SAN FRANCISCO, Feb. 18, 2022 /PRNewswire/ -- Nearly 1
percent of all children are born with congenital heart disease—a
range of potentially life-threatening problems with the structure
and function of their hearts. For most children, the precise causes
of these frightening defects are unknown.
The culprits appear to be abnormal versions, or variants, of
genes that are involved in the formation of the heart in the womb.
But much remains to be learned about exactly which genes contribute
to congenital heart disease and how they interact with each
other.
Now, reported in the scientific journal Cell, researchers
at Gladstone Institutes have developed a novel method for
identifying genetic variants that are likely to play important
roles in congenital heart disease, opening up opportunities to
accelerate research into this serious condition. The study was led
by Gladstone President and Senior Investigator Deepak Srivastava, MD, and Katie Pollard, PhD, director of the Gladstone
Institute of Data Science and Biotechnology.
The new strategy—which combines techniques from genetics,
computational biology, stem cell biology, and proteomics—could also
be applied to study numerous other diseases with complex genetic
causes.
"Previous methods have generated long lists of variants detected
in patients, but many actually turned out to be inconsequential, so
a major challenge in the field has been identifying which variants
are most important," says Srivastava, who is also a pediatric
cardiologist and a professor in the Department of Pediatrics at UC
San Francisco (UCSF). "Our approach pinpoints variants that are
most likely to be involved in disease, allowing us to focus on
those variants, deepen understanding of the underlying biology of
the disease, and, we hope, move more rapidly toward new
treatments."
Leveraging Interactions between Proteins
Rather than looking at variants in isolation, the novel strategy
considers the interactions between proteins to zero in on which
might variants be causing disease—in this case, congenital heart
disease.
The proteins GATA4 and TBX5 were already known to be required
for healthy human heart formation, and to collaborate with a
network of additional proteins to help grow a heart. Mutations in
the other proteins in the network could, in theory, contribute to
heart malformation.
To identify these potential culprit genes, the researchers
carefully mapped out the entire network of interactions between the
GATA4 and TBX5 proteins using precursor heart cells grown from
human induced pluripotent stem cells. Next, they cross-referenced
this 273-protein network with DNA sequencing data from over 3,000
children with congenital heart disease and their parents, developed
by a National Institutes of Health–funded consortium.
Several dozen variants in the children's sequencing data matched
specific proteins also found in the GATA4-TBX5 network, far more
than expected, pinpointing them as candidates that may contribute
to congenital heart disease.
"We first identified important protein networks in the types of
cells affected in congenital heart disease, and then integrated
large-scale, protein-coding sequencing data," says Bárbara González
Terán, PhD, lead author of the study and a postdoctoral scholar in
Srivastava's lab. "Many scientists had speculated this approach was
possible, but to our knowledge, this is the first time it has
actually been done, for any disease."
New Top-Ranking Variant Discovered
Determining whether each of the candidate variants identified in
the GATA4-TBX5 network actually contribute to heart disease would
involve years of research. So instead, for the final step of their
new method, Maureen Pittman, a UCSF
graduate student in Pollard's lab, developed a computational tool
that ranks the candidates according to their likelihood of
contributing to congenital heart disease. This ranking algorithm
takes into account characteristics of the variant, the affected
gene, and the type of heart defect found in patients with the
variant.
"Of the top-ranking variants we identified with the algorithm,
some were in genes already known to contribute to congenital heart
defects," says Pittman. "But many had never before been linked to
heart development, including a protein called GLYR1, which is
involved in turning other genes on and off."
Additional experiments in cells and mice indicated that GLYR1
indeed plays a central role in the formation of the heart, and a
patient variant of GLYR1 disrupts heart development by hampering
its interaction with GATA4.
"Identifying GLYR1 as a key gene in heart development opens up a
whole new biological space for understanding how this system
works," says Srivastava. "We will continue to study the biology of
GLYR1, and we hope that others will follow up on the other
high-scoring variants we found."
