The Huck Institutes of the Life Sciences

Studying rare genetic mutations with metabolomics

The Hanna-Rose Lab’s collaboration with the Metabolomics Facility yields new discoveries, projects, and funding.

“We use a small nematode, C. elegans,” says Wendy Hanna-Rose, “as a model system to study development and reproductive function through forward genetics. You don’t always know where you’re going with forward genetics, because you end up with a mutant and you don’t know what the responsible gene is, but we figured out that we were dealing with a mutation that affected metabolism.”

Hanna-Rose explains that, through a program at the National Institutes of Health, she was able to secure supplemental funding to pursue a metabolomics-based approach in collaboration with Andrew Patterson, Philip Smith, and the Metabolomics Facility.

“I’m relatively new to using these tools,” she says, “but a substantial part of what we do now in the lab is focused on using metabolomics in combination with genetics to understand development, reproductive function, muscle function – actually a lot of different phenotypes – in our model system.”

Hanna-Rose is quick to stress the impact that Patterson, Smith, and the Metabolomics Facility have had on her work.

“I want to say that without Andrew, Phil, and the Facility, we wouldn’t have made the progress that we have on our project,” she states. “It became really clear that, through genetics, we can manipulate all the genes in C. elegans without too much difficulty; but you don’t exactly know what’s happening until you can get in there and measure at that level. So we developed, with Andrew and Phil, the metabolomics tools to be able to do that in our model system.”

New direction

Hanna-Rose explains that her initial funding was for studying the metabolism of a specific coenzyme known as nicotinamide adenine dinucleotide (NAD), but after developing her lab’s new metabolomics assays, she decided to take her work in a different direction.

“I felt like we were in a very unique position,” she says. “We’re C. elegans developmental geneticists and we know this system really well – I’ve studied development in this system for 20 years – but we had added on this capability of looking at the metabolome, and I knew that there would be other problems out there where we could apply our skills. So after doing a fair amount of reading and thinking, I settled on purine metabolism as a new project to go after, most of all because the phenotypes in some of the related diseases – Lesch–Nyhan syndrome and adenylosuccinate lyase deficiency – really intrigued me.”

“They’re actually both very rare,” Hanna-Rose explains, “and they’re both caused by mutations in the genes required to make or recycle purines – which are necessary for DNA synthesis. These diseases have intriguing links to very specific neurological dysfunctions – Lesch–Nyhan syndrome is often first definitively diagnosed because of the associated compulsive self-injury behavior, and kids with adenylosuccinate lyase deficiency have autistic-like features – and nobody really understands the mechanisms that are causing these dysfunctions in the nervous system.”

According to the National Organization for Rare Disorders, Lesch–Nyhan syndrome occurs at a rate of roughly 1 in 380,000 births in the United States, and adenylosuccinate lyase deficiency has been diagnosed, to date, in about 90 individuals worldwide.

Given the rarity of these diseases, funding for related scientific studies is extremely limited.

“And so I thought,” says Hanna-Rose, “worms are going to be a useful system for studying these diseases. Because these conditions are very rare and there’s not as much money put into studying them, you can’t afford to do mouse models, but worms are cheap and fast. If we can model the disease in worms, working with the Metabolomics Facility to understand what’s happening at the metabolic level, I think we can make some progress. So we wrote up a grant to start to model these diseases in C. elegans, and that was awarded to allow us to do the metabolomics analysis. Now we’re trying to start to figure out what’s going on, and we’re doing that by looking at the whole metabolome.”

Again, Hanna-Rose emphasizes the significance of the Metabolomics Facility to her work.

“They have just been absolutely key,” she says, “especially to being able to learn how to do this ourselves. Some people collaborate to do metabolomic analysis, and I suppose that would have been an option for us, but I don’t think we would have gotten as far that way as we have doing it ourselves. In some ways, doing it yourself is a little bit slower, because you have to first get up to speed. But with Andrew, Phil, and the Facility here, that’s been possible and has already led to a new funding direction for us, and new discoveries, and more to come.”