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1.
BMC Med Genet ; 21(1): 13, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937257

RESUMO

BACKGROUND: Mutations of the WFS1 gene are responsible for most cases of Wolfram syndrome (WS), a rare, recessively inherited neurodegenerative disorder characterized by juvenile-onset non-autoimmune diabetes mellitus and optic atrophy. Variants of WFS1 are also associated with non-syndromic hearing loss and type-2 diabetes mellitus (T2DM). Our study adds to literature significant associations between WS and T2DM. CASE PRESENTATION: In this study, we analyzed the clinical and genetic data of two families with high prevalence of WS and T2DM. Genetic linkage analysis and DNA sequencing were exploited to identify pathogenic variants. One novel pathogenic variant (c.2243-2244insC) and one known pathogenic (c.1232_1233delCT) (frameshift) variant were identified in exon eight of WFS1 gene. CONCLUSIONS: The mutational and phenotypic spectrum of WS is broadened by our report of novel WFS1 mutation. Our results reveal the value of molecular analysis of WFS1 in the improvement of clinical diagnostics for WS. This study also confirms the role of WFS1 in T2DM.


Assuntos
Diabetes Mellitus Tipo 2/genética , Testes Genéticos , Proteínas de Membrana/genética , Síndrome de Wolfram/genética , Adulto , Criança , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Éxons/genética , Feminino , Mutação da Fase de Leitura/genética , Ligação Genética , Predisposição Genética para Doença , Perda Auditiva/complicações , Perda Auditiva/genética , Perda Auditiva/patologia , Humanos , Irã (Geográfico)/epidemiologia , Masculino , Atrofia Óptica/complicações , Atrofia Óptica/genética , Atrofia Óptica/patologia , Linhagem , Fenótipo , Mutação Puntual/genética , Síndrome de Wolfram/complicações , Síndrome de Wolfram/patologia , Adulto Jovem
2.
World Neurosurg ; 135: e488-e493, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31843724

RESUMO

BACKGROUND: Vestibular schwannoma (VS) is the most common benign tumor originating in the cerebellopontine angle. In most cases, tumors tend to grow and deserve proper treatment. Sometimes they stabilize, and rarely they decrease in size spontaneously. METHODS: We evaluated retrospectively the images of patients with spontaneous tumor regression. We describe the common neuroimage findings of patients with spontaneous tumoral regression. RESULTS: Four patients with diagnosis of VS were followed with magnetic resonance imaging (MRI). There were some relevant features in MRI: a heterogeneous contrast enhancement in the outer layer of the tumor and presence of a cerebrospinal fluid column between the tumor and the entrance of the internal auditory canal. The percentage of tumor diameter reduction ranged from 20% to 40%. CONCLUSIONS: Some MRI features may demonstrate a spontaneous involution of VS and may be closely followed in asymptomatic or oligosymptomatic patients.


Assuntos
Neoplasias Cerebelares/patologia , Ângulo Cerebelopontino/patologia , Neuroma Acústico/patologia , Adulto , Idoso , Neoplasias Cerebelares/complicações , Feminino , Perda Auditiva/etiologia , Perda Auditiva/patologia , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Regressão Neoplásica Espontânea/patologia , Neuroma Acústico/complicações , Estudos Retrospectivos , Zumbido/etiologia , Zumbido/patologia
3.
Cell Mol Life Sci ; 76(21): 4221-4232, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31584127

RESUMO

In the past two decades, transmembrane channel-like (TMC) proteins have attracted a significant amount of research interest, because mutations of Tmc1 lead to hereditary deafness. As evolutionarily conserved membrane proteins, TMC proteins are widely involved in diverse sensorimotor functions of many species, such as hearing, chemosensation, egg laying, and food texture detection. Interestingly, recent structural and physiological studies suggest that TMC channels may share a similar membrane topology with the Ca2+-activated Cl- channel TMEM16 and the mechanically activated OSCA1.2/TMEM63 channel. Namely, these channels form dimers and each subunit consists of ten transmembrane segments. Despite this important structural insight, a key question remains: what is the gating mechanism of TMC channels? The major technical hurdle to answer this question is that the reconstitution of TMC proteins as functional ion channels has been challenging in mammalian heterologous systems. Since TMC channels are conserved across taxa, genetic studies of TMC channels in model organisms such as C. elegans, Drosophila, and zebrafish may provide us critical information on the physiological function and regulation of TMCs. Here, we present a comparative overview on the diverse functions of TMC channels in different species.


