Document Detail


The LINC complex is essential for hearing.
MedLine Citation:
PMID:  23348741     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-25
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-04-19     Completed Date:  2013-05-13     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  740-50     Citation Subset:  AIM; IM    
Affiliation:
Institute of Medical Biology, A STAR, Singapore.
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MeSH Terms
Descriptor/Qualifier:
Animals
DNA Mutational Analysis
Female
Ferrous Compounds
Hair Cells, Auditory, Outer / pathology,  physiology
Hearing / genetics,  physiology*
Hearing Loss, High-Frequency / etiology,  genetics,  physiopathology
Humans
Iraq / ethnology
Israel
Jews / genetics
Male
Membrane Proteins / deficiency,  genetics,  physiology
Mice
Mice, Inbred C57BL
Mice, Knockout
Multiprotein Complexes / deficiency,  genetics,  physiology*
Mutation
Nuclear Envelope / metabolism
Nuclear Proteins / deficiency,  genetics,  physiology
Pedigree
Grant Support
ID/Acronym/Agency:
R01DC011835/DC/NIDCD NIH HHS
Chemical
Reg. No./Substance:
0/BAE-2Fc; 0/Ferrous Compounds; 0/Membrane Proteins; 0/Multiprotein Complexes; 0/Nuclear Proteins; 0/nesprin 4 protein, mouse
Comments/Corrections
Comment In:
J Clin Invest. 2013 Feb 1;123(2):553-5   [PMID:  23348730 ]

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