The LINC complex is essential for hearing
Henning F. Horn, … , Colin L. Stewart, Karen B. Avraham
Henning F. Horn, … , Colin L. Stewart, Karen B. Avraham
Published January 25, 2013
Citation Information: J Clin Invest. 2013;123(2):740-750. https://doi.org/10.1172/JCI66911.
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Research Article

The LINC complex is essential for hearing

Abstract

Hereditary hearing loss is the most common sensory deficit. We determined that progressive high-frequency hearing loss in 2 families of Iraqi Jewish ancestry was due to homozygosity for the protein truncating mutation SYNE4 c.228delAT. SYNE4, a gene not previously associated with hearing loss, encodes nesprin-4 (NESP4), an outer nuclear membrane (ONM) protein expressed in the hair cells of the inner ear. The truncated NESP4 encoded by the families’ mutation did not localize to the ONM. NESP4 and SUN domain–containing protein 1 (SUN1), which localizes to the inner nuclear membrane (INM), are part of the linker of nucleoskeleton and cytoskeleton (LINC) complex in the nuclear envelope. Mice lacking either Nesp4 or Sun1 were evaluated for hair cell defects and hearing loss. In both Nesp4–/– and Sun1–/– mice, 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 demonstrate that the LINC complex is essential for viability and normal morphology of OHCs and suggest that the position of the nucleus in sensory epithelial cells is critical for maintenance of normal hearing.

Authors

Henning F. Horn, Zippora Brownstein, Danielle R. Lenz, Shaked Shivatzki, Amiel A. Dror, Orit Dagan-Rosenfeld, Lilach M. Friedman, Kyle J. Roux, Serguei Kozlov, Kuan-Teh Jeang, Moshe Frydman, Brian Burke, Colin L. Stewart, Karen B. Avraham

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Figure 1

Identification of SYNE4, encoding nesprin-4, as a gene responsible for hearing loss.

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Identification of SYNE4, encoding nesprin-4, as a gene responsible for h...
(A) Pedigrees of 2 families of Iraqi Jewish origin with hearing loss (black symbols). Hearing loss in the families was mapped by linkage analysis to chromosome 19q, including a 5.4-Mb region homozygous in all affected individuals (highlighted in yellow). (B) Audiograms of affected individuals, demonstrating high-frequency hearing loss. (C) Sanger sequencing (patient II-3) of the site of the c.228delAT mutation (upper sequence) revealing the deletion of 2 bp and surrounding sequence extending to the new stop codon (W77VfsX16). The bottom Sanger sequence (patient II-3) demonstrates a portion of the mutant transcript, with the deletion of exon 2 (delEx2), showing a part of exon 1 and part of exon 3, until the premature stop codon. (D) Amplification of exons 1–4 from cDNA derived from lymphoblasts resulted in a PCR product of 491-bp fragment, whereas skipping of exon 2 resulted in a product of 151-bp in all individuals carrying the c.228delAT mutation.