Assuntos
Canais Iônicos/metabolismo , Animais , Perda Auditiva/genética , Perda Auditiva/patologia , Humanos , Canais Iônicos/química , Canais Iônicos/genética , Mecanotransdução Celular , Mutação de Sentido Incorreto , Neurônios/metabolismo , Propriocepção , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo
4.
Hum Genet ; 138(11-12): 1275-1286, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31586237

RESUMO

Although most disease-causing variants are within coding region of genes, it is now well established that cis-acting regulatory sequences, depending on 3D-chromatin organization, are required for temporal and spatial control of gene expression. Disruptions of such regulatory elements and/or chromatin conformation are likely to play a critical role in human genetic disease. Hence, recurrent monoallelic cases, who present the most common hereditary type of nonsyndromic hearing loss (i.e., DFNB1), carry only one identified pathogenic allele. This strongly suggests the presence of uncharacterized distal cis-acting elements in the missing allele. Here within, we study the spatial organization of a large DFNB1 locus encompassing the gap junction protein beta 2 (GJB2) gene, the most frequently mutated gene in this inherited hearing loss phenotype, with the chromosome conformation capture carbon copy technology (5C). By combining this approach with functional activity reporter assays and mapping of CCCTC-binding factor (CTCF) along the DFNB1 locus, we identify a novel set of cooperating GJB2 cis-acting elements and suggest a DFNB1 three-dimensional looping regulation model.


Assuntos
Fator de Ligação a CCCTC/metabolismo , Conexinas/genética , Perda Auditiva/genética , Perda Auditiva/patologia , Sequências Reguladoras de Ácido Nucleico , Fator de Ligação a CCCTC/genética , Células Cultivadas , Conexinas/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Testes Genéticos , Genótipo , Humanos , Mutação , Mucosa Nasal/citologia , Mucosa Nasal/metabolismo , Fenótipo
5.
Int J Mol Sci ; 20(19)2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31547176

RESUMO

Noise-induced hearing loss (NIHL) relates closely to auditory cortex (AC) injury, so countermeasures aiming at the AC recovery would be of benefit. In this work, the effect of hyperbaric oxygen treatment on NIHL was elucidated, which was imposed on mice before (HBOP), during (HBOD) or after (HBOA) noise exposure. Morphology of neurons was assayed by hematoxylin-eosin or Nissl staining. Ceramide (Cer) level was measured through immunohistochemistry analysis. Apoptotic neurons were counted using transferase-mediated dUTP nick end labeling (TUNEL) staining. We demonstrated that the intense, broad band noise raised the threshold of auditory brainstem response, evoked neuronal degeneration or apoptosis and triggered the Cer accumulation in AC, all of which were restored significantly by HBOP, but not HBOD or HBOA. Cer over-generation reversed the advantages of HBOP significantly, while its curtailment recapitulated the effect. Next, noise exposure raised the superoxide or malondialdehyde (MDA) production which was blocked by HBOP or Cer repression. Oxidative control not only attenuated the hearing loss or neurodegeneration but, in turn, reduced the Cer formation significantly. In summary, mutual regulation between Cer and oxidative stress underlies the HBOP's curative effect on hearing loss and neuronal damage in noise-exposed mice.


Assuntos
Córtex Auditivo , Ceramidas/metabolismo , Perda Auditiva , Oxigenação Hiperbárica , Ruído/efeitos adversos , Animais , Córtex Auditivo/patologia , Córtex Auditivo/fisiopatologia , Perda Auditiva/metabolismo , Perda Auditiva/patologia , Perda Auditiva/fisiopatologia , Perda Auditiva/terapia , Masculino , Camundongos
6.
Genes (Basel) ; 10(9)2019 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527525

