A Thorough NUDT15 Variant Catalogue

Thiopurine drugs serve a wide variety of purposes – from treating childhood leukemias to managing autoimmune disorders. However, not all patients tolerate thiopurines equally well. Until recently, doctors couldn’t predict how individual patients might react to treatment – but a research group at St. Jude Children’s Research Hospital in Memphis, Tennessee, recently catalogued almost every variant in the NUDT15 enzyme to better understand the potential for side effects (1). Senior author Jun Yang tells us more…

We first discovered that NUDT15 regulates drug toxicity in 2015 – and the evidence that the NUDT15 gene can predict side effects of thiopurines continues to grow. There are many variants in this gene, but the vast majority have been not studied carefully, so we do not know if they cause drug toxicity. A couple of years ago, we launched a major effort to map every possible pharmacogenetic variant in the NUDT15 gene – a lofty goal, but one whose results are very exciting.

NUDT15 breaks down thiopurine drug metabolites; its activity is important to keep toxicity in check. Some genetic variants disrupt the protein’s function. Patients with these loss-of-function genetic variants cannot break down thiopurine drugs and have excessive toxicities.

There are lots of NUDT15 variants in humans. Traditional characterization requires the creation of each variant protein one at a time – extremely tedious and obviously not scalable. Our new high-throughput method studies the function of thousands of variants simultaneously by introducing each one into a single cell and then characterizing tens of thousands of cells.

Our results offer a comprehensive reference of potential pharmacogenetic variants in NUDT15. Most diagnostic laboratories currently test only a couple of variants in the context of thiopurine pharmacogenetics – but there are many more variants equally likely to cause thiopurine toxicities. The data is particularly relevant when NUDT15 is sequenced and novel variants identified. In the past, these variants would have been considered of “unknown significance.” Now, labs can look up their variants in our data for an improved understanding of their results.

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References

1. CC Suiter et al., Proc Natl Acad Sci USA, 117, 5394 (2020). PMID: 32094176.

About the Author(s)

Michael Schubert

While obtaining degrees in biology from the University of Alberta and biochemistry from Penn State College of Medicine, I worked as a freelance science and medical writer. I was able to hone my skills in research, presentation and scientific writing by assembling grants and journal articles, speaking at international conferences, and consulting on topics ranging from medical education to comic book science. As much as I’ve enjoyed designing new bacteria and plausible superheroes, though, I’m more pleased than ever to be at Texere, using my writing and editing skills to create great content for a professional audience.

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