription factor protein interactomes reveal genetic determinants in heart disease'. Together they form a unique fingerprint.

Cite this