RESUMO

The OTOA gene (Locus: DFNB22) is reported to be one of the causative genes for non-syndromic autosomal recessive hearing loss. The copy number variations (CNVs) identified in this gene are also known to cause hearing loss, but have not been identified in Japanese patients with hearing loss. Furthermore, the clinical features of OTOA-associated hearing loss have not yet been clarified. In this study, we performed CNV analyses of a large Japanese hearing loss cohort, and identified CNVs in 234 of 2262 (10.3%, 234/2262) patients with autosomal recessive hearing loss. Among the identified CNVs, OTOA gene-related CNVs were the second most frequent (0.6%, 14/2262). Among the 14 cases, 2 individuals carried OTOA homozygous deletions, 4 carried heterozygous deletions with single nucleotide variants (SNVs) in another allele. Additionally, 1 individual with homozygous SNVs in the OTOA gene was also identified. Finally, we identified 7 probands with OTOA-associated hearing loss, so that its prevalence in Japanese patients with autosomal recessive hearing loss was calculated to be 0.3% (7/2262). As novel clinical features identified in this study, the audiometric configurations of patients with OTOA-associated hearing loss were found to be mid-frequency. This is the first study focused on the detailed clinical features of hearing loss caused by this gene mutation and/or gene deletion.


Assuntos
Proteínas Ligadas por GPI/genética , Frequência do Gene , Perda Auditiva/genética , Adolescente , Adulto , Audiometria , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Feminino , Perda Auditiva/patologia , Humanos , Lactente , Masculino , Polimorfismo de Nucleotídeo Único
7.
Nat Commun ; 10(1): 3801, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31444330

RESUMO

The bundle of stereocilia on inner ear hair cells responds to subnanometer deflections produced by sound or head movement. Stereocilia are interconnected by a variety of links and also carry an electron-dense surface coat. The coat may contribute to stereocilia adhesion or protect from stereocilia fusion, but its molecular identity remains unknown. From a database of hair-cell-enriched translated proteins, we identify Polycystic Kidney and Hepatic Disease 1-Like 1 (PKHD1L1), a large, mostly extracellular protein of 4249 amino acids with a single transmembrane domain. Using serial immunogold scanning electron microscopy, we show that PKHD1L1 is expressed at the tips of stereocilia, especially in the high-frequency regions of the cochlea. PKHD1L1-deficient mice lack the surface coat at the upper but not lower regions of stereocilia, and they develop progressive hearing loss. We conclude that PKHD1L1 is a component of the surface coat and is required for normal hearing in mice.


Assuntos
Células Ciliadas Auditivas Internas/metabolismo , Perda Auditiva/genética , Audição , Receptores de Superfície Celular/metabolismo , Estereocílios/metabolismo , Estimulação Acústica , Animais , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Células Ciliadas Auditivas Internas/ultraestrutura , Perda Auditiva/diagnóstico , Perda Auditiva/patologia , Humanos , Camundongos , Camundongos Knockout , Microscopia Eletrônica de Varredura , Receptores de Superfície Celular/genética , Estereocílios/ultraestrutura
8.
PLoS One ; 14(7): e0219600, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31295316

RESUMO

CONTEXT: Permanent childhood hearing loss (PCHL) can affect speech, language, and wider outcomes. Adverse effects are mitigated through universal newborn hearing screening (UNHS) and early intervention. OBJECTIVE: We undertook a systematic review and meta-analysis to estimate prevalence of UNHS-detected PCHL (bilateral loss ≥26 dB HL) and its variation by admission to neonatal intensive care unit (NICU). A secondary objective was to report UNHS programme performance (PROSPERO: CRD42016051267). DATA SOURCES: Multiple electronic databases were interrogated in January 2017, with further reports identified from article citations and unpublished literature (November 2017). STUDY SELECTION: UNHS reports from very highly-developed (VHD) countries with relevant prevalence and performance data; no language or date restrictions. DATA EXTRACTION: Three reviewers independently extracted data and assessed quality. RESULTS: We identified 41 eligible reports from 32 study populations (1799863 screened infants) in 6195 non-duplicate references. Pooled UNHS-detected PCHL prevalence was 1.1 per 1000 screened children (95% confidence interval [CI]: 0.9, 1.3; I2 = 89.2%). This was 6.9 times (95% CI: 3.8, 12.5) higher among those admitted to NICU. Smaller studies were significantly associated with higher prevalences (Egger's test: p = 0.02). Sensitivity and specificity ranged from 89-100% and 92-100% respectively, positive predictive values from 2-84%, with all negative predictive values 100%. LIMITATIONS: Results are generalisable to VHD countries only. Estimates and inferences were limited by available data. CONCLUSIONS: In VHD countries, 1 per 1000 screened newborns require referral to clinical services for PCHL. Prevalence is higher in those admitted to NICU. Improved reporting would support further examination of screen performance and child demographics.


