Tim Yu, MD, PhD, a neurologist and genomics researcher at Boston Children’s Hospital, was studying autism genes when he saw something on a list that rang a bell. It was a mutation that completely knocked out the so-called Deleted in Colorectal Carcinoma gene (DCC), originally identified in cancer patients. The mutation wasn’t in a patient with autism, but in a control group of patients with brain malformations he’d been studying in the lab of Chris Walsh, MD, PhD.
Yu’s mind went back more than 20 years. As a graduate student at University of California, San Francisco, he’d conducted research in roundworms, studying genetic mutations that made the worms, which normally move in smooth S-shaped undulations, move awkwardly and erratically.
Yu recognized DCC as the human counterpart of UNC-40 (with the “UNC” short for “uncoordinated”), one of two key genes he’d been studying that influence how neurons chart their paths, following guidance cues. When one of the genes was mutated or lacking, nerve fibers (axons) failed to grow towards the midline of the worms’ bodies.
As a graduate student, Yu had helped tease out the workings of these genes — also found in flies, chick embryos and mice — and helped characterize two parallel systems for axon guidance. One system attracted neurons, via the chemical netrin and its cellular receptor, UNC-40 (a.k.a. DCC). The other repelled neurons, via the chemical Slit and its receptor, Robo. Yu demonstrated how these systems, working in concert, ensured axons would grow in the right direction and cross over in the brain, brainstem and spinal cord.
“We had known these molecules for a long time,” says Yu. “I had always been curious about how they related to human development.”
A missing gene
Fast forward to about five years ago. Now a postdoc in Walsh’s lab at Boston Children’s, Yu was heading up a massive genetic analysis looking for autism genes in about 300 families from the Middle East, Europe and the U.S. This analysis identified several new autism-related genes.
The team decided to also look for copy number variants — in particular, complete deletions of DNA.
“One of my colleagues, Klaus Schmitz-Abe, showed me a list of interesting genetic knockouts he had found,” says Yu. “Two thirds of the way down, I saw DCC.”
The mutation was in the control group — in two brothers from Mexico with agenesis of the corpus callosum, a birth defect in which the bridge connecting the left and right sides of the brain is missing. “I said ‘we ought to follow this up,’” says Yu.
Interestingly, he found that the brothers also had horizontal gaze palsy, meaning they couldn’t move their eyes from left to right or vice versa. To Yu, this suggested that disruption of axon guidance can affect not only the brain, but also wiring of nerves in the brainstem that control eye movement.
He recalled a paper by his Boston Children’s colleague Elizabeth Engle, MD, a specialist in eye-movement disorders, also describing patients with horizontal gaze palsy. Yu had another “aha” moment: Engle’s work linked the defect to a gene called Robo3 — encoding the same Robo protein that receives growth-repelling cues.
From brain to brainstem to spine
The paper had another twist. “Elizabeth’s patients also had very striking scoliosis,” says Yu. So did the brothers from Mexico. Yu suspects that mutations in the axon-guidance pathway can also cause miswiring in the spinal cord, an idea supported by data from mice with DCC mutations. But how would this cause curvature of the spine?
“If the two sides are not coordinated correctly, you won’t have enough muscle innervation to provide the spine with proper biomechanical support,” Yu speculates.
Yu, Klaus Schmitz-Abe, PhD, and Saumya Jamuar, MBBS, MRCPCH, cofounder of Global Gene Corporation and an ex-research fellow in the Walsh lab, went on to identify two other families with knockout of DCC, from the U.S. and Saudi Arabia. In a paper in Nature Genetics last week, they describe a disorder they call “developmental split-brain syndrome.” It includes intellectual disability, horizontal gaze palsy, scoliosis and in some cases mirror movements, together with a striking disconnection of the brain’s two hemispheres. Walsh, Engle and neuroradiologist Ellen Grant, MD, were other key contributors from Boston Children’s.
The research team hopes to find more cases to further characterize the syndrome. Yu thinks that with so many genes involved in axon guidance, there are many more cases to be found, perhaps even among patients with scoliosis that wouldn’t normally be thought to have a problem with their nerve fibers.
Yu also believes these patients could provide interesting insights into how our brains operate, adding to a growing body of research (including studies of patients undergoing hemispherectomy for severe epilepsy). “Studying these individuals may teach us a lot about how and why our brain hemispheres have evolved to talk to one another via these interconnecting bridges.”
But what about colorectal cancer? So far these patients seem not to have it. While DCC is deleted in many colorectal cancers, its exact connection to colorectal cancer pathogenesis still remains unclear.