The LINC complex is essential for hearing

Henning 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

Research output: Contribution to journalArticle

82 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)740-750
Number of pages11
JournalJournal of Clinical Investigation
Volume123
Issue number2
DOIs
Publication statusPublished - 1 Feb 2013
Externally publishedYes

Fingerprint

Nuclear Matrix
Nuclear Envelope
Cytoskeleton
Hearing Loss
Hearing
High-Frequency Hearing Loss
Mutation
Inner Ear
Nuclear Proteins
Cell Movement
Membrane Proteins
Epithelial Cells
Maintenance
Genes
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Horn, H., Brownstein, Z., Lenz, D. R., Shivatzki, S., Dror, A. A., Dagan-Rosenfeld, O., ... Avraham, K. B. (2013). The LINC complex is essential for hearing. Journal of Clinical Investigation, 123(2), 740-750. https://doi.org/10.1172/JCI66911

The LINC complex is essential for hearing. / Horn, Henning; Brownstein, Zippora; Lenz, Danielle R.; Shivatzki, Shaked; Dror, Amiel A.; Dagan-Rosenfeld, Orit; Friedman, Lilach M.; Roux, Kyle J.; Kozlov, Serguei; Jeang, Kuan Teh; Frydman, Moshe; Burke, Brian; Stewart, Colin L.; Avraham, Karen B.

In: Journal of Clinical Investigation, Vol. 123, No. 2, 01.02.2013, p. 740-750.

Research output: Contribution to journalArticle

Horn, H, Brownstein, Z, Lenz, DR, Shivatzki, S, Dror, AA, Dagan-Rosenfeld, O, Friedman, LM, Roux, KJ, Kozlov, S, Jeang, KT, Frydman, M, Burke, B, Stewart, CL & Avraham, KB 2013, 'The LINC complex is essential for hearing', Journal of Clinical Investigation, vol. 123, no. 2, pp. 740-750. https://doi.org/10.1172/JCI66911
Horn H, Brownstein Z, Lenz DR, Shivatzki S, Dror AA, Dagan-Rosenfeld O et al. The LINC complex is essential for hearing. Journal of Clinical Investigation. 2013 Feb 1;123(2):740-750. https://doi.org/10.1172/JCI66911
Horn, Henning ; Brownstein, Zippora ; Lenz, Danielle R. ; Shivatzki, Shaked ; Dror, Amiel A. ; Dagan-Rosenfeld, Orit ; Friedman, Lilach M. ; Roux, Kyle J. ; Kozlov, Serguei ; Jeang, Kuan Teh ; Frydman, Moshe ; Burke, Brian ; Stewart, Colin L. ; Avraham, Karen B. / The LINC complex is essential for hearing. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 2. pp. 740-750.
@article{78acd7b70e374d88b7f5ad680998f2ef,
title = "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.",
author = "Henning Horn and Zippora Brownstein and Lenz, {Danielle R.} and Shaked Shivatzki and Dror, {Amiel A.} and Orit Dagan-Rosenfeld and Friedman, {Lilach M.} and Roux, {Kyle J.} and Serguei Kozlov and Jeang, {Kuan Teh} and Moshe Frydman and Brian Burke and Stewart, {Colin L.} and Avraham, {Karen B.}",
year = "2013",
month = "2",
day = "1",
doi = "10.1172/JCI66911",
language = "English",
volume = "123",
pages = "740--750",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "2",

}

TY - JOUR

T1 - The LINC complex is essential for hearing

AU - Horn, Henning

AU - Brownstein, Zippora

AU - Lenz, Danielle R.

AU - Shivatzki, Shaked

AU - Dror, Amiel A.

AU - Dagan-Rosenfeld, Orit

AU - Friedman, Lilach M.

AU - Roux, Kyle J.

AU - Kozlov, Serguei

AU - Jeang, Kuan Teh

AU - Frydman, Moshe

AU - Burke, Brian

AU - Stewart, Colin L.

AU - Avraham, Karen B.

PY - 2013/2/1

Y1 - 2013/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84873329892&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84873329892&partnerID=8YFLogxK

U2 - 10.1172/JCI66911

DO - 10.1172/JCI66911

M3 - Article

VL - 123

SP - 740

EP - 750

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 2

ER -