New Insights into NARS1: Understanding How Mutations Affect Our Children
We’re so proud to share that Dr. Ingrid Vallée, our very own scientific advisor at The Rory Belle Foundation, has had a major research paper published as part of her PhD.
Ingrid completed her PhD at Scripps Research in San Diego, California, where she worked in the laboratory of Professor Xiang-Lei Yang. Her research focused on a group of essential proteins called aminoacyl-tRNA synthetases, and in particular one called NARS1, the very gene that affects our children.
This work, which was made possible thanks to funding from The Rory Belle Foundation and Uplifting Athletes, has helped us move a step closer to understanding how mutations in NARS1 change the way the protein works inside cells. In this paper, she studied two specific NARS1 mutations (R534* and R545C) and looked at how they disrupt the protein’s activity.
This is complex science – but every piece of knowledge is another step toward understanding how NARS1 disorder develops, and ultimately how we might one day target the faulty protein with treatment.
What did the Research Look At?
Ingrid and her colleagues wanted to understand what happens when the NARS1 gene has changes (mutations) and how these changes affect the cells in our body. Normally, the NARS1 gene provides the instructions for making a tool inside our cells called the AsnRS enzyme, which is essential for life.
They focused on two specific changes (mutations) in the NARS1 gene, called R534* and R545C. Both of these have been linked to severe forms of NARS1 disorder.
The big question was: why does R534* cause such significant problems, even when the “healthy” version of the gene is still present? In contrast, R545C only causes issues when both copies of the gene carry the change.
By looking closely at what happens inside cells, they compared the two mutations to understand how they behave differently and why one is more damaging than the other.
What We Found
Here’s where it gets interesting. They discovered that the R534* mutation is especially harmful because it interferes with the healthy version of the protein, like a broken tool jamming the rest of the toolbox.
The faulty R534* protein is produced in the same amounts as the healthy one.
It cannot do its job, so normal cell function slows down.
It “sticks” to the healthy protein, stopping it from working too. This is called a dominant negative effect because the faulty version takes over and causes damage.
By comparison, R545C does not interfere in the same way, which explains why symptoms only appear if no healthy version is left.
Why Does this Matter for Nars1 Families?
For families, the key takeaway is that scientists are getting closer to understanding why certain NARS1 mutations affect children differently.
In the case of R534*, the faulty protein doesn’t just sit there, it blocks the healthy protein too. This gives researchers important clues about where future therapies might focus. For example, if treatments could remove or “switch off” the faulty version, the healthy one might be able to work properly again.
It also helps us understand how healthy NARS1 usually works. The more scientists know about the normal role of NARS1, the quicker they can recognise when something is going wrong.
This is still early research, but it brings us a step closer to answers. It also shows the value of investing in fundamental science, every piece of the puzzle brings us closer to a better future for children with NARS1 disorder.
So, What’s Next?
This is just the beginning of the journey. Ingrid and her colleague’s work lays the groundwork for future studies and therapeutic ideas. The next step is to see how these findings play out on a bigger scale, not just in single cells but across tissues, organs and even whole organisms.
Researchers will use different models (such as yeast, cells and mice) to study what happens when NARS1 function is lost and to test whether potential therapies can restore it.
Every piece of research adds to the bigger picture. Thanks to your continued support, the RBF community is helping to build the roadmap from lab discoveries all the way to possible treatments.