Published online September 4 in the American Journal of Human Genetics, the study, “Mutations in Synaptotagmin 2 cause a novel human presynaptic syndrome,” describes the first association of mutations in the synaptic vesicle protein, synaptotagmin 2, with human disease.
The study was led at the Miller School by Stephan Züchner, M.D., Ph.D., professor of human genetics and neurology and interim Chair of the Dr. John T. Macdonald Foundation Department of Human Genetics. Michael Gonzalez, a senior graduate student in the human genetics and genomics program at the Miller School, was a coauthor on the study.
A variety of neuromuscular disorders interfere with the communication that occurs at the neuromuscular junction, the point at which the nerves meet the muscle that they supply. Interruptions in the chemical signals across the junction result in muscle weakness and fatigue, primarily in the limbs.
The researchers diagnosed the new neuromuscular disorder in multiple generations of two families – one from the United States and the other from the United Kingdom. While the family members in the study had at one point been diagnosed with other neuromuscular disorders, the researchers identified them as unique, due to their particular motor abnormalities, including problems resembling the cancer associated-Lambert-Eaton myasthenic syndrome, and because the disease was passed from one generation to the next.
Using whole exome sequencing, the researchers found that the affected family members had mutations in the code that creates the protein synaptotagmin 2 (SYT2), disrupting the ability of the nerve cells to sense changes in calcium levels that would normally trigger the release of acetylcholine, a chemical responsible for passing communication between the nerve and muscle cells. As a result, communication was disrupted, and muscle control was impaired.
“We are very encouraged by our findings,” said Dr. Züchner. “Carefully studying these rare diseases teaches us important aspects of more common medical problems that are very hard to decipher.”
Co-lead authors include J. Troy Littleton, M.D., Ph.D., at the Massachusetts Institute of Technology, David Herrmann, M.D., M.B.B.Ch., at the University of Rochester, and Rita Horvath, M.D., Ph.D., of the University of Newcastle.
The research was supported with funds from the National Institute of Neurological Disorders and Stroke, the Picower Neurological Disease Research Fund, the JPB Foundation, the Muscular Dystrophy Association, the Medical Research Council (U.K.), the Wellcome Trust, and the European Union Seventh Framework Programme.
Miller School of Medicine