Assuntos
Análise Custo-Benefício , Transtornos da Audição/epidemiologia , Perda Auditiva/epidemiologia , Criança , Pré-Escolar , Feminino , Transtornos da Audição/diagnóstico , Transtornos da Audição/economia , Transtornos da Audição/patologia , Perda Auditiva/diagnóstico , Perda Auditiva/economia , Perda Auditiva/patologia , Testes Auditivos/economia , Humanos , Lactente , Recém-Nascido , Masculino , Triagem Neonatal/economia
9.
Trends Hear ; 23: 2331216519857267, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31213143

RESUMO

Age-related hearing loss has been associated with varied auditory cortex morphology in human neuroimaging studies. These findings have suggested that peripheral auditory system declines cause changes in brain morphology but could also be due to latent variables that affect the auditory periphery and brain. The current longitudinal study was designed to evaluate these explanations for pure-tone threshold and brain morphology associations. Thirty adults (mean age at Time 1 = 64.12 ± 10.32 years) were studied at two time points (average duration between visits = 2.62 ± 0.81 years). Small- to medium-effect size associations were observed between high-frequency pure-tone thresholds and auditory cortex gray matter volume at each time point. Although there were significant longitudinal changes in low- and high-frequency hearing measures and brain morphology, those longitudinal changes were not significantly correlated across participants. High-frequency hearing measures at Time 1 were significantly related to more lateral ventricle expansion, such that participants with higher measures exhibited larger increases in ventricle size. This ventricle effect was statistically independent of high-frequency hearing associations with auditory cortex morphology. Together, these results indicate that there are at least two mechanisms for associations between age-related hearing loss and brain morphology. Potential explanations for a direct hearing loss effect on brain morphology, as well as latent variables that likely affect both the inner ear and brain, are discussed.


Assuntos
Encéfalo , Perda Auditiva , Fatores Etários , Audiometria de Tons Puros , Limiar Auditivo , Encéfalo/anatomia & histologia , Feminino , Perda Auditiva/patologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade
10.
Neuroscience ; 410: 202-216, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31102762

RESUMO

DFNA2 is a progressive deafness caused by mutations in the voltage-activated potassium channel KCNQ4. Hearing loss develops with age from a mild increase in the hearing threshold to profound deafness. Studies using transgenic mice for Kcnq4 expressed in a mixed background demonstrated the implication of outer hair cells at the initial phase. However, it could not explain the last phase mechanisms of the disease. Genetic backgrounds are known to influence disease expressivity. To unmask the cause of profound deafness phenotype, we backcrossed the Kcnq4 knock-out allele to the inbred strain C3H/HeJ and investigated inner and outer hair cell and spiral ganglion neuron degeneration across the lifespan. In addition to the already reported outer hair cell death, the C3H/HeJ strain also exhibited inner hair cell and spiral ganglion neuron death. We tracked the spatiotemporal survival of cochlear cells by plotting cytocochleograms and neuronal counts at different ages. Cell loss progressed from basal to apical turns with age. Interestingly, the time-course of cell degeneration was different for each cell-type. While for outer hair cells it was already present by week 3, inner hair cell and neuronal loss started 30 weeks later. We also established that outer hair cell loss kinetics slowed down from basal to apical regions correlating with KCNQ4 expression pattern determined in wild-type mice. Our findings indicate that KCNQ4 plays differential roles in each cochlear cell-type impacting in their survival ability. Inner hair cell and spiral ganglion neuron death generates severe hearing loss that could be associated with the last phase of DFNA2.


Assuntos
Modelos Animais de Doenças , Células Ciliadas Auditivas Internas/metabolismo , Perda Auditiva/metabolismo , Canais de Potássio KCNQ/deficiência , Degeneração Neural/metabolismo , Animais , Feminino , Células Ciliadas Auditivas Internas/patologia , Perda Auditiva/genética , Perda Auditiva/patologia , Canais de Potássio KCNQ/genética , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Degeneração Neural/genética , Degeneração Neural/patologia
11.
Cells ; 8(5)2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31052605

