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1.
Hair cell synaptic dysfunction,auditory fatigue and thermal sensitivity in otoferlin Ile515Thr mutants
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Nicola Strenzke Alexandra Müller Gerhard Hoch Tina Pangrsic Gulnara Yamanbaeva Christof Lenz Kuan‐Ting Pan Elisabeth Auge Ruth Geiss‐Friedlander Henning Urlaub Nils Brose Carolin Wichmann Ellen Reisinger 《The EMBO journal》2016,35(23):2519-2535
The multi‐C2 domain protein otoferlin is required for hearing and mutated in human deafness. Some OTOF mutations cause a mild elevation of auditory thresholds but strong impairment of speech perception. At elevated body temperature, hearing is lost. Mice homozygous for one of these mutations, OtofI515T/I515T, exhibit a moderate hearing impairment involving enhanced adaptation to continuous or repetitive sound stimulation. In OtofI515T/I515T inner hair cells (IHCs), otoferlin levels are diminished by 65%, and synaptic vesicles are enlarged. Exocytosis during prolonged stimulation is strongly reduced. This indicates that otoferlin is critical for the reformation of properly sized and fusion‐competent synaptic vesicles. Moreover, we found sustained exocytosis and sound encoding to scale with the amount of otoferlin at the plasma membrane. We identified a 20 amino acid motif including an RXR motif, presumably present in human but not in mouse otoferlin, which reduces the plasma membrane abundance of Ile515Thr‐otoferlin. Together, this likely explains the auditory synaptopathy at normal temperature and the temperature‐sensitive deafness in humans carrying the Ile515Thr mutation. 相似文献
2.
Tryptophan‐rich basic protein (WRB) mediates insertion of the tail‐anchored protein otoferlin and is required for hair cell exocytosis and hearing
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Rosamaria Santarelli Montserrat Rodriguez‐Ballesteros Thomas Weber Sangyong Jung Elena Cardenas Xudong Wu Sonja M Wojcik Kelvin Y Kwan Ignacio del Castillo Blanche Schwappach Nicola Strenzke David P Corey Shuh‐Yow Lin Tobias Moser 《The EMBO journal》2016,35(23):2536-2552
The transmembrane recognition complex (TRC40) pathway mediates the insertion of tail‐anchored (TA) proteins into membranes. Here, we demonstrate that otoferlin, a TA protein essential for hair cell exocytosis, is inserted into the endoplasmic reticulum (ER) via the TRC40 pathway. We mutated the TRC40 receptor tryptophan‐rich basic protein (Wrb) in hair cells of zebrafish and mice and studied the impact of defective TA protein insertion. Wrb disruption reduced otoferlin levels in hair cells and impaired hearing, which could be restored in zebrafish by transgenic Wrb rescue and otoferlin overexpression. Wrb‐deficient mouse inner hair cells (IHCs) displayed normal numbers of afferent synapses, Ca2+ channels, and membrane‐proximal vesicles, but contained fewer ribbon‐associated vesicles. Patch‐clamp of IHCs revealed impaired synaptic vesicle replenishment. In vivo recordings from postsynaptic spiral ganglion neurons showed a use‐dependent reduction in sound‐evoked spiking, corroborating the notion of impaired IHC vesicle replenishment. A human mutation affecting the transmembrane domain of otoferlin impaired its ER targeting and caused an auditory synaptopathy. We conclude that the TRC40 pathway is critical for hearing and propose that otoferlin is an essential substrate of this pathway in hair cells. 相似文献
3.
Paroma Chatterjee Murugesh Padmanarayana Nazish Abdullah Chelsea L. Holman Jane LaDu Robert L. Tanguay Colin P. Johnson 《Molecular and cellular biology》2015,35(6):1043-1054
Sensory hair cells convert mechanical motion into chemical signals. Otoferlin, a six-C2 domain transmembrane protein linked to deafness in humans, is hypothesized to play a role in exocytosis at hair cell ribbon synapses. To date, however, otoferlin has been studied almost exclusively in mouse models, and no rescue experiments have been reported. Here we describe the phenotype associated with morpholino-induced otoferlin knockdown in zebrafish and report the results of rescue experiments conducted with full-length and truncated forms of otoferlin. We found that expression of otoferlin occurs early in development and is restricted to hair cells and the midbrain. Immunofluorescence microscopy revealed localization to both apical and basolateral regions of hair cells. Knockdown of otoferlin resulted in hearing and balance defects, as well as locomotion deficiencies. Further, otoferlin morphants had uninflated swim bladders. Rescue experiments conducted with mouse otoferlin restored hearing, balance, and inflation of the swim bladder. Remarkably, truncated forms of otoferlin retaining the C-terminal C2F domain also rescued the otoferlin knockdown phenotype, while the individual N-terminal C2A domain did not. We conclude that otoferlin plays an evolutionarily conserved role in vertebrate hearing and that truncated forms of otoferlin can rescue hearing and balance. 相似文献
4.
