In 2007, a woman took four of her sons to see Joanna Jen, a neurologist at the University of California, Los Angeles. The brothers ranged from 5 to 14 years old and all had the same mysterious disease.
The boys had appeared normal at birth, except their muscles were a bit floppy. They quickly got worse. They didn’t gain control of their heads and didn’t grow as they should have. By 10 months, they were smaller than 95 percent of kids their age. They never reached any of their motor milestones, and never learned to eat, stand up, or speak. “They had the sweetest smiles,” Jen recalls. “It was heartbreaking that they were just so severely affected.”
Over the years the family had been to many doctors, who had ordered various brain scans and muscle tests. No one had any idea what was wrong. The parents had nine children, in all, and felt strongly that each one was a gift from god, Jen says. “They were at peace with their children’s condition. But at the same time, they couldn’t help being curious what their children have.”
All of the other doctors had focused on a striking feature in the boys’ brain scans: an especially tiny cerebellum, the bulb at the bottom of the brain that’s involved in movement, balance, and learning. Jen was more intrigued by the boys’ bodies. “What was striking to me was that they had no muscle,” she says. “They were so skinny.”
Jen referred back to the boys’ medical records and found tests indicating irregularities in their spinal motor neurons, which help control muscles. This was odd. There are lots of diseases that stem from problems with motor neurons, like Lou Gehrig’s disease. And there are lots of others that are tied to glitches in the cerebellum. But the combination? “It’s exceptionally unusual,” she says.
Digging through the medical literature for similar cases, Jen found a rare condition — pontocerebellar hypoplasia type 1, or PCH1 — characterized by exactly those two features. A handful of genetic variants had been identified in individuals with this disease, but since they were in different genes, no one know which, if any, were causing trouble.
With these four brothers, all showing exactly the same disease, Jen knew that a genome screen would likely pinpoint the culprit. So her team sequenced the exome (the protein-coding part of the genome) of each boy. Sure enough, they all carried a mutation in a gene called ‘encoding exosome component 3′ or EXOSC3.
Jen got in touch with the few researchers across the globe who had previously reported cases of PCH1 and asked them for samples of the patients’ DNA. After screening the exomes of 12 additional families, she found 8 with mutations in EXOSC3.
No one ever would have guessed that EXOSC3 is involved in PCH1. As its name suggests, the gene codes for a protein that’s part of the exosome complex, a cellular machine responsible for degrading RNA. In evolutionary time, exosomes are old — found even in simple archaea. That probably means they’re essential for the proper function of a cell.
Jen’s team engineered an animal model lacking EXOSC3. Unlike the vast majority of biomedical research studies, which depend on rats and mice, hers used eyelash-sized baby zebrafish.
As I describe in a new story in Popular Science, a growing number of researchers are turning to the humble fish to model genetic diseases:
Zebrafish offer three major advantages over rodents. First, they quickly make more zebrafish. A female spawns hundreds of embryos three days after fertilization; mice take three weeks to produce just 10 pups. They are also inexpensive to maintain—about 6.5 cents a day for a tank of a few dozen fish, compared with 90 cents for five mice in a cage. Finally, because larval fish are transparent, researchers can literally watch their organs grow, which makes them especially good for studying problems with organ development.
Jen’s study, for example, showed that fish lacking EXOSC3 have abnormal development, super-small brains and barely move. “By the time the controls are swimming about, [the mutants] are curled up embryos with very little movement,” she says. These experiments proved that this gene is indeed the cause of the boys’ problems. In the world of rare-disease genetics, this was a slam dunk. The data came out last summer in Nature Genetics.
Still, the findings bring up many new questions. Why would messing up a gene so fundamental lead to relatively specific problems in muscle and brain? And within the brain, why the cerebellum, and why neurons? Jen’s team will continue to study the fish to try to figure this all out.
Unfortunately, like most research on rare diseases, none of Jen’s discoveries have yet led to treatments for the boys. The oldest died during the course of the study, when he was 18. Still, the family was happy to finally have a diagnosis, Jen says. And the study did give them a bit of hope, in that two of the eight new patients found with EXOSC3 mutations had survived to adulthood.
After the study came out, one of the boys’ healthy siblings, a 14-year-old brother, offered another kind of hope. “He told me he would like to become a biologist,” Jen says. “And he would like to work in our laboratory, on the zebrafish.”