A new mouse mutant of the Cdh23 gene with early-onset hearing loss facilitates evaluation of otoprotection drugs

Han, Fengchan; Yu, He; Tian, Cong; Chen, Hui E; Benedict-Alderfer, Cindy; Zheng, Yunhui; Wang, Qiuju; Xu, Han; Zheng, Qing Yin

doi:10.1038/tpj.2010.60

Cited by 40 publications

(78 citation statements)

References 43 publications

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“…A recent study has provided evidence that drug therapy can preserve auditory function in animal models of early-onset sensorineural hearing loss [35]. Here, we examine the effects of adult human olfactory stem cell transplantation on hearing levels in A/J mice exhibiting well-characterized early-onset sensorineural hearing loss.…”

Section: Discussionmentioning

confidence: 99%

Functional Effects of Adult Human Olfactory Stem Cells on Early-Onset Sensorineural Hearing Loss

et al. 2011

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Transplantation of exogenous stem cells has been proposed as a treatment to prevent or reverse sensorineural hearing loss. Here, we investigate the effects of transplantation of adult human olfactory mucosa-derived stem cells on auditory function in A/J mice, a strain exhibiting early-onset progressive sensorineural hearing loss. Recent evidence indicates that these stem cells exhibit multipotency in transplantation settings and may represent a subtype of mesenchymal stem cell. Olfactory stem cells were injected into the cochleae of A/J mice via a lateral wall cochleostomy during the time period in which hearing loss first becomes apparent. Changes in auditory function were assessed 1 month after transplantation and compared against animals that received sham injections. Hearing threshold levels in stem cell-transplanted mice were found to be significantly lower than those of sham-injected mice (p < .05) for both click and pure tone stimuli. Transplanted cells survived within the perilymphatic compartments but did not integrate into cochlear tissues. These results indicate that transplantation of adult human olfactory mucosa-derived stem cells can help preserve auditory function during early-onset progressive sensorineural hearing loss. STEM CELLS 2011;29:670-677 Disclosure of potential conflicts of interest is found at the end of this article.

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Section: Discussionmentioning

confidence: 99%

Functional Effects of Adult Human Olfactory Stem Cells on Early-Onset Sensorineural Hearing Loss

et al. 2011

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“…39,40 Recently, two ENU-generated Cdh23 mouse mutants, salsa and erlong, were reported; recessively inherited progressive hearing loss commenced at 3 to 4 weeks without any vestibular dysfunction, unlike the waltzer mutants. 14,15 The salsa mutant harbors a point mutation, Cdh23 p.E737V, that is located in the more distal EC7 Ca 2ϩ -binding domain and leads to loss of tip links and tenting of stereociliary tips because of its effect on interaction/binding with Pcdh15. 14 The erlong missense mutation Cdh23 p.S70P resides in the EC1 domain but not within a Ca 2ϩ -binding motif and has a less severe hearing loss phenotype than salsa.…”

Section: Discussionmentioning

confidence: 99%

“…14 The erlong missense mutation Cdh23 p.S70P resides in the EC1 domain but not within a Ca 2ϩ -binding motif and has a less severe hearing loss phenotype than salsa. 15 Similar to salsa, the jera Cdh23 p.V2360E missense mutation is located within a Ca 2ϩ -binding domain in EC22. A similar process of tip link loss occurs in the jera mutant, as reported in salsa.…”

Section: Discussionmentioning

confidence: 99%

“…9 -13 Two N-ethyl-N-nitrosourea (ENU)-generated mouse strains, salsa and erlong, carry a recessive Cdh23 missense mutation. 14,15 Both mutants have progressive hearing loss, with no vestibular abnormalities, and are, therefore, models for DFNB12 deafness. Retinal degeneration is not a clinical Supported by grant 436944 from the National Health and Medical Research Council, the HEARing CRC, and J.…”

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confidence: 99%

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An ENU-Induced Mutation of Cdh23 Causes Congenital Hearing Loss, but No Vestibular Dysfunction, in Mice

Manji

Miller

Williams

et al. 2011

The American Journal of Pathology

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Mutations in the human cadherin 23 (CDH23) gene cause deafness, neurosensory, autosomal recessive 12 (DFNB12) nonsyndromic hearing loss or Usher syndrome, type 1D (characterized by hearing impairment, vestibular dysfunction, and visual impairment). Reported waltzer mouse strains each harbor a Cdh23-null mutation and present with hearing loss and vestibular dysfunction. Two additional Cdh23 mouse mutants, salsa and erlong, each carry a homozygous Cdh23 missense mutation and have progressive hearing loss. We report the identification of a novel mouse strain, jera, with inherited hearing loss caused by an N-ethyl-N-nitrosourea-induced c.7079T>A mutation in the Cdh23 gene. The mutation generates a missense change, p.V2360E, in Cdh23. Affected mice have profound sensorineural deafness, with no vestibular dysfunction. The p.V2360E mutation is semidominant because heterozygous mice have milder and more progressive hearing loss in advanced age. The mutation affects a highly conserved Ca 2؉ -binding motif in extracellular domain 22, thought to be important for Cdh23 structure and dimerization. Molecular modeling suggests that the Cdh23 V2360E/V2360E mutation alters the structural conformation of the protein and affects Ca 2؉ -binding properties. Similar to salsa mice, but in contrast to waltzer mice, hair bundle development is normal in jera and hearing loss appears to be due to the loss of tip links. Thus, jera is a novel mouse model for DFNB12. (Am J Pathol 2011, 179:903-914;

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“…The erl mice suffered hearing loss through apoptosis beginning from postnatal day 27 (P27) [106]. Further investigation showed that the PERK-eIF2α-ATF4-CHOP pathway is activated in erl mice, which eventually causes apoptosis of OHCs [61].…”

Section: Ush Proteins and Er Stressmentioning

confidence: 99%

Endoplasmic Reticulum Stress in Hearing Loss

Wang

2017

JOHBM

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Abstract:The endoplasmic reticulum (ER) plays important roles in coordinating protein biosynthesis and secretion in the cell. Accumulation of misfolded and/or unfolded proteins in the ER causes ER stress and the so-called unfolded protein response (UPR). The UPR alleviates ER stress through blocking protein synthesis and activating expression of chaperone genes, whereas prolonged UPR could induce cell death. Recent research has showed that ER stress and UPR are involved in hearing loss. Accordingly, animal experiments showed that chemical chaperones or ER stress inducers alleviate environment-related hearing loss, whereas ER stress inhibitor has been used to treat certain types of hereditary deafness. Further investigations are needed to fully understand the detailed mechanisms of how ER stress contributes to the loss of auditory function, which will help us to eventually develop ER-stress-related treatment of various types of deafness.

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A new mouse mutant of the Cdh23 gene with early-onset hearing loss facilitates evaluation of otoprotection drugs

Cited by 40 publications

References 43 publications

Functional Effects of Adult Human Olfactory Stem Cells on Early-Onset Sensorineural Hearing Loss

Functional Effects of Adult Human Olfactory Stem Cells on Early-Onset Sensorineural Hearing Loss

An ENU-Induced Mutation of Cdh23 Causes Congenital Hearing Loss, but No Vestibular Dysfunction, in Mice

Endoplasmic Reticulum Stress in Hearing Loss

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