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Integration of Protein Interactome Networks With Congenital Heart Disease Variants Reveals Candidate Disease Genes

101 Pages Posted: 25 Nov 2020 Publication Status: Published

See all articles by Barbara Gonzalez-Teran

Barbara Gonzalez-Teran

Gladstone Institutes

Maureen Pittman

Gladstone Institutes

Franco Felix

Gladstone Institutes

Desmond Richmond-Buccola

Gladstone Institutes

Reuben Thomas

Gladstone Institutes

Krishna Choudhary

Gladstone Institutes

Elisabetta Moroni

SCITEC-CNR

Giorgio Colombo

University of Pavia - Department of Chemistry

Michael Alexanian

Gladstone Institutes

Bonnie Cole

Gladstone Institutes

Kaitlen Samse-Knapp

Gladstone Institutes

Michael McGregor

Gladstone Institutes

Casey A. Gifford

Gladstone Institutes

Ruth Huttenhain

Gladstone Institutes

Bruce D. Gelb

Icahn School of Medicine at Mount Sinai - Department of Genetics and Genomic Sciences, Mindich Child Health and Development Institute, and Department of Pediatrics

Bruce Conklin

Gladstone Institutes

Brian L. Black

University of California, San Francisco - Cardiovascular Research Institute

Benoit G. Bruneau

Gladstone Institutes

Nevan J. Krogan

Gladstone Institutes; Mount Sinai Health System - Department of Microbiology; University of California, San Francisco (UCSF) - Quantitative Biosciences Institute

Katherine S. Pollard

Gladstone Institutes

Deepak Srivastava

Gladstone Institutes

More...

Abstract

Congenital heart disease (CHD) is present in 1% of live births, yet identification of causal mutations remains a challenge despite large-scale genomic sequencing efforts. We hypothesized that genetic determinants for CHDs may lie in protein interactomes of GATA4 and TBX5, two transcription factors that cause CHDs. Defining their interactomes in human cardiac progenitors via affinity purification-mass spectrometry and integrating results with genetic data from the Pediatric Cardiac Genomic Consortium revealed an enrichment of de novo variants among proteins that interact with GATA4 or TBX5. A consolidative score that prioritized interactome members based on variant, gene, and proband features identified likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied cardiac developmental genes, resulting in co-activation, and the GLYR1 missense variant associated with CHD disrupted interaction with GATA4. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating the contribution of genetic variants in disease.

Suggested Citation

Gonzalez-Teran, Barbara and Pittman, Maureen and Felix, Franco and Richmond-Buccola, Desmond and Thomas, Reuben and Choudhary, Krishna and Moroni, Elisabetta and Colombo, Giorgio and Alexanian, Michael and Cole, Bonnie and Samse-Knapp, Kaitlen and McGregor, Michael and Gifford, Casey A. and Huttenhain, Ruth and Gelb, Bruce D. and Conklin, Bruce and Black, Brian L. and Bruneau, Benoit G. and Krogan, Nevan J. and Krogan, Nevan J. and Pollard, Katherine S. and Srivastava, Deepak, Integration of Protein Interactome Networks With Congenital Heart Disease Variants Reveals Candidate Disease Genes. Available at SSRN: https://ssrn.com/abstract=3737640 or http://dx.doi.org/10.2139/ssrn.3737640
This version of the paper has not been formally peer reviewed.

Barbara Gonzalez-Teran

Gladstone Institutes ( email )

1650 OWENS STREET
San Francisco, CA 94158
United States

Maureen Pittman

Gladstone Institutes ( email )

1650 OWENS STREET
San Francisco, CA 94158
United States

Franco Felix

Gladstone Institutes ( email )

1650 OWENS STREET
San Francisco, CA 94158
United States

Desmond Richmond-Buccola

Gladstone Institutes ( email )

1650 OWENS STREET
San Francisco, CA 94158
United States

Reuben Thomas

Gladstone Institutes

1650 OWENS STREET
San Francisco, CA 94158
United States

Krishna Choudhary

Gladstone Institutes ( email )

1650 OWENS STREET
San Francisco, CA 94158
United States

Elisabetta Moroni

SCITEC-CNR ( email )

Giorgio Colombo

University of Pavia - Department of Chemistry

Italy

Michael Alexanian

Gladstone Institutes ( email )

1650 OWENS STREET
San Francisco, CA 94158
United States

Bonnie Cole

Gladstone Institutes ( email )

1650 OWENS STREET
San Francisco, CA 94158
United States

Kaitlen Samse-Knapp

Gladstone Institutes ( email )

1650 OWENS STREET
San Francisco, CA 94158
United States

Michael McGregor

Gladstone Institutes

1650 OWENS STREET
San Francisco, CA 94158
United States

Casey A. Gifford

Gladstone Institutes

1650 OWENS STREET
San Francisco, CA 94158
United States

Ruth Huttenhain

Gladstone Institutes ( email )

1650 OWENS STREET
San Francisco, CA 94158
United States

Bruce D. Gelb

Icahn School of Medicine at Mount Sinai - Department of Genetics and Genomic Sciences, Mindich Child Health and Development Institute, and Department of Pediatrics ( email )

One Gustave L. Levy Place
New York, NY 10029-6574
United States

Bruce Conklin

Gladstone Institutes ( email )

1650 OWENS STREET
San Francisco, CA 94158
United States

Brian L. Black

University of California, San Francisco - Cardiovascular Research Institute ( email )

Third Avenue and Parnassus
San Francisco, CA 94143
United States

Benoit G. Bruneau

Gladstone Institutes ( email )

1650 OWENS STREET
San Francisco, CA 94158
United States

Nevan J. Krogan

Gladstone Institutes ( email )

1650 OWENS STREET
San Francisco, CA 94158
United States

Mount Sinai Health System - Department of Microbiology ( email )

United States

University of California, San Francisco (UCSF) - Quantitative Biosciences Institute ( email )

Katherine S. Pollard (Contact Author)

Gladstone Institutes ( email )

1650 OWENS STREET
San Francisco, CA 94158
United States

Deepak Srivastava

Gladstone Institutes ( email )

1650 OWENS STREET
San Francisco, CA 94158
United States

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