RESUMO

Cisplatin-induced early-onset ototoxicity is linked to hearing loss. The mechanism by which cisplatin causes ototoxicity remains unclear. The purpose of this study was to identify the involvement of receptor-interacting protein kinase (RIP)3-dependent necroptosis in cisplatin-induced ototoxicity in vitro and in vivo. Sprague-Dawley rats (SD, 8 week) were treated via intraperitoneal (i.p.) injection with cisplatin (16 mg/kg for 1 day), and their hearing thresholds were measured by the auditory brainstem response (ABR) method. Hematoxylin and eosin (H & E) staining, immunohistochemistry, and western blots were performed to determine the effect of cisplatin-induced ototoxicity on cochlear morphology. Inhibitor experiments with necrostatin 1 (Nec-1) and Z-VAD were also performed in HEI-OC1 cell line. H&E stains revealed that the necroptotic changes were increased in the organ of Corti (OC) and spiral ganglion neurons (SGNs). Moreover, immunohistochemistry and western blot analysis showed that cisplatin treatment increased the protein levels of RIP3 in both OCs and SGNs. The treatment of Nec-1, a selective RIP1 inhibitor, resulted in markedly suppression of cisplatin-induced cell death in HEI-OC1 cells, whereas Z-VAD treatment did not change the cisplatin-induced cell death. Our results suggest that RIP3-dependent necroptosis was substantial in cisplatin-induced ototoxicity; inner cochlear regions, the OCs, and SGNs were especially sensitive to necroptosis.


Assuntos
Cisplatino/efeitos adversos , /patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Perda Auditiva/induzido quimicamente , Perda Auditiva/patologia , Masculino , Órgão Espiral/efeitos dos fármacos , Órgão Espiral/patologia , Ratos Sprague-Dawley , Gânglio Espiral da Cóclea/efeitos dos fármacos , Gânglio Espiral da Cóclea/patologia
12.
Int J Pediatr Otorhinolaryngol ; 123: 123-127, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31100707

RESUMO

OBJECTIVE: To evaluate the incidence of vascular canal variations in the pediatric cochlear implant (CI) candidates. METHODS: We retrospectively reviewed temporal bone computed tomography (CT) images of the CI candidates between November 2013 and November 2018. The presence of high riding jugular bulb, dehiscent jugular bulb, jugular bulb diverticulum, bulging of sigmoid sinus, mastoid emissary vein (MEV), carotid canal dehiscence, and aberrant internal carotid canal were evaluated. Findings were compared with a control group of normal-hearing subjects. RESULTS: Temporal CT images of 118 CI candidates and 119 control group participants were evaluated. The vascular canal anomalies were found in 88 (37.3%) temporal bones of the CI candidates and 49 (20.6%) of the control group (p < 0.001). In 236 temporal CT scans of the CI candidates and 238 temporal CT scans of the control group, we found MEV in 19.1% and 6.3%, high riding jugular bulb in 11.4% and 10.5%, dehiscent jugular bulb in 2.1% and 1.3%, jugular bulb diverticulum in 6.4% and 1.7%, bulging sigmoid sinus in 11.4% and 4.2%, carotid canal dehiscence in 0.8% and 1.3%, and aberrant internal carotid canal in 0 and 0.8%, respectively. Jugular bulb diverticulum (p = 0.01), bulging of the sigmoid sinus (p = 0.003), and MEV (p < 0.001) were more frequent in the CI candidates. CONCLUSION: Vascular canal variations are more common in the CI candidates and should be evaluated before CI surgery.


Assuntos
Implante Coclear , Implantes Cocleares , Perda Auditiva/patologia , Osso Temporal/irrigação sanguínea , Adolescente , Criança , Pré-Escolar , Cavidades Cranianas/diagnóstico por imagem , Cavidades Cranianas/patologia , Feminino , Perda Auditiva/diagnóstico por imagem , Perda Auditiva/terapia , Humanos , Incidência , Lactente , Veias Jugulares/diagnóstico por imagem , Veias Jugulares/patologia , Masculino , Estudos Retrospectivos , Osso Temporal/diagnóstico por imagem , Osso Temporal/patologia , Tomografia Computadorizada por Raios X
13.
Trends Hear ; 23: 2331216519830237, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30995887