Neeliyath A. Ramakrishnan Marian J. Drescher Barbara J. Morley Philip M. Kelley Dennis G. Drescher 《The Journal of biological chemistry》2014,289(13):8750-8766
Mutations in otoferlin, a C2 domain-containing ferlin family protein, cause non-syndromic hearing loss in humans (DFNB9 deafness). Furthermore, transmitter secretion of cochlear inner hair cells is compromised in mice lacking otoferlin. In the present study, we show that the C2F domain of otoferlin directly binds calcium (KD = 267 μm) with diminished binding in a pachanga (D1767G) C2F mouse mutation. Calcium was found to differentially regulate binding of otoferlin C2 domains to target SNARE (t-SNARE) proteins and phospholipids. C2D–F domains interact with the syntaxin-1 t-SNARE motif with maximum binding within the range of 20–50 μm Ca2+. At 20 μm Ca2+, the dissociation rate was substantially lower, indicating increased binding (KD = ∼10−9) compared with 0 μm Ca2+ (KD = ∼10−8), suggesting a calcium-mediated stabilization of the C2 domain·t-SNARE complex. C2A and C2B interactions with t-SNAREs were insensitive to calcium. The C2F domain directly binds the t-SNARE SNAP-25 maximally at 100 μm and with reduction at 0 μm Ca2+, a pattern repeated for C2F domain interactions with phosphatidylinositol 4,5-bisphosphate. In contrast, C2F did not bind the vesicle SNARE protein synaptobrevin-1 (VAMP-1). Moreover, an antibody targeting otoferlin immunoprecipitated syntaxin-1 and SNAP-25 but not synaptobrevin-1. As opposed to an increase in binding with increased calcium, interactions between otoferlin C2F domain and intramolecular C2 domains occurred in the absence of calcium, consistent with intra-C2 domain interactions forming a “closed” tertiary structure at low calcium that “opens” as calcium increases. These results suggest a direct role for otoferlin in exocytosis and modulation of calcium-dependent membrane fusion. 相似文献
5.
Sandrine Marlin Delphine Feldmann Yann Nguyen Natalie Loundon Laurence Jonard Crystel Bonnet Eréa Noel Garabedian Christine Petit Françoise Denoyelle 《Biochemical and biophysical research communications》2010,394(3):737-742
Transient deafness associated with an increase in core body temperature is a rare and puzzling disorder. Temperature-dependent deafness has been previously observed in patients suffering from auditory neuropathy. Auditory neuropathy is a clinical entity of sensorineural deafness characterized by absent auditory brainstem response and normal otoacoustic emissions. Mutations in OTOF, which encodes otoferlin, have been previously reported to cause DFNB9, a non-syndromic form of deafness characterized by severe to profound prelingual hearing impairment and auditory neuropathy.Here we report a novel mutation in OTOF gene in a large family affected by temperature-dependent auditory neuropathy. Three siblings aged 10, 9 and 7 years from a consanguineous family were found to be affected by severe or profound hearing impairment that was only present when they were febrile. The non-febrile patients had only mild if any hearing impairment. Electrophysiological tests revealed auditory neuropathy. Mapping with microsatellite markers revealed a compatible linkage in the DFNB9/OTOF region in the family, prompting us to run a molecular analysis of the 48 exons and of the OTOF intron-exon boundaries. This study revealed a novel mutation p.Glu1804del in exon 44 of OTOF. The mutation was found to be homozygous in the three patients and segregated with the hearing impairment within the family. The deletion affects an amino acid that is conserved in mammalian otoferlin sequences and located in the calcium-binding domain C2F of the protein. 相似文献
6.
