A rare genetic disease may be going to the dogs. About six in 100,000 babies are born with centronuclear myopathy, which weakens skeletal muscles so severely that children have trouble eating and breathing and often die before age 18. Now, by discovering a very similar condition in canines, researchers have a means to diagnose the disease, unravel its molecular intricacies, and target new therapies.
The story began when Jocelyn Laporte, a geneticist at the Institute of Genetics and Molecular and Cellular Biology in Strasbourg, France, uncovered the genetic roots of an odd form of centronuclear myopathy that showed up in a Turkish family. Three children, two of them fraternal twins, were born normal. Then, at the age of 3-and-a-half, they grew progressively and rapidly ill. (Most forms of the illness do not come on so suddenly.) The twins died by the age of 9. Their younger brother recently reached the same age but is very ill. Investigators traced the problem to a mutation in a gene called BIN1, which makes a protein that helps shape the muscle so that it can respond to nerve signals that initiate muscle contraction.
To find out how mutations in this gene could lead to such dire consequences, other researchers tried to genetically engineer mice models. But deleting the BIN1 gene failed to recreate the disease in mice, so the researchers had to look elsewhere.
Enter the dogs.
Laporte's team joined with geneticist and veterinarian Laurent Tiret, at the Alfort School of Veterinary Medicine in Paris, to tap a network of vets in the United States, United Kingdom, Canada, Australia, and France. The idea was to track down and analyze dogs that had spontaneously acquired a similar condition. Because of their longer lifespans and larger size, the canines could model how the disease progresses and might respond to new therapies. Using veterinary records and muscle biopsies, the researchers found five dogs with features that mimicked human symptoms. The animals first showed problems at the age of 6 months, collapsing after exercise due to muscle weakness, for example. Biopsies of their muscle tissue also appeared similar to those of afflicted children.
Gene sequencing confirmed that the animals bore an analogous DNA mutation to the one seen in humans, which removes a large chunk of the BIN1 gene, known as exon 11. The finding of dogs with a similar defect that developed similar symptoms was key to confirming that the BIN1 is, indeed, the culprit in the human disease, Laporte says.
The team then tackled the question of how the BIN1 mutation causes such devastation. Using genomics tools, studies in cells, and analyses of biopsies, the researchers showed that the problem hovers around the formation of balloonlike structures called T-tubules deep in the muscle fibers. They are part of a muscle structure called a triad that helps convert electrical stimuli from nerve cells into mechanical muscle motion. When the T-tubules gradually become faulty, due to mutation, the muscles cannot receive the electrical stimulus to properly contract, leading to devastating symptoms. First comes muscle pain during exercise and trouble with walking, then weakness in muscles that control eye movement, and eventually problems with breathing. Using the dogs, researchers correlated the destruction of the tubules to these kinds of symptoms, as they report this month in PLOS Genetics.
Going forward, dogs will continue to be critical to unraveling this disease, Tiret says. In addition to the Great Danes, researchers, including Laporte, have found Labrador retrievers that bear two other gene mutations that cause different forms of recessive centronuclear myopathy, one linked to chromosome 2 and the other to the X chromosome. The investigators have bred those animals into two colonies. They can be used to study the natural progression of the illnesses and also to test new treatments, such as gene therapy. In fact, those treatments are already showing promise in the dogs, improving leg strength and diaphragm function during breathing, paving the way for clinical trials in humans.
The canines get around a huge hurdle that mice, zebrafish, and other organisms present when researchers try to recapitulate human disease. Often, those smaller animals express the genetic abnormality very differently from humans, says clinical scientist and pediatric neurologist James Dowling at the University of Michigan, Ann Arbor, who studies the myopathies and their genetic causes in both children and zebrafish. "The fact that the dog model seems to really faithfully recapitulate the clinical disease is really very telling," he says. "Something that intervenes there would have a very good chance of working in patients."
"Thanks to genomic comparison, we are understanding finally that dogs and humans are sick in the same way and can be treated the same way," Tiret says. "Dogs help us and we help them."