Understanding NARS1: How Yeast Can Help Unlock the Mysteries of NARS1 Disorder

When it comes to understanding rare genetic conditions like NARS1 Disorder, every new piece of research brings us one step closer to answers, and hopefully, one day, treatments.

A recent study from Professor Antony Antonellis’ laboratory conducted by Sheila Peeples has taken an exciting step forward. While it might sound unusual, this work uses yeast (yes, the same kind used in baking!) to help scientists understand how changes in the NARS1 gene affect the body.

Why Study Yeast?

It might seem strange that something as tiny as yeast could teach us about a human condition. But yeast actually shares many similarities with our own cells, and it grows quickly, making it ideal for studying how genes work.

Drop-inoculation of laboratory baker´s yeast (Saccharomyces cerevisiae) mutants on agar plate. By Rainis Venta (Own work) [CC BY-SA 3.0], via Wikimedia Commons

In this study, researchers wanted to see what happens when the NARS1 gene doesn’t work as it should. The NARS1 gene makes a protein that’s essential for life. In yeast, like in humans, if this gene is removed, the yeast can’t survive.

However, scientists can “rescue” the yeast by adding a human version of the NARS1 gene, allowing it to live and grow again. This clever approach means they can swap in different variants (or mutations) of the human NARS1 gene to see how each one affects the yeast’s ability to survive.

If the yeast grows normally, the variant doesn’t seem to cause harm. But if growth slows down or stops, that suggests the variant damages the NARS1 protein’s function, something scientists call a loss of function.

What the Research Looked at

There are different types of NARS1 variants that can cause health problems.

Some cause NARS1 Disorder, which can affect development and the brain. Others cause a different condition called Charcot-Marie-Tooth disease (CMT), which tends to affect the nerves in the hands and feet, leading to muscle weakness, high-arched feet, and reduced sensation.

Although both conditions are caused by variants in the same gene, the symptoms, and their severity, are very different.

In this study, the team compared several NARS1 variants, including those linked to both NARS1 Disorder and CMT, to understand how each one affects the gene’s activity.

What the Research Found

The results were clear and align with previous research:

• Loss of Function (LOF): Six of the seven variants tested (both NARS1 Disorder and CMT) caused the yeast to struggle and grow poorly. This confirmed that the variants cause a loss of NARS1 activity.

• Dominant-Negative Effect: When the researchers paired a healthy NARS1 copy with a mutated copy, the healthy gene couldn't compensate. The mutated copy was dominant, meaning it actively interfered with the healthy NARS1 protein. This is what scientists call a dominant-negative effect.

Severity Matters: Crucially, the variants that cause NARS1 disorder had a greater negative (toxic) effect on the yeast than the variants that cause CMT. This suggests a direct link: the greater the loss of NARS1 activity, the more severe the disease outcome.

Why does this research matter to NARS1 Families?

This study represents a huge step forward in the Care and Change we strive for.

1. We Have a Stronger Foundation: Science gets stronger when different labs find the same results using different models. This research confirms what a previous study suggested: we now have independent, consolidated proof of the NARS1 Disorder mechanism. This solid foundation is critical when we move towards launching clinical trials.

2. We Have a New Tool for Testing Treatments: Yeast is a highly effective model for drug testing, scientists call it "drugable." Because the researchers successfully mirrored the disease severity in yeast, they now have a fast, accessible model ready to test potential drugs, such as asparagine. This model moves us closer to finding a path to treatment before we invest in more complex, expensive models.

What Happens Next?

This study is the purposeful groundwork for the next wave of discoveries. The Antonellis lab's model is now a powerful starting point.

Our next steps, alongside our research partners, are to:

• Translate these findings to more complex models, including human cell lines and eventually, whole organisms like mice.

• Test potential therapies, seeing if we can restore NARS1 function and reverse the dominant-negative effect.

We champion the research that creates this roadmap from the lab to treatments. Every family who supports our mission helps build that roadmap.