Tomoji Mashimo Alexandra E. Erven Sarah L. Spiden Jean-Louis Guénet Karen P. Steel 《Mammalian genome》2006,17(8):841-850
Although recent progress in identifying genes involved in deafness has been remarkable, the genetic basis of progressive hearing
loss (or age-related hearing loss) is poorly understood because of the extreme difficulty in studying such a late-onset, complex
disease in human populations. Several inbred strains of mice such as 129P1/ReJ, C57BL/6J, DBA/2J, and BALB/cByJ have been
reported to exhibit age-related hearing loss and provide valuable models for human nonsyndromic progressive deafness. In this
article we show that 101/H mice also exhibit progressive deafness with early onset. Linkage analysis of F2 populations derived from crosses between the 101/H and the MAI/Pas and MBT/Pas wild-derived mice suggested at least two major
quantitative trait loci (QTLs) that influence progressive hearing loss. A first QTL, designated Phl1, was mapped with a maximum LOD score of 6.7 to the centromeric region of Chromosome 17, where no deafness-related QTL has
been mapped so far. A second QTL, designated Phl2, mapped to Chromosome 10 and exhibited a maximum LOD score of 5.3. The map position of Phl2 near the well-known QTL of age-related hearing loss (Ahl) suggested the possibility of allelism, although the Ahl mutation itself did not segregate in these crosses. Finally, we found some evidence of epistatic interaction between Phl1 and Phl2.
Electronic Supplementary Material Electronic Supplementary material is available for this article at
and accessible for authorised users.
Tomoji Mashimo, Alexandra E. Erven, and Sarah L. Spiden contributed equally to this work. 相似文献
7.
Hearing vulnerability after noise exposure in a mouse model of reactive oxygen species overproduction
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Shigefumi Morioka Hirofumi Sakaguchi Taro Yamaguchi Yuzuru Ninoyu Hiroaki Mohri Takashi Nakamura Yasuo Hisa Kiyokazu Ogita Naoaki Saito Takehiko Ueyama 《Journal of neurochemistry》2018,146(4):459-473
8.
Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations 总被引:23,自引:0,他引:23
Enlarged vestibular aqueduct (EVA), known as the most common form of inner ear abnormality, has recently been of particular
genetic interest because this anomaly is inherited in a recessive manner. The locus for non-syndromic sensorineural hearing
loss with EVA has been mapped to the same chromosomal region, 7q31, as the Pendred syndrome locus. In the present study, seven
mutations in the PDS gene (PDS), the gene responsible for Pendred syndrome, have been found in families of non-syndromic sensorineural hearing loss with
EVA. One family is homozygous, three families are compound heterozygotes, and two families are heterozygous but with no other
mutation detected. The present results provide evidence that mutations in PDS cause both syndromic and non-syndromic hearing loss.
Received: 21 October 1998 / Accepted: 5 December 1998 相似文献
9.
The deaf waddler (dfw) mutation is a model system to study the biology of neuroepithelial hearing defects in mice. Here we describe the identification and characterization of a new allele of deaf waddler (dfw2J) and present evidence for a hearing susceptibility locus (mdfw) that interacts withdfw.We found that CBy-dfw2J/dfw2Jhomozygotes exhibit no discernible auditory brainstem responses (ABR) to sound pressure level stimuli up to 100 dB, indicating a profound deafness. Interestingly, the ABR in CBy-dfw2J/+ heterozygotes is also abnormal, showing age-dependent elevated thresholds characteristic of a progressive hearing loss. When outcrossed onto the CAST/Ei strain, only 24% of the F2 CBy/CAST-dfw2J/+ heterozygotes displayed increased ABR thresholds, suggesting that a second locus, controlling hearing function indfw2J/+ heterozygotes, was segregating in the CBy/CAST-dfw2Jintercross. By linkage analysis, we localized this locus (mdfw) to Chromosome 10, between markersD10Mit127andD10Mit185,within a 4.0 ± 1.1 cM genetic interval. All CBy/CAST-dfw2J/+ heterozygotes that develop hearing loss are homozygous for the CBy-derived recessive allele (mdfwC). In contrast, CBy/CAST-dfw2J/+ heterozygotes expressing even a single copy of the CAST/Ei-derivedmdfwallele (Mdfw) retain their normal hearing function. Our results reveal an epistatic relationship between themdfwand thedfwgenes and provide a model system to study nonsyndromic hearing loss in mice. 相似文献
10.
