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Scientists finally discover the cause of a rare brain disease

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The condition, known as hypomyelinating leukodystrophies, is caused by a mutation in the gene that regulates the transport of zinc out of cells.

Researchers discover a new mechanism behind a rare brain disease.

Thanks to research teams around the world, a rare but potentially debilitating brain disorder now has a definitive cause.

The disorder, known as hypomyelinating leukodystrophy, is caused by a mutation in the gene that controls the transport out of cells of zinc, an important dietary micronutrient. The study was published in the journal Brain and was jointly led by Dr. Quasar Padiath of the University of Pittsburgh and Dr. Anju Shukla of Kasturba Medical College in India.

Quasar Padiath

Quasar Padiath, Ph.D. Credit: Joshua Franzos, University of Pittsburgh

This is the first instance in which a mutation in a zinc transporter gene, in this case, TMEM163, has been definitively linked to the development of any brain disorder. It has the potential to shed light on the function of zinc in healthy brain development as well as brain 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 at 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 that surrounds neurons and helps transmit electrical impulses. As the myelin layer thins and is lost in these patients, nerve signals multiply leading to a plethora of neurological issues such as impaired movement control and balance, muscle wasting , vision problems, hearing loss and memory loss.

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 not an easy task. 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 in Manipal, 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 TMEM163 mutations impair the ability of the transporter to efficiently scavenge zinc from within the cell, resulting in reduced production of proteins responsible for myelin synthesis and maintenance 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.

Reference: “Variants of the Zinc Transporter TMEM163 cause hypomyelinating leukodystrophy” by Michelle C do Rosario, Guillermo Rodriguez Bey, Bruce Nmezi, Fang Liu, Talia Oranburg, Ana SA Cohen, Keith A Coffman, Maya R Brown, Kirill Kiselyov, Quinten Waisfisz, Myrthe T Flohil, Shahyan Siddiqui, Jill To Rosenfeld, Alejandro Iglesias, Katta Mohan Girisha, Nicole I Wolf, Quasar Saleem Padiath and Anju Shukla, August 12, 2022, Brain.
DOI: 10.1093/brain/awac295

The study was funded by the National Institutes of Health.

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