Transcription factor protein interactomes reveal genetic determinants in heart disease.

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.

• Authors: 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 Seidman, Bruce D Gelb, Giorgio Colombo, Bruce R Conklin, Brian L Black, Benoit G Bruneau, Nevan J Krogan, Katherine S Pollard, Deepak Srivastava
• Journal: Cell (Cell) Vol. 185 Issue 5 Pg. 794-814.e30 (03 03 2022) ISSN: 1097-4172 [Electronic] United States
• PMID: 35182466 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• GATA4 Transcription Factor
• Gata4 protein, mouse
• Nuclear Proteins
• T-Box Domain Proteins
• Transcription Factors
• Glyr1 protein, mouse
• Oxidoreductases

Topics

• Animals
• GATA4 Transcription Factor (metabolism)
• Heart Defects, Congenital (genetics)
• Mice
• Mutation
• Nuclear Proteins (metabolism)
• Oxidoreductases (metabolism)
• Proteomics
• T-Box Domain Proteins (genetics)
• Transcription Factors (genetics)