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25-02-2013 | Genetics | Article

Mutation in LINC protein underlies hereditary hearing loss


Free abstract

medwireNews: A gene not previously linked with hearing loss has been shown to be associated with hereditary deafness in two families.

Family members had a mutation in SYNE4, a gene that encodes a linker of the nucleoskeleton and cytoskeleton (LINC) complex protein.

"This reveals yet another piece of the intricate puzzle that characterizes genetic heterogeneity of deafness, with a multitude of proteins involved in this sensory disease," according to Henning Horn (Institute of Medical Biology, A∗STAR, Singapore) and Zippora Brownstein (Tel Aviv University, Israel), the two researchers who led the study.

As reported in the Journal of Clinical Investigation, the researchers studied hereditary hearing loss in two families of Iraqi Jewish ancestry.

SYNE4 encodes nesprin-4, a member of a complex of proteins that localize to the outer nuclear membrane in the hair cells of the inner ear. In the affected family members, the truncated form of nesprin-4 encoded by the mutant SYNE4 did not localize to the outer nuclear membrane.

Nesprin-4 and Sun1 are both part of the LINC complex in the nuclear envelope.

After determining that autosomal recessive non-syndromic hearing loss in the two families was caused by mutations in SYNE4, the researchers next studied mice lacking either nesprin-4 or Sun1 for hair cell defects and hearing loss.

In the nesprin-4 and Sun1 knockout mice the outer hair cells formed normally but degenerated as hearing matured. This led eventually to hearing loss.

Importantly, the researchers observed that the loss of nesprin-4 and Sun1 resulted in the abnormal positioning of the nucleus in the outer hair cells.

Normal cochlear outer hair cells have a columnar appearance and the nucleus is positioned at the base of the cell.

However, in analyzing the cells of nesprin-4 and Sun1 knockout mice, the team found that nuclei of the degenerating outer hair cells were instead located at the apical region.

"This aberrant nuclear positioning is observed in all regions of the cochlea that we examined, from the middle region to the apex," report Horn and colleagues.

The nucleus is important for receiving the electrical signals that determine hearing. The degenerated outer hair cells in the knockout mice may have interference in their sound-induced motility or a compromised ability to withstand the rigors of motility, suggest the researchers.

"Overall, our observations demonstrate a critical role for nuclear positioning in sensory hair cells, a fundamental criterion for normally functioning cells, and link nesprin-4 and Sun1 to this phenomenon," they write.

medwireNews ( is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2013

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