When a protective gene buffers a bad one, a heart can beat

Date:
February 15, 2022
Source:
University of Pittsburgh
Summary:
It was a medical mystery: When scientists induced a particular
genetic mutation in mouse eggs, the resulting embryos would all
die in the womb within a week. And yet, people with the same
troublesome gene are thriving.



FULL STORY ==========================================================================
It was a medical mystery: When University of Pittsburgh School of
Medicine scientists induced a particular genetic mutation in mouse eggs,
the resulting embryos would all die in the womb within a week.


==========================================================================
And yet, people with the same troublesome gene are thriving.

"This gene is clearly very deleterious -- the mice did not even develop
a heartbeat, let alone survive to birth," said Cecilia Lo, Ph.D.,
distinguished professor and F. Sargent Cheever Chair of Pitt's Department
of Developmental Biology. "That led us to wonder: How are people who we
know have this gene walking around?" The team found that a protective
gene was countering the bad one, explaining why some people with this
very deleterious gene not only survived but did so with only an atrial
septal defect -- a hole in the heart. The findings - - reported today
in Cell Reports Medicine -- provide valuable clinical and personal
information to guide families with a history of the disease and could
lead to future genetic treatments.

Congenital heart disease is one of the most common birth defects,
affecting about 1% of live births. Atrial septal defects -- which
involve a hole in the wall between the upper chambers of the heart,
allowing blood to flow in ways that can damage the heart and lungs --
are among the most common forms of congenital heart disease, affecting
as many as 10,000 babies born in the U.S.

each year.

Working with Brian Feingold, M.D., M.S., medical director of the pediatric heart failure and heart transplant programs at UPMC Children's Hospital
of Pittsburgh, Lo's team obtained genetic samples from eight members of
a family who all had large atrial septal defect. Whole genome sequencing revealed that they all carried an extremely rare mutation in a gene called
TPM1 that didn't appear in more than 900 unrelated samples from people
with congenital heart disease; worldwide, it has been seen only twice.



==========================================================================
To learn more about this genetic mutation, Lo's team used CRISPR-Cas9
gene editing to introduce this mutation in mouse embryos. The embryos
would develop normally to about 8.5 days -- exactly when the heart should
start to beat - - and then die without a heartbeat. Co-lead author Xinxiu "Cindy" Xu, Ph.D., a postdoctoral associate at Pitt, determined that
the TPM1 mutation was inhibiting production of a protein essential for
heart beating.

The mouse deaths and the extreme rarity in humans indicated that nobody
with this mutation should live, but since the scientists had genetic
samples from eight related people with beating hearts, Xu created a "disease-in-a-dish" model to see what would happen with the patient
cells in a petri dish. This confirmed the patient-derived heart cells
beat normally.

So, Lo's team knew there had to be more to the story. That's when they
started to suspect a protective gene was at play. They went back to the
drawing board and further scoured the genomic sequences.

"With the modern tools we have for exploring genetics, we're learning
that not everything is as it seems," Lo said. "There are complexities that
are important for our understanding of the genetic etiology of disease." Focusing on the same three sections of the chromosome inherited by all
eight family members, Lo's team found nine additional genetic variations
in close proximity to the bad TPM1 mutation. Only one -- TLN2 -- was co-expressed with TPM1 in the cardiac cells responsible for making the
heart beat.



==========================================================================
When the team introduced both the deleterious and protective mutations simultaneously in the mouse embryos, beating hearts were observed. Atrial septal defect still occurred, as seen in the family members with these
two mutations. The protective gene wasn't strong enough to completely
overpower the damage caused by the bad one, but the heart could beat
well enough to sustain life.

The discovery can have immediate implications for helping families
understand the risk of passing the mutations to future generations,
as well as help guide clinical treatment, such as prompting doctors to
consider early treatments or more frequent assessments for heart dilation
and rhythm disturbances. For example, with some heartbeat irregularities, surgically implanting a pacemaker or a defibrillator could be helpful
in restoring normal heart beating.

Scientific advances also can uncover big picture implications,
Lo said. "The future of genetic therapy doesn't have to be about
turning off bad genes. It can also be about turning on good ones."
Additional co-lead authors on this research are Polakit Teekakirikul,
M.D., of Pitt and the Chinese University of Hong Kong; Wenjuan Zhu,
Ph.D., of the Chinese University of Hong Kong; and Cullen B. Young, of
Pitt. Additional authors are listed in the Cell Reports Medicine article.

This research was supported by National Institutes of Health grants
HL132024, HL142788 and R01HL036153. Additional funding sources are listed
in the Cell Reports Medicine article.

========================================================================== Story Source: Materials provided by University_of_Pittsburgh. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Polakit Teekakirikul, Wenjuan Zhu, Xinxiu Xu, Cullen B. Young,
Tuantuan
Tan, Amanda M. Smith, Chengdong Wang, Kevin A. Peterson, George C.

Gabriel, Sebastian Ho, Yi Sheng, Anne Moreau de Bellaing, Daniel A.

Sonnenberg, Jiuann-huey Lin, Elisavet Fotiou, Gennadiy Tenin,
Michael X.

Wang, Yijen L. Wu, Timothy Feinstein, William Devine, Honglan
Gou, Abha S. Bais, Benjamin J. Glennon, Maliha Zahid, Timothy
C. Wong, Ferhaan Ahmad, Michael J. Rynkiewicz, William J. Lehman,
Bernard Keavney, Tero- Pekka Alastalo, Mary-Louise Freckmann,
Kyle Orwig, Steve Murray, Stephanie M. Ware, Hui Zhao, Brian
Feingold, Cecilia W. Lo. Genetic resiliency associated with
dominant lethal TPM1 mutation causing atrial septal defect with
high heritability. Cell Reports Medicine, 2022; 3 (2): 100501 DOI:
10.1016/j.xcrm.2021.100501 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220215113408.htm
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