Scientists have finally discovered the cause of a rare brain disease

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

Researchers have discovered a new mechanism for a rare brain disease.

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

The disease, known as hypomyelinating leukodystrophy, is caused by a mutation in a gene that controls the transport of zinc, an important dietary trace element, out of cells. The study was published in the journal The brain and was co-chaired by Dr. Quasar Padiat of University of Pittsburgh and Dr. Anju Shukla of Kasturba Medical College in India.

Quasar Padiat

Kwazar Padiyat, Ph.D. By Joshua Franzos, University of Pittsburgh

This is the first time that a mutation in a zinc transporter gene, in this case, TMEM163, has been conclusively linked to the development of any brain disorder. It may shed light on zinc’s role in healthy brain development, as well as in brain injury and disease.

“The discovery of a new gene responsible for a disease is always exciting; that feeling never gets old,” said Padiat, assistant professor of human genetics and neurobiology at Pitt. “And finding out that the zinc transporter is really important for proper myelin development could have many clinical implications and offer new ways to treat other neurological diseases.”

Hypomyelinating leukodystrophies are rare and often fatal neurological diseases caused by defects in genes involved in the growth or maintenance of myelin, the fatty insulating layer that surrounds neurons and helps transmit electrical impulses. As the myelin layer thins and is lost in these patients, nerve signals are disrupted, leading to a host of neurological problems such as impaired movement control and balance, muscle loss, vision problems, hearing and memory loss.

While genes have been linked to leukodystrophy, the genetic basis of most cases is still unknown. To discover the underlying cause of a patient’s condition and recommend the most appropriate therapy, clinical neurologists often turn to researchers like Padiath.

By combing patient genomes, Padiath looks for mutations and analyzes the effect of those mutations on cells and animal models such as mice. Such an analysis is no small feat. In order to definitively connect a new gene mutation with the symptoms of the disease, it is necessary to identify several independent cases of patients who have the same gene defect and clinical picture.

For rare diseases such as hypomyelinating leukodystrophies, finding such cases is only possible through a network of scientific and clinical collaborators from around the world. In this study, the first patient sample was obtained from Shukla, a professor of medical genetics in Manipal, southwest India. Queries in other groups in the US and the Netherlands revealed additional families who also carried mutations in the same gene.

A series of in-depth laboratory studies showed that TMEM163 mutations impair the transporter’s ability to effectively shunt zinc out of the cell, causing a decrease in the 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,” Padiat said. “It is important to remember that diseases that are rare in a global context are very important and real for patients and their families. Studying these diseases helps find cures and provides hope for patients and valuable insight into the therapeutic targets needed for normal cellular function.”

Reference: “Variants in the zinc transporter TMEM163 cause hypomyelinating leukodystrophy” Michelle C. Du Rosario, Guillermo Rodríguez Bey, Bruce Nmezi, Fang Liu, Thalia Orenburg, Ana SA Cohen, Keith A. Coffman, Maya R. Brown, Kirill Kiselev, Quinten Weisfis, Myrta T. Flohill , Shahayan Siddiqui, Jill A Rosenfeld, Alejandra Iglesias, Kata Mohan Girisha, Nicole I Wolff, Quasar Salim Padiyat, and Anju Shukla, August 12, 2022. The brain.
DOI: 10.1093/brain/awac295

The study was funded by the National Institutes of Health. Scientists have finally discovered the cause of a rare brain disease

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