Neeliyath A. Ramakrishnan Marian J. Drescher Dennis G. Drescher 《The Journal of biological chemistry》2009,284(3):1364-1372
The molecular mechanisms underlying synaptic exocytosis in the hair cell,
the auditory and vestibular receptor cell, are not well understood. Otoferlin,
a C2 domain-containing Ca2+-binding protein, has been implicated as
having a role in vesicular release. Mutations in the OTOF gene cause
nonsyndromic deafness in humans, and OTOF knock-out mice are deaf. In
the present study, we generated otoferlin fusion proteins containing two of
the same amino acid substitutions detected in DFNB9 patients (P1825A in C2F
and L1011P in C2D). The native otoferlin C2F domain bound syntaxin 1A and
SNAP-25 in a Ca2+-dependent manner (with optimal 61
μm free Ca2+ required for binding). These
interactions were greatly diminished for C2F with the P1825A mutation,
possibly because of a reduction in tertiary structural change, induced by
Ca2+, for the mutated C2F compared with the native C2F. The
otoferlin C2D domain also bound syntaxin 1A, but with weaker affinity
(Kd = 1.7 × 10–5 m) than
for the C2F interaction (Kd = 2.6 ×
10–9 m). In contrast, it was the otoferlin C2D
domain that bound the Cav1.3 II-III loop, in a
Ca2+-dependent manner. The L1011P mutation in C2D rendered this
binding insensitive to Ca2+ and considerably diminished. Overall,
we demonstrated that otoferlin interacts with two main target-SNARE proteins
of the hair-cell synaptic complex, syntaxin 1A and SNAP-25, as well as the
calcium channel, with the otoferlin C2F and C2D domains of central importance
for binding. Because mutations in the otoferlin C2 domains that cause deafness
in humans impair the ability of otoferlin to bind syntaxin, SNAP-25, and the
Cav1.3 calcium channel, it is these interactions that may mediate
regulation by otoferlin of hair cell synaptic exocytosis critical to inner ear
hair cell function.Calcium is a key regulator of synaptic vesicle fusion (reviewed in Ref.
1). In mechanosensory hair
cells, calcium microdomains (2)
and possibly nanodomains (3)
are formed when voltage-gated calcium channels open upon depolarization.
Calcium at these sites is thought to activate protein interactions, leading to
vesicle fusion. Some of the key players in this process are the
target-SNARE2
proteins, syntaxin 1A and SNAP-25, and the vesicle-SNARE, synaptobrevin
(4). Vesicle-SNARE
synaptotagmin 1 plays a crucial role as a calcium sensor at the neuronal
synapse, modulating calcium channels and vesicle release by a
Ca2+-dependent interaction with other SNARE proteins in the
presence of lipid molecules
(4–6).
However, in vertebrate mechanosensory hair cells, synaptotagmin 1 is not
detected (7). Instead, fast
neurotransmitter release in auditory and vestibular hair cells, facilitated
largely by an L-type voltagegated calcium channel, Cav1.3
(8,
9), is thought to be modulated
by a newly discovered protein, otoferlin, acting as the Ca2+ sensor
and vesicle-binding protein. When mutated, otoferlin causes DFNB9 nonsyndromic
deafness (10). Gene sequences
of different deaf families show that the OTOF gene can undergo
mutation at multiple locations
(11–13).
Recently, it has been demonstrated that otoferlin is necessary for synaptic
exocytosis from hair cells
(14). Further, an engineered
mutation in the C2B domain of otoferlin has been shown to cause deafness in
mice (15). However, the
precise function of otoferlin as a synaptic protein is not well
understood.Specific mutations in the otoferlin C2F (P1825A) or C2D (L1011P) domains in
humans have been documented to cause DFNB9 deafness
(11,
12). Previous studies
suggested that a region of otoferlin containing all three C2 domains, D, E,
and F, binds directly to the t-SNARE molecules syntaxin 1A and SNAP-25 in
response to an increase in Ca2+ concentration
(14). However, it is not
understood how a single amino acid substitution in one domain of otoferlin,
such as C2F (11) or C2D
(12), might independently lead
to deafness. Here, we examine the role of otoferlin as a Ca2+
sensor as well as a facilitator of vesicle fusion, as indicated by
protein-protein interactions and their [Ca2+] dependence. 相似文献
11.