RESUMO

Chronic subjective tinnitus is a widespread disorder. This perceptual anomaly is assumed to result from a dysbalance of excitatory and inhibitory mechanisms on different levels of the auditory pathways. However, the brain areas involved are still under discussion. Using resting-state functional magnetic resonance imaging, we investigate differences in cerebral regional homogeneity (ReHo) between patients with unilateral chronic tinnitus and nontinnitus control subjects. To our knowledge, our study is the first to investigate the intraregional connectivity of patients with unilateral tinnitus in relation to hearing loss. Our analyses, based on strict recruitment and characterization of the participants, showed reduced ReHo in the primary auditory cortex contralateral to the side of the perceived tinnitus percept in patients. Reduced ReHo in this same region was also correlated with increased Tinnitus Handicap Inventory and Visual Analogue Scale for loudness scores, reflecting an alteration of synchronization in this region related to the perceived loudness of the tinnitus and the related distress. Furthermore, increased ReHo in the supramarginal and angular gyri ipsilateral to the tinnitus side was correlated with increased tinnitus duration and hearing threshold at the tinnitus pitch. The correlations observed in these brain areas, which are normally related to the nontinnitus ear, could highlight compensatory mechanisms in these secondary auditory regions.


Assuntos
Encéfalo/diagnóstico por imagem , Perda Auditiva/diagnóstico por imagem , Imagem por Ressonância Magnética , Zumbido/diagnóstico por imagem , Adulto , Vias Auditivas/diagnóstico por imagem , Vias Auditivas/fisiopatologia , Mapeamento Encefálico , Feminino , Perda Auditiva/patologia , Humanos , Percepção Sonora , Masculino , Pessoa de Meia-Idade , Zumbido/fisiopatologia
14.
Dis Markers ; 2019: 8705989, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30881523

RESUMO

Mutations in the COL4A3 gene are frequently reported to be associated with various types of hereditary nephropathy. COL4A3 encodes the α3 chain of type IV collagen, which is the main structural protein in the basement membrane. Mutations in this gene are always related to kidney performance, and deafness and ocular lesion have also been reported. In this study, using next-generation sequencing, we investigated the DNA of a family visiting a clinic for hearing loss. A new missense mutation was found in COL4A3 of 5 patients, c.3227C>T (p.P1076L). Based on these results, we predict that the mutation is pathogenic and leads to abnormal collagen IV. Here, we report for the first time on this autosomal dominant syndrome, characterized by hearing loss and eye abnormalities, but without renal damage, in all carriers. Since the oldest patient in the trial was less than 50 years old, however, we recommend that renal examination be reviewed regularly. Our results reveal expansion in the mutation spectrum of the COL4A3 gene and phenotypic spectrum of collagen IV disease. Our study suggests that next-generation sequencing is an economical and effective method and may help in the accurate diagnosis and treatment of these patients.


Assuntos
Autoantígenos/genética , Colágeno Tipo IV/genética , Perda Auditiva/genética , Hematúria/genética , Nefrite Hereditária/genética , Fenótipo , Adolescente , Adulto , Feminino , Perda Auditiva/patologia , Hematúria/patologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Nefrite Hereditária/patologia , Linhagem
15.
J Int Med Res ; 47(4): 1717-1730, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30819013

RESUMO

BACKGROUND: Heterozygous purinergic receptor p2x gene ( P2RX2) c.178G>T (p.V60L) mutations can lead to progressive hearing loss (HL) and increased susceptibility to noise. However, the underlying mechanisms remain unclear. A combination of human induced pluripotent stem cell (hiPSC) technology with clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein (Cas)9-mediated gene editing may provide a promising tool to study gene function and treat hereditary deafness in humans. METHODS: hiPSC technology and CRISPR/Cas9-mediated gene editing were used to generate heterozygous and homozygous P2RX2 c.178G>T (p.V60L) cell models. RESULTS: We generated non-integrative hiPSCs from urine samples derived from three members of a large Chinese family carrying heterozygous P2RX2 c.178G>T mutations (designated P2RX2+/-) as a model to study P2RX2-mediated hereditary HL. Furthermore, we used CRISPR/Cas9 and single-stranded donor oligonucleotides to genetically establish homozygous P2RX2 c.178G>T hiPSCs (designated P2RX2-/-) from heterozygous patient-specific hiPSCs as a control to further study the pathological gene function. CONCLUSIONS: Heterozygous and homozygous P2RX2-mutated hiPSC lines are good models to investigate the pathological mechanisms of P2RX2 mutations in HL pathogenesis. Our findings confirmed our hypothesis that it is feasible and convenient to introduce precise point mutations into genomic loci of interest to generate gene-mutated hiPSC models.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Perda Auditiva/genética , Homozigoto , Células-Tronco Pluripotentes Induzidas/patologia , Mutação , Receptores Purinérgicos P2X2/genética , Adulto , Criança , Feminino , Perda Auditiva/patologia , Heterozigoto , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Pessoa de Meia-Idade , Oligonucleotídeos/administração & dosagem , Linhagem , Fenótipo , Prognóstico
16.
Neurosci Lett ; 701: 175-179, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-30822439