Srivastava notes that the new study relied heavily not only on
computational techniques developed in the Pollard Lab, but also on
proteomics techniques from the lab of Nevan
Krogan, PhD, senior investigator at Gladstone and director
of the Quantitative Biosciences Institute at UCSF.
"The dynamic and teamwork-focused efforts at Gladstone really
made this possible," says Srivastava.
A New Tool for Studying Complex Disease
Thanks to advancements in surgery, millions of children with
heart defects now survive to adulthood. But many continue to face
lifelong problems, such as an increased risk of heart failure.
"A better understanding of the genetic basis of congenital heart
disease could point to new strategies for not only blocking the
development of the disease, which is currently very challenging,
but also for alleviating issues that persist after surgery in order
to improve quality and length of life," says González Terán.
The researchers believe the power of their new method lies in
its promise to help illuminate how combinations of variants—rather
than single variants on their own—work together to cause congenital
heart disease.
"Rarely is this disease caused by a single gene; a patient with
the GLYR1 variant, for instance, could perhaps have additional
variants inherited from their parents that by themselves were not
enough to cause disease, but do so alongside the GLYR1 variant,"
says Pollard, who is also a professor at UCSF and a Chan Zuckerberg
Biohub investigator. "Our new approach could help identify specific
combinations of variants that cause heart defects."
This method could also be adapted to identify combinations of
variants that may underlie other complex diseases. For instance,
Pollard's team is already looking into applying it to
neurodevelopmental disorders, including autism and epilepsy.
"With more and more sequencing data being generated every year
from patients with complex diseases, our approach will help guide
where to focus among all the detected variants," Srivastava
says.
About the Study
The paper, "Transcription Factor Protein Interactomes Reveal
Genetic Determinants in Heart Disease," was published by the
journal Cell on February 18,
2022.
Other authors are Franco Felix,
Reuben Thomas, Desmond Richmond-Buccola, Ruth Hüttenhain,
Krishna Choudhary, Mauro W.Costa, Yu
Huang, Arun Padmanabhan,
Michael Alexanian, Clara Youngna
Lee, Bonnie E. J. Maven,
Kaitlen Samse-Knapp, Michael McGregor, Casey
A. Gifford, Bruce R. Conklin,
and Benoit G. Bruneau of Gladstone;
Elisabetta Moroni of SCITEC-CNR in
Italy; Sarah U. Morton of Boston Children's Hospital;
J. G. Seidman and Christine E.
Seidman of Harvard Medical
School; Bruce D. Gelb of the
Icahn School of Medicine at Mount Sinai; Giorgio Colombo of the University of Pavia,
Italy; and Brian L. Black of UCSF.
The work was supported by the National Institutes of Health
(grants P01 HL098707, P01 HL146366, R01 HL057181, R01HL127240, UM1
HL098179, 1U01MH115747), the American Heart Association, and
Gladstone. The researchers were also supported by an AHA/CHF
Congenital Heart Defect Research Award, the Swiss National Science
Foundation, the San Simeon Fund, the Roddenberry Foundation, the
L.K. Whittier Foundation, the Younger Family Fund, the
Tobacco–Related Disease Research Program, the A. P. Giannini
Foundation, the Michael Antonov Charitable Foundation, the Sarnoff
Cardiovascular Research Foundation, and the Boston Children's
Hospital Office of Faculty Development.
About Gladstone Institutes
To ensure our work does the greatest good, Gladstone Institutes
focuses on conditions with profound medical, economic, and social
impact—unsolved diseases. Gladstone is an independent, nonprofit
life science research organization that uses visionary science and
technology to overcome disease. It has an academic affiliation with
the University of California, San
Francisco.
Media Contact: Julie Langelier |
Associate Director, Communications | julie.langelier@gladstone.org
| 415.734.5000 |1650 Owens Street, San
Francisco, CA 94158 | gladstone.org |
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