Khan SY Riazuddin S Tariq M Anwar S Shabbir MI Riazuddin SA Khan SN Husnain T Ahmed ZM Friedman TB Riazuddin S 《Human genetics》2007,120(6):789-793
A genome wide linkage analysis of nonsyndromic deafness segregating in a consanguineous Pakistani family (PKDF537) was used
to identify DFNB63, a new locus for congenital profound sensorineural hearing loss. A maximum two-point lod score of 6.98 at θ = 0 was obtained for marker D11S1337 (68.55 cM). Genotyping of 550 families revealed three additional families (PKDF295,
PKDF702 and PKDF817) segregating hearing loss linked to chromosome 11q13.2-q13.3. Meiotic recombination events in these four
families define a critical interval of 4.81 cM bounded by markers D11S4113 (68.01 cM) and D11S4162 (72.82 cM), and SHANK2, FGF-3, TPCN2 and CTTN are among the candidate genes in this interval. Positional identification of this deafness gene should reveal a protein necessary
for normal development and/or function of the auditory system. 相似文献
12.
《Free radical research》2013,47(3):264-272
AbstractObjective. The objective of this study was to investigate the dose-dependent therapeutic effect of the orally administrated antioxidant drugs [4-hydroxy alpha-phenyl-tert-butylnitrone (4-OHPBN) and N-acetyl-L-cysteine (NAC)] on acute noise-induced hearing loss because oral administration is the most commonly used method of drug administration due to its convenience, safety, and economical efficiency. Methods. Thirty chinchilla were exposed to a 105 dB octave band noise centered at 4 kHz for 6 h and randomly assigned to a control group (saline only) and three experimental groups [4-OHPBN (10 mg/kg) plus NAC (20 mg/kg), 4-OHPBN (20 mg/kg) plus NAC (50 mg/kg), and 4-OHPBN (50 mg/kg) plus NAC (100 mg/kg)]. The drugs were orally administrated beginning 4 h after noise exposure and then administered twice daily for the next 2 days. Permanent auditory brainstem response threshold shifts, distortion product otoacoustic emission threshold shifts, and the percentage of missing outer hair cell were determined. Results. The oral administration significantly reduced permanent hearing threshold shift, distortion product otoacoustic emission threshold shift, and the percentage of missing outer hair cell in a dose-dependent manner. Discussion. This result demonstrates that orally administered drugs can treat acute noise-induced hearing loss in a dose-dependent manner. This suggests that oral administration was effective in treating acute noise-induced hearing loss as in intraperitoneal administration. 相似文献
13.
Hui-Mei Hong Jiann-Jou Yang Jia-Ching Shieh Mei-Ling Li Shuan-Yow Li 《Human genetics》2010,127(5):545-551
Connexins (CXs), a large family of membrane proteins, are key components of gap junction channels. Among a cohort of patients
with nonsyndromic hearing loss, we have recently identified three novel missense mutations in the GJA1 gene and GJA1 pseudogene (ρGJA1) as likely being causally related to hearing loss. However, the functional alteration of CX43 caused by the mutations of
GJA1 and ρGJA1 gene remains unclear. This study compares the intracellular distribution and assembly of three CX43 mutants expressed in
HeLa cells with their wild-type (WT) counterparts and the effects of the mutant proteins on those cells. Localization assay
of WT CX43 reveals a typical punctuate fluorescence pattern of a gap junction channel between neighboring expression cells.
Additionally, immunoblotting analysis of the transfectants confirms the production of mutant proteins, in which their distributions
along appositional membranes are determined using immunofluorescent staining procedures. Furthermore, dye transfer assay results
demonstrate that gap junctional intercellular communication is less in HeLa cells carrying mutant GJA1 or ρGJA1 gene than in WT-expressing cells. The results of this study suggest that the three mutations in GJA1 or ρGJA1 that we previously reported result in at least partial loss of normal functions carried out by CX43, which may form a basis
for the mechanism contributing to hearing loss in patients. 相似文献
14.
15.