RESUMO

The use of light as a tool to manipulate cellular processes or optogenetics has developed rapidly in various biological fields over the past decade. Through the addition of photosensitive proteins, light can be used to control intracellular mechanisms, map neuronal pathways, and alter variables that would be difficult to control using other mechanisms. Photons of a specific wavelength affect these light sensitive targets for in vitro or in vivo experiments. Optogenetics is beneficial because it gives the investigator spatial and temporal control over experimental variables. Precise control is achieved by sequential activation of different ion channels and the ability to non-invasively control membrane potential. In this review, we will discuss the recent use of optogenetics in biological fields to understand the role of different cell types in hearing and creating a new cochlear implant, as well as future uses such as light controlled drug delivery and gene expression.


Assuntos
Audição/genética , Optogenética , Animais , Implantes Cocleares , Sistemas de Liberação de Medicamentos , Expressão Gênica , Células Ciliadas Auditivas/patologia , Células Ciliadas Auditivas/fisiologia , Células Ciliadas Auditivas/efeitos da radiação , Perda Auditiva/genética , Perda Auditiva/patologia , Perda Auditiva/terapia , Humanos , Raios Infravermelhos , Nanopartículas , Opsinas/genética , Opsinas/metabolismo
17.
Sci Transl Med ; 11(482)2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30842313

RESUMO

Permanent hearing loss affects more than 5% of the world's population, yet there are no nondevice therapies that can protect or restore hearing. Delivery of therapeutics to the cochlea and vestibular system of the inner ear is complicated by their inaccessible location. Drug delivery to the inner ear via the vasculature is an attractive noninvasive strategy, yet the blood-labyrinth barrier at the luminal surface of inner ear capillaries restricts entry of most blood-borne compounds into inner ear tissues. Here, we compare the blood-labyrinth barrier to the blood-brain barrier, discuss invasive intratympanic and intracochlear drug delivery methods, and evaluate noninvasive strategies for drug delivery to the inner ear.


Assuntos
Sistemas de Liberação de Medicamentos , Orelha Interna/patologia , Preparações Farmacêuticas/administração & dosagem , Animais , Cóclea/irrigação sanguínea , Perda Auditiva/patologia , Humanos , Permeabilidade
18.
Otol Neurotol ; 40(3): e178-e185, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30741891

RESUMO

INTRODUCTION: The aim was to investigate the progress of hearing loss over time in a cohort of pendred syndrome and non-syndromic enlarged vestibular aqueduct (PS/NSEVA) with one or two confirmed pathogenic variations in SLC26A4. STUDY DESIGN: Retrospective cohort study. SUBJECTS AND METHODS: At our tertiary referral center, a retrospective search of all patients with enlarged vestibular aqueduct, hearing loss and SLC26A4 mutations yielded 103 individuals by March 2017, 96 of whom had records of hearing levels; both an early audiometry and the latest between 3 and 668 months follow-up. Pure-tone average (PTA; average of thresholds at 0.5, 1, 2 and 4 kHz) was calculated for both ears at time 1 and time 2. Neonatal screening results were retrieved. RESULTS: Eighty-seven (87) individuals had biallelic (M2) and 16 had monoallelic alterations (M1) in their SLC26A4. On average, the PTA progressed to 80 dB HL by the age of 6 years for the entire cohort, and 3.2 years for the biallelic (M2) affected individuals. 25% of the cohort was screened in the neonatal screening program; of these 42% had "passed" at least monaurally. Audiometric profiles related to age show faster deterioration in high frequencies than in low frequencies. CONCLUSION: In patients with PS/NSEVA and SLC26A4 mutations, the average hearing loss progresses to 80 dB HL by the age of 6 years. For biallelic (M2) affected individuals it was 3.2 years. Although hearing levels reached severe to profound during childhood, almost 1/2 had passed neonatal hearing screening, at least monaurally, emphasizing the need for close follow-up.


