Mutations in LINC Genes Cause Rare Inherited Hearing Loss

A unique case of familial hearing loss has been attributed to mutations in LINC family proteins expressed in the hair cells of the inner ear.

Investigators at Tel Aviv University (Israel) were attempting to explain the genetic mechanism that caused progressive high-frequency hearing loss in two families of Iraqi Jewish ancestry.

They reported in the January 25, 2013, online edition of the Journal of Clinical Investigation that the defect was due to homozygosity for a protein truncating mutation in SYNE4, a gene not previously associated with hearing loss. This gene encodes the protein nesprin-4 (NESP4), an outer nuclear membrane (ONM) protein expressed in the hair cells of the inner ear. This protein, NESP4, and the SUN domain-containing protein 1 (SUN1), which localizes to the inner nuclear membrane (INM), are components of the LINC (linker of nucleoskeleton and cytoskeleton) complex in the nuclear envelope.

The LINC-complex is a protein complex associated with both inner and outer membranes of the nucleus and actin in the microfilament cytoskeleton. This complex is involved in the anchoring of both nuclear membranes and nuclear lamina to the actin cytoskeleton via transmembrane proteins. The LINC complex consists of SUN2 and Samp1 of the inner nuclear membrane and nesprin-2G of the outer nuclear membrane. SUN2 anchors to the nuclear lamina aided by Samp1, while nesprin-2G associates with the actin microfilaments.

To better understand the connection between the LINC proteins and hearing loss, the investigators studied lines of mice that had been genetically engineered to lack a specific LINC gene. They found that in mice lacking both Nesp4 and SUN1, outer hair cells (OHCs) formed normally, but degenerated as hearing matured, leading to progressive hearing loss. The nuclei of OHCs from mutant mice failed to maintain their basal localization, potentially affecting cell motility and hence the response to sound.

These results demonstrated that the LINC complex was essential for viability and normal morphology of OHCs and suggested that the position of the nucleus in sensory epithelial cells was critical for maintenance of normal hearing.

"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," said senior author Dr. Keren Avraham, professor of human molecular genetics and biochemistry at Tel Aviv University. "The position of the nucleus is important for receiving the electrical signals that determine proper hearing. Without the ability to receive these signals correctly, the entire cascade of hearing fails. Now that we have reported it, scientists around the world can test for mutations in this gene."

Related Links:
Tel Aviv University