Diana Rigueur Ryan R. Roberts Lauren Bobzin Amy E. Merrill 《Genesis (New York, N.Y. : 2000)》2019,57(1)
The skeletal structure of the mammalian middle ear, which is composed of three endochondral ossicles suspended within a membranous air‐filled capsule, plays a critical role in conducting sound. Gene mutations that alter skeletal development in the middle ear result in auditory impairment. Mutations in fibroblast growth factor receptor 2 (FGFR2), an important regulator of endochondral and intramembranous bone formation, cause a spectrum of congenital skeletal disorders featuring conductive hearing loss. Although the middle ear malformations in multiple FGFR2 gain‐of‐function disorders are clinically characterized, those in the FGFR2 loss‐of‐function disorder lacrimo‐auriculo‐dento‐digital (LADD) syndrome are relatively undescribed. To better understand conductive hearing loss in LADD, we examined the middle ear skeleton of mice with conditional loss of Fgfr2. We find that decreased auditory function in Fgfr2 mutant mice correlates with hypoplasia of the auditory bulla and ectopic bone growth at sites of tendon/ligament attachment. We show that ectopic bone associated with the intra‐articular ligaments of the incudomalleal joint is derived from Scx‐expressing cells and preceded by decreased expression of the joint progenitor marker Gdf5. Together, these results identify a role for Fgfr2 in development of the middle ear skeletal tissues and suggest potential causes for conductive hearing loss in LADD syndrome. 相似文献
16.
E. A. Bliznetz V. A. Galkina G. N. Matyushchenko A. G. Kisina T. G. Markova A. V. Polyakov 《Russian Journal of Genetics》2012,48(1):101-112
Molecular testing for mutations in the connexin 26 gene (GJB2) is a routine diagnostic analysis for subjects with hereditary hearing loss worldwide. However, till now there is no assessment
of the diagnostic significance of this analysis for Russian patients, and there are difficulties in interpretation of the
results of DNA diagnostics. In the present study, a sample of 705 patients with nonsyndromic autosomal recessive hearing loss
from different regions of Russian Federation was investigated. A portion of DFNB1 hearing loss caused by mutations in the
GJB2 gene among the sample was 46%. The frequency of DFNB1 hearing loss was 1:1000, that is, the frequency of isolated autosomal
recessive hearing loss 1:500 in the population. It was found that each sixteenth individual in Russia is a heterozygous carrier
of the mutation in the GJB2 gene. Totally, 20 pathological GJB2 alleles were detected; among them, a c.35delG mutation with the allelic frequency 81% prevails. Six most frequent mutations
(c.35delG, c.313_326del14, c.23+1G>A (IVS1+1G>A), c.235delC, c.167delT, and p.Glu120del), which account for 95% of pathological
GJB2 alleles, were detected. Mutations previously not described in the GJB2 gene (c.129delG, p.Gly200Arg, and c[Arg127His, Gly160Ser]) were found. An optimal algorithm of molecular testing of Russian
patients which detects up to 100% of mutations in the GJB2 gene was suggested. Data concerning a clinical significance of p.Met34Thr and p.Val37Ile mutations are confirmed in the study.
Eight polymorphic substitutions in the GJB2 gene which do not have clinical significance (p.Val27Ile, c.*3C>A, p.Val153Ile, p.Gly160Ser, c.Arg127His, p.Glu114Gly (c.341A>G),
c.-45C>A, and p.Ala149Thr) were also detected. 相似文献
17.
Non-syndromic X-linked deafness is a rare form of genetic deafness in humans accounting for a small proportion of all hereditary
hearing loss. Different clinical forms of non-syndromic X-linked deafness have been described, and most of these have been
mapped. Here, we report a Chinese family affected by a congenital profound sensorineural hearing loss. All phenotypes of this
family are clinically compatible with non-syndromic sensorineural deafness (DFN2). A maximum two-point Lod score of 2.32 was
obtained at markerDXS6797 (θ = 0.00). Recombinants define a region of 4.3 cm flanked by markersDXS6799 andGATA172D05. This region overlaps the previously reported DFN2 region by 2.0 cm. 相似文献
18.
