Transcription factor protein interactomes reveal genetic determinants in heart disease.
Cell
; 185(5): 794-814.e30, 2022 03 03.
Article
in En
| MEDLINE
| ID: mdl-35182466
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Oxidoreductases
/
Transcription Factors
/
Nuclear Proteins
/
GATA4 Transcription Factor
/
Heart Defects, Congenital
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Cell
Year:
2022
Type:
Article
Affiliation country:
United States