Discovering The Missing “LINC” To Deafness

Because half of all instances of hearing loss are linked to genetic mutations, advanced gene research is an invaluable tool to uncover causes of deafness — and one of the biggest hopes for the development of new therapies. While researching two families of Iraqi Jews with a long family history of hearing loss, Professor Karen Avraham of the Sackler Faculty of Medicine at Tel Aviv University discovered a significant mutation in a LINC family protein — part of the cells of the inner ear — that could lead to new treatments for hearing disorders.

For generations, members of these families had been suffering from hearing loss, but the medical cause remained a mystery. Using deep genetic sequencing, a technology used to sequence the entire human genome, Avraham discovered that the hearing impaired members of both families had a mutated version of the protein Nesprin4, a part of the LINC group of proteins that links the cell’s nucleus to the inner wall of the cell.

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In these families, the cell nucleus, which contains our entire DNA, moves to the top of the cell rather than being anchored to the bottom, its normal place. Though this has little impact on the functioning of most of the body’s cells, it is devastating for the cells responsible for hearing, Avraham explains. “The position of the nucleus is important for receiving the electrical signals that determine proper hearing,” she says. “Without the ability to receive these signals correctly, the entire cascade of hearing fails.”

Finding a way to anchor the nucleus

In the lab, Avraham recreated this phenomenon by engineering the mutation in single cells. With the mutation in place, Nesprin4 was not found in the area around the cell nucleus, as in healthy cells, but was spread throughout the entire cell. Avraham then wanted to test live specimens, so she contacted a lab in Singapore which, for an unrelated research about LINC proteins, engineered mice that lack the Nesprin4 protein. The researchers there were amazed to find that the mice were deaf.

As it turns out, when the specific protein is missing – the nucleus “floats” throughout the cell. This causes chaos within the cell and damages the functions that are in charge of transferring sound in the inner-ear. Since the human inner-ear is not that different than mice, it is safe to assume that the lack of Nesprin4 is also the cause for hearing loss in humans.

Prof. Avraham says that she and her collaborators are the first to reveal this mutation as a cause of deafness. “Now that we have reported it, scientists around the world can test for mutations in this gene,” she notes. The mutation could indeed be a more common genetic cause of deafness in a number of populations. And because Nesprin4 belongs to a family of proteins that have been linked to other diseases, such as muscular coordination and degeneration disorders, this could prove a ripe area for further research.

This discovery was recently reported in the Journal of Clinical Investigation. Avraham’s team of researchers included Dr. Henning Horn and Profs. Colin Stewart and Brian Burke of the Institute of Medical Biology at A*STAR in Singapore.

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