Morin hydrate promotes inner ear neural stem cell survival and differentiation and protects cochlea against neuronal hearing loss
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Qiang He Zhanwei Jia Ying Zhang Xiumin Ren 《Journal of cellular and molecular medicine》2017,21(3):600-608
We aimed to investigate the effect of morin hydrate on neural stem cells (NSCs) isolated from mouse inner ear and its potential in protecting neuronal hearing loss. 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2‐H‐tetrazolium bromide (MTT) and bromodeoxyuridine incorporation assays were employed to assess the effect of morin hydrate on the viability and proliferation of in vitro NSC culture. The NSCs were then differentiated into neurons, in which neurosphere formation and differentiation were evaluated, followed by neurite outgrowth and neural excitability measurements in the subsequent in vitro neuronal network. Mechanotransduction of cochlea ex vivo culture and auditory brainstem responses threshold and distortion product optoacoustic emissions amplitude in mouse ototoxicity model were also measured following gentamicin treatment to investigate the protective role of morin hydrate against neuronal hearing loss. Morin hydrate improved viability and proliferation, neurosphere formation and neuronal differentiation of inner ear NSCs, and promoted in vitro neuronal network functions. In both ex vivo and in vivo ototoxicity models, morin hydrate prevented gentamicin‐induced neuronal hearing loss. Morin hydrate exhibited potent properties in promoting growth and differentiation of inner ear NSCs into functional neurons and protecting from gentamicin ototoxicity. Our study supports its clinical potential in treating neuronal hearing loss. 相似文献
19.
Song MH Choi SY Wu L Oh SK Lee HK Lee DJ Shim DB Choi JY Kim UK Bok J 《Biochemical and biophysical research communications》2011,(1):528-533
DFN3, the most prevalent X-linked hearing loss, is caused by mutations in the POU3F4 gene. Previous studies in Pou3f4 knockout mice suggest that defective otic fibrocytes in the spiral ligament of the cochlear lateral wall may underlie the hearing loss in DFN3. To better understand the pathological mechanisms of the DFN3 hearing loss, we analyzed inner ears of Pou3f4-deficient mice during development. Our results indicate that compartmentalization of the spiral ligament mesenchyme setting up boundaries for specific otic fibrocytes occurs normally in Pou3f4-deficient cochlea. However, differentiation of the compartmentalized mesenchyme into specific otic fibrocytes was blocked in the absence of Pou3f4 function. In addition, we found that stria vascularis in the cochlear lateral wall was also affected in Pou3f4-deficient cochlea. Unlike the otic fibrocytes, differentiation of stria vascularis was completed in the absence of Pou3f4 function, yet expression of Kir4.1 channels in the strial intermediate cells, essential for the sound transduction, was lost afterwards. These results suggest that Pou3f4 deficiency causes defects in both otic fibrocytes and stria vascularis at different developmental stages and by different pathological mechanisms, which may account for the progressive nature of DFN3 hearing loss. 相似文献
20.
Sari SUZUKI Masashi ISHIKAWA Takuya UEDA Yasuhiro OHSHIBA Yuki MIYASAKA Kazuhiro OKUMURA Michinari YOKOHAMA Choji TAYA Kunie MATSUOKA Yoshiaki KIKKAWA 《Experimental Animals》2015,64(3):241-251
The DBA/2J strain is a model for early-onset, progressive hearing loss in humans, as
confirmed in the present study. DBA/2J mice showed progression of hearing loss to
low-frequency sounds from ultrasonic-frequency sounds and profound hearing loss at all
frequencies before 7 months of age. It is known that the early-onset hearing loss of
DBA/2J mice is caused by affects in the ahl
(Cdh23ahl) and ahl8
(Fscn2ahl8) alleles of the cadherin 23 and fascin 2 genes,
respectively. Although the strong contributions of the
Fscn2ahl8 allele were detected in hearing loss at 8- and
16-kHz stimuli with LOD scores of 5.02 at 8 kHz and 8.84 at 16 kHz, hearing loss effects
were also demonstrated for three new quantitative trait loci (QTLs) for the intervals of
50.3–54.5, 64.6–119.9, and 119.9–137.0 Mb, respectively, on chromosome 5, with significant
LOD scores of 2.80–3.91 for specific high-frequency hearing loss at 16 kHz by quantitative
trait loci linkage mapping using a (DBA/2J × C57BL/6J) F1 × DBA/2J backcross
mice. Moreover, we showed that the contribution of Fscn2ahl8
to early-onset hearing loss with 32-kHz stimuli is extremely low and raised the
possibility of effects from the Cdh23ahl allele and another
dominant quantitative trait locus (loci) for hearing loss at this ultrasonic frequency.
Therefore, our results suggested that frequency-specific QTLs control early-onset hearing
loss in DBA/2J mice. 相似文献