| Literature DB >> 35182466 |
Barbara Gonzalez-Teran1, Maureen Pittman2, Franco Felix1, Reuben Thomas3, Desmond Richmond-Buccola1, Ruth Hüttenhain4, Krishna Choudhary3, Elisabetta Moroni5, Mauro W Costa1, Yu Huang1, Arun Padmanabhan6, Michael Alexanian1, Clara Youngna Lee1, Bonnie E J Maven7, Kaitlen Samse-Knapp1, Sarah U Morton8, Michael McGregor4, Casey A Gifford1, J G Seidman9, Christine E Seidman10, Bruce D Gelb11, Giorgio Colombo12, Bruce R Conklin1, Brian L Black13, Benoit G Bruneau14, Nevan J Krogan4, Katherine S Pollard15, Deepak Srivastava16.
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.Entities:
Keywords: GATA4; GLYR1; NPAC; TBX5; congenital heart disease; de novo variants; disease variants; genetics; protein interactome networks
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Year: 2022 PMID： 35182466 PMCID： PMC8923057 DOI： 10.1016/j.cell.2022.01.021
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 66.850