Scientists discover a new mechanism that causes a rare brain disease
A rare but potentially debilitating brain disorder finally has a definitive cause, thanks to research teams working across the globe.
A mutation in the gene that controls the transport out of cells of zinc, an essential dietary micronutrient, is responsible for the disease, called hypomyelinating leukodystrophy. The research, co-led by Dr Quasar Padiath at University of Pittsburgh and Dr. Anju Shukla at Kasturba Medical College in India, is reported in the newspaper Brain.
This is the first time that a mutation in a zinc transporter gene – in this case, TMEM163 – has been definitively linked to the development of any brain disorder, and it has the potential to provide insight into the role of zinc in normal brain development, injury and disease.
“Discovering a new gene responsible for a disease is always exciting; that feeling never gets old,” said Padiath, associate professor of human genetics and neurobiology to Pitt. “And finding out that a zinc transporter is really important for the proper development of myelin could have many clinical implications and offer new ways to treat other related neurological conditions.”
Hypomyelinating leukodystrophies are rare and often fatal neurological disorders caused by defects in genes involved in the growth or maintenance of myelin, the fatty layer of insulation surrounding nerves that helps them transmit electrical impulses. As the myelin layer thins and is lost in these patients, nerve signals slow, leading to a host of neurological problems, including impaired movement control and balance, muscle wasting, vision, hearing and memory loss problems.
While genes have been linked to leukodystrophies, the genetic underpinnings of the majority of cases are still unknown. To identify the root cause of a patient’s condition and recommend the most appropriate treatment, clinical neurologists often turn to researchers like Padiath.
By combing through patient genomes, Padiath searches for mutations and analyzes the effect of those mutations in cells and animal models, such as mice. Such an analysis is no mean feat. To definitively link a novel genetic mutation to disease symptoms, multiple independent patient cases sharing the same genetic defect and clinical presentation must be identified.
For rare diseases, such as hypomyelinating leukodystrophies, the discovery of such cases is only possible by exploiting a network of scientific and clinical collaborators around the world. In this study, the first patient sample came from Shukla, a professor of medical genetics at Manipal in southwestern India. Surveys of other groups in the United States and the Netherlands identified other families who also carried mutations in the same gene.
A series of extensive laboratory studies have shown that the TMEM163 the mutations impair the ability of the transporter to efficiently derive zinc from within the cell, leading to reduced production of proteins responsible for the synthesis and maintenance of myelin and increasing cell death.
“Understanding how genes cause rare diseases is the first step in the process of finding treatments,” Padiath said. “It is important to remember that rare diseases in the global context are very important and real for patients and their families. The study of these diseases makes it possible to find cures and to give hope to patients and precious information on the therapeutic targets essential to the normal functioning of cells.
Michelle do Rosario, of Manipal, and Dr. Guillermo Rodriguez Bey, of Pitt, were co-lead authors of the study. Other authors can be found in the Brain article.