Assuntos
Bócio Nodular/complicações , Perda Auditiva Neurossensorial/complicações , Perda Auditiva/genética , Aqueduto Vestibular/anormalidades , Adulto , Criança , Estudos de Coortes , Feminino , Bócio Nodular/genética , Bócio Nodular/patologia , Perda Auditiva/patologia , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Humanos , Lactente , Masculino , Mutação , Estudos Retrospectivos , Transportadores de Sulfato/genética , Aqueduto Vestibular/patologia , Adulto Jovem
19.
Mol Neurobiol ; 56(8): 5950-5969, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30693443

RESUMO

In our aging society, age-related hearing loss (ARHL) has become a major socioeconomic issue. Reactive oxygen species (ROS) may be one of the main causal factors of age-related cochlear cell degeneration. We examined whether ROS-induced DNA damage response drives cochlear cell senescence and contributes to ARHL from the cellular up to the system level. Our results revealed that sublethal concentrations of hydrogen peroxide (H2O2) exposure initiated a DNA damage response illustrated by increased γH2AX and 53BP1 expression and foci formation mainly in sensory hair cells, together with increased levels of p-Chk2 and p53. Interestingly, postmitotic cochlear cells exposed to H2O2 displayed key hallmarks of senescent cells, including dramatically increased levels of p21, p38, and p-p38 expression, concomitant with decreased p19 and BubR1 expression and positive senescence-associated ß-galactosidase labeling. Importantly, the synthetic superoxide dismutase/catalase mimetic EUK-207 attenuated H2O2-induced DNA damage and senescence phenotypes in cochlear cells in vitro. Furthermore, systemic administration of EUK-207 reduced age-related loss of hearing and hair cell degeneration in senescence-accelerated mouse-prone 8 (SAMP8) mice. Altogether, these findings highlight that ROS-induced DNA damage responses drive cochlear cell senescence and contribute to accelerated ARHL. EUK-207 and likely other antioxidants with similar mechanisms of action could potentially postpone cochlear aging and prevent ARHL in humans.


Assuntos
Senescência Celular , Cóclea/patologia , Cóclea/fisiopatologia , Dano ao DNA , Audição/fisiologia , Mitose , Espécies Reativas de Oxigênio/toxicidade , Animais , Elementos de Resposta Antioxidante/genética , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Cóclea/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Perda Auditiva/patologia , Perda Auditiva/fisiopatologia , Camundongos , Mitose/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fenótipo , Regulação para Cima/efeitos dos fármacos
20.
Histol Histopathol ; 34(7): 811-820, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30675896

RESUMO

OBJECTIVE: Inbred strains of mice offer promising models for understanding the genetic basis of age-related hearing loss (AHL). NOD/LtJ, A/J, DBA/2J and C57BL/6J mice are classical models of age-related hearing loss and exhibit early onset of pathology of AHL. This study was carried out to characterize the early pathology of cochlear stereocilia in the four mouse strains with age-related hearing loss. METHODS: The structural features of stereocilia in NOD/LtJ, A/J, DBA/2J and C57BL/6J mice were observed by scanning electron microscopy (SEM) at age 2, 4, 6 or 8, and 10 or 12 weeks. Meanwhile, auditory-evoked brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) amplitudes of the mice were measured at various intervals (3, 4, 6, 8, 10 and 12 weeks of age). RESULTS: The ABR thresholds in NOD/LtJ, A/J and DBA/2J mice increased with age from 3 to 12 weeks. DPOAE amplitudes in NOD/LtJ, A/J, DBA/2J mice were very low at 4 weeks and became negative at 8 weeks at f2 frequency of 17 672 Hz. In addition to the progressive hearing loss, the four mouse strains displayed early onset (at 2 weeks of age) and progressive degeneration of stereocilia in hair cells. CONCLUSION: Early degeneration of stereocilia contributes to the functional impairment of hair cells and hearing loss in NOD/LtJ, A/J, DBA/2J and C57BL/6J mice.


Assuntos
Cóclea/ultraestrutura , Perda Auditiva/patologia , Estereocílios/ultraestrutura , Animais , Limiar Auditivo/fisiologia , Caderinas/genética , Proteínas de Transporte/genética , Cóclea/patologia , Potenciais Evocados Auditivos do Tronco Encefálico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Endogâmicos NOD , Camundongos Endogâmicos , Proteínas dos Microfilamentos/genética , Microscopia Eletrônica de Varredura , Estereocílios/patologia , Fatores de Tempo
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