Although not widely known, RASopathies are among the most common
genetic disorders, affecting approximately one child out of 1,000.
RASopathies are caused by mutations within the RAS pathway, a
biochemical system cells use to transmit information from their exterior
to their interior.
Two Princeton University studies are opening important new windows
into understanding RASopathies that are characterized by distinct facial features,
developmental delays, cognitive impairment and heart problems. The
findings could help point the way toward personalized precision
therapies for these conditions.
‘A way to rank the severity of different mutations involved in RASopathies has been presented in a new study.’
"Human development is very complex and it's amazing that it goes
right so often. However, there are certain cases where it does not, as
with RASopathies," said Granton Jindal, co-lead author of the two
studies. Both Jindal and the other co-lead author, Yogesh Goyal, are
graduate students in the Department of Chemical and Biological
Engineering and the Lewis-Sigler Institute for Integrative Genomics
(LSI). Jindal and Goyal do their thesis research in the lab of Stanislav
Shvartsman, professor of chemical and biological engineering and LSI.
"Our new studies are helping to explain the mechanisms underlying these disorders," Jindal said.
These studies were published this year, one in the Proceedings of the National Academy of Sciences
(PNAS) and the other in Nature Genetics
online. The researchers made the discoveries in zebrafish and fruit
flies - animals commonly used as simplified models of human genetics
and Jindal and Goyal's specialties, respectively.
Due to the
evolutionary similarities in the RAS pathway across diverse species,
changes in this pathway would also be similar. Thus, it is likely that
significant parts of findings in animals would apply to humans as well,
although further research is needed to confirm this.
The first paper published in PNAS
presented a way to rank the severity of different mutations involved in
RASopathies. The researchers introduced 16 mutations one at a time in
developing zebrafish embryos. As each organism developed, clear
differences in the embryos' shapes became evident, revealing the
strength of each mutation.
The same mutant proteins produced similarly
varying degrees of defects in fruit flies. Some of the mutations the
researchers tested were already known to be involved in human cancers.
The researchers noted that these cancer-related mutations caused more
severe deformations in the embryos, aligning with the medical
community's ongoing efforts to adapt anti-cancer compounds to treat
"Until now, there was no systematic way of comparing different mutation severities for RASopathies effectively," Goyal said.
Jindal added, "This study is an important step for personalized
medicine in determining a diagnosis to a first approximation." The study
therefore suggested a path forward to human diagnostic advances,
potentially enabling health care professionals to offer better diagnoses
and inform caretakers about patients' disease progression.
The study went further and examined the use of an experimental
cancer-fighting drug being investigated as a possible way to treat
RASopathies. The researchers demonstrated that the amount of medication
necessary to correct the developmental defects in the zebrafish embryos
corresponded with the mutation's severity - more severe mutations
required higher dosages.
The more recent paper, published online by Nature Genetics
reports an unexpected twist in treatment approach to some RASopathies.
Like all cellular pathways, the RAS pathway is a series of molecular
interactions that changes a cell's condition. Conventional wisdom has
held that RASopathies are triggered by overactive RAS pathways, which a
biologist would call excessive signaling.
The Nature Genetics
study, however, found that some RASopathies
could result from insufficient signaling along the RAS pathway in
certain regions of the body. This means that drugs intended to treat
RASopathies by tamping down RAS pathway signaling might actually make
certain defects worse.
"To our knowledge, our study is the first to find lower signaling
levels that correspond to a RASopathy disease," Goyal said. "Drugs under
development are primarily RAS-pathway inhibitors aimed at reducing the
higher activity, so maybe we need to design drugs that only target
specific affected tissues, or investigate alternative, novel treatment
The Nature Genetics
study also found that gRAS pathway mutations
cause defects by changing the timing and specific locations of embryonic
development. For example, in normal fruit fly cells, the RAS pathway
only turns on when certain natural cues are received from outside the
cell. In the mutant cells, however, the RAS pathway in certain parts of
fly embryo abnormally activated before these cues were received. This
early activation disturbed the delicate process of embryonic
development. The researchers found similar behavior in zebrafish cells.
"Our integrative approach has allowed us to make enormous progress
in understanding RASopathies, some of which have just been identified in
the last couple of decades," Shvartsman said. "With continued steps
forward in both basic and applied science, as we've shown with our new
publications, we hope to develop new ideas for understanding and
treatment of a large class of developmental defects."
Princeton co-authors of the two papers include Trudi Schüpbach, the
Henry Fairfield Osborn Professor of Biology and professor of molecular
biology, and Rebecca Burdine, an associate professor of molecular
biology, as well as co-advisers to Goyal and Jindal; Alan Futran, a
former graduate student in the Department of Chemical and Biological
Engineering and LSI; graduate student Eyan Yeung of the Department of
Molecular Biology and LSI; José Pelliccia, a graduate student in the
Department of Molecular Biology; seniors in molecular biology Iason
Kountouridis and Kei Yamaya; and Courtney Balgobin Class of 2015.
Bruce Gelb, a pediatric cardiologist specializing in cardiovascular
genetics and the director of the Mindich Child Health and Development
Institute at the Mount Sinai School of Medicine in New York, described
the two new studies as "wonderful" in advancing the understanding of
altered biology in RASopathies and developing a framework for comparing
mutation strengths, bringing effective treatments significantly closer.
"At this time, most of the issues that arise from the RASopathies
are either addressed symptomatically or cannot be addressed," Gelb said.
"The work [these researchers] are undertaking could lead to true
therapies for the underlying problem."
The paper, "In vivo severity ranking of Ras pathway mutations
associated with developmental disorders," was published in the Proceedings of the National Academy of Sciences
The paper, "Divergent effects of intrinsically active MEK variants on
developmental Ras signaling," was published in Nature Genetics
online. The research for both papers was supported in part by the
National Institutes of Health and the National Science Foundation.