If Dorothy K. Grange’s name hadn’t looked quite so out of place among the authors listed in a 2012 paper, Colin Nichols might have missed it. But the oddity of an English name buried in a long list of Dutch ones jumped out at the British-born Nichols even before he saw her affiliation: Washington University School of Medicine in St. Louis, same as his.
The two had never met, even though they worked in neighboring buildings. Their research interests could not be more different. Nichols, PhD, the Carl F. Cori Professor of Cell Biology and Physiology, had spent three decades studying a complex of proteins that regulates potassium levels in cells. Grange, MD, a professor of pediatrics, was one of the few people in the world studying patients with Cantu syndrome, a genetic disease linked to a hodgepodge of curious symptoms including excessive hair growth, enlarged hearts, bone abnormalities and swollen legs.
But as Nichols read the paper by Grange and her Dutch collaborators, he realized they had been looking at two sides of the same coin. The researchers showed that people with Cantu syndrome carry mutations in one of the proteins that makes up a potassium channel – the very one to which Nichols had dedicated his career.
“I ran over there the same day, knocked on her door, and said, ‘Hi, can I talk to you?’” recalled Nichols. Before the day was out, Nichols and Grange had started hammering out plans to combine their disparate expertise, to save lives.
That was almost six years ago. In the meantime, Nichols and Grange have established a dedicated research clinic and have a clinical trial in the works to evaluate a repurposed diabetes drug as the first potential treatment for the syndrome.
They also have set up a worldwide registry of diagnosed Cantu syndrome patients, which today numbers about 100.
Most recently, the National Institutes of Health (NIH) awarded Nichols a $6.8 million grant to study a significant component of the disease.
The most noticeable sign of Cantu syndrome is unusual hairiness all over the body. The hair on such patients’ heads sometimes grows onto the forehead and face. They also suffer from heart problems and misshapen bones.
People with the syndrome have mutations in one of two genes – ABCC9 or KCNJ11 – whose protein products together form a channel for potassium to flow into or out of muscle cells. The channels are embedded in the membranes of heart muscle cells, as well as the smooth muscle cells that line the blood vessels, the gut and other internal organs.
These potassium channels serve as a kind of brake on the electrical activity of the muscle so that when the channels open, muscle contraction is reduced or stopped. This might help protect the muscles when something is going very wrong, such as during a heart attack. But in people with Cantu syndrome the channels stay open all the time, making for lazy muscles reluctant to contract.
“We’re getting close to doing a clinical trial with a drug to block these channels,” Nichols said. “In mice, it reverses many of the Cantu syndrome symptoms, and we’re hoping to see the same reversal in people. I suspect everything is reversible, once you close the channels.”
Nichols’ new grant will allow him to study the role of potassium channels in not just Cantu syndrome but cardiovascular disease more generally.
Cardiovascular disease is the number one cause of death worldwide, and Cantu syndrome patients have striking cardiovascular abnormalities. Among other things, they have low blood pressure and dramatically enlarged hearts. Low blood pressure is directly due to the Cantu mutations, which cause the smooth muscle in blood vessels to relax and the vessels to dilate.
But the cause of the enlarged hearts is more obscure. By studying mice with the Cantu mutations, Nichols traced a cascade of physiological changes triggered by low blood pressure that leads to overburdening the heart. The heart muscle grew big as it struggled to cope with a heavy workload.
In solving the puzzle of enlarged hearts in Cantu patients, Nichols is uncovering new details of how the cardiovascular system functions.
“There are people who have enlarged hearts for unknown reasons,” Nichols said. “Many treatments for cardiac problems address symptoms without knowing how they arise. Now we know one way that patients could have ended up with large hearts. And if we know how they got there, we might be able to figure out how to get them back.”
Nichols also is investigating why Cantu babies sometimes struggle to breathe due to a failure to pass blood through the lungs to pick up oxygen. For unknown reasons, some premature babies without Cantu syndrome also fail to route blood through their lungs. Finding the root of the problem in Cantu babies could provide clues to understanding and treating preemies with the same symptoms.
The new grant funding represents a vote of confidence from other scientists that the study of this very rare genetic disease – and the molecular mechanism of the ion channel complexes that underlie it – will yield broad insights into human physiology that could help many people with cardiovascular and other problems.
“I can’t point to a specific major disease like cancer and say, ‘This research applies to this’,” Nichols said. “What we’re really studying is smooth muscle contractions and what happens when that fails. But I think we’ll be surprised how broadly this research can be applied.”