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1.
Cell Prolif ; 53(11): e12915, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33047870

RESUMO

Programmed cell death (PCD)-apoptosis, autophagy and programmed necrosis-is any pathological form of cell death mediated by intracellular processes. Ototoxic drugs, ageing and noise exposure are some common pathogenic factors of sensorineural hearing loss (SNHL) that can induce the programmed death of auditory hair cells through different pathways, and eventually lead to the loss of hair cells. Furthermore, several mutations in apoptotic genes including DFNA5, DFNA51 and DFNB74 have been suggested to be responsible for the new functional classes of monogenic hearing loss (HL). Therefore, in this review, we elucidate the role of these three forms of PCD in different types of HL and discuss their guiding significance for HL treatment. We believe that further studies of PCD pathways are necessary to understand the pathogenesis of HL and guide scientists and clinicians to identify new drug targets for HL treatment.


Assuntos
Apoptose , Morte Celular Autofágica , Células Ciliadas Auditivas/patologia , Perda Auditiva/patologia , Necroptose , Envelhecimento , Animais , Apoptose/efeitos dos fármacos , Morte Celular Autofágica/efeitos dos fármacos , Células Ciliadas Auditivas/efeitos dos fármacos , Células Ciliadas Auditivas/metabolismo , Perda Auditiva/etiologia , Perda Auditiva/genética , Perda Auditiva/metabolismo , Humanos , Mutação , Necroptose/efeitos dos fármacos , Ruído/efeitos adversos
2.
Neurology ; 95(16): e2225-e2234, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-32878991

RESUMO

OBJECTIVE: To test the hypothesis that incipient Alzheimer disease (AD) may adversely affect hearing and that hearing loss may adversely affect cognition, we evaluated whether genetic variants that increase AD risk also increase problem hearing and genetic variants that increase hearing impairment risk do not influence cognition. METHODS: UK Biobank participants without dementia ≥56 years of age with Caucasian genetic ancestry completed a Digit Triplets Test of speech-in-noise hearing (n = 80,074), self-reported problem hearing and hearing with background noise (n = 244,915), and completed brief cognitive assessments. A genetic risk score for AD (AD-GRS) was calculated as a weighted sum of 23 previously identified AD-related polymorphisms. A genetic risk score for hearing (hearing-GRS) was calculated using 3 previously identified polymorphisms related to hearing impairment. Using age-, sex-, and genetic ancestry-adjusted logistic and linear regression models, we evaluated whether the AD-GRS predicted poor hearing and whether the hearing-GRS predicted worse cognition. RESULTS: Poor speech-in-noise hearing (>-5.5-dB speech reception threshold; prevalence 14%) was associated with lower cognitive scores (ß = -1.28; 95% confidence interval [CI] -1.54 to -1.03). Higher AD-GRS was significantly associated with poor speech-in-noise hearing (odds ratio [OR] 1.06; 95% CI 1.01-1.11) and self-reported problems hearing with background noise (OR 1.03; 95% CI 1.00-1.05). Hearing-GRS was not significantly associated with cognitive scores (ß = -0.05; 95% CI -0.17 to 0.07). CONCLUSIONS: Genetic risk for AD also influences speech-in-noise hearing. We failed to find evidence that genetic risk for hearing impairment affects cognition. AD disease processes or a that shared etiology may cause speech-in-noise difficulty before dementia onset.


Assuntos
Doença de Alzheimer/genética , Disfunção Cognitiva/genética , Predisposição Genética para Doença , Perda Auditiva/genética , Doença de Alzheimer/complicações , Disfunção Cognitiva/complicações , Feminino , Perda Auditiva/complicações , Testes Auditivos , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Autorrelato , Percepção da Fala
3.
Am J Physiol Cell Physiol ; 319(3): C569-C578, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32755449

RESUMO

Mutations in connexin 30 (Cx30) are known to cause severe congenital hearing impairment; however, the mechanism by which Cx30 mediates homeostasis of endocochlear gap junctions is unclear. We used a gene deletion mouse model to explore the mechanisms of Cx30 in preventing hearing loss. Our results suggest that despite severe loss of the auditory brain-stem response and endocochlear potential at postnatal day 18, Cx30-/- mice only show sporadic loss of the outer hair cells. This inconsistency in the time course and severity of hearing and hair cell losses in Cx30-/- mice might be explained, in part, by an increase in reactive oxygen species generation beginning at postnatal day 10. The expression of oxidative stress genes was increased in Cx30-/- mice in the stria vascularis, spiral ligament, and organ of Corti. Furthermore, Cx30 deficiency caused mitochondrial dysfunction at postnatal day 18, as assessed by decreased ATP levels and decreased expression of mitochondrial complex I proteins, especially in the stria vascularis. Proteomic analysis further identified 444 proteins that were dysregulated in Cx30-/- mice, including several that are involved in mitochondria electron transport, ATP synthesis, or ion transport. Additionally, proapoptotic proteins, including Bax, Bad, and caspase-3, were upregulated at postnatal day 18, providing a molecular basis to explain the loss of hearing that occurs before hair cell loss. Therefore, our results are consistent with an environment of oxidative stress and mitochondrial damage in the cochlea of Cx30-/- mice that is coincident with hearing loss but precedes hair cell loss.


Assuntos
Morte Celular/fisiologia , Conexinas/genética , Perda Auditiva Neurossensorial/metabolismo , Perda Auditiva/genética , Animais , Cóclea/metabolismo , Junções Comunicantes/metabolismo , Camundongos Knockout , Proteômica
4.
Gene ; 761: 144996, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32738421

RESUMO

Sensorineural deafness in mammals is most commonly caused by damage to inner ear sensory epithelia, or hair cells, and can be attributed to genetic and environmental causes. After undergoing trauma, many non-mammalian organisms, including reptiles, birds, and zebrafish, are capable of regenerating damaged hair cells. Mammals, however, are not capable of regenerating damaged inner ear sensory epithelia, so that hair cell damage is permanent and can lead to hearing loss. The field of epigenetics, which is the study of various phenotypic changes caused by modification of genetic expression rather than alteration of DNA sequence, has seen numerous developments in uncovering biological mechanisms of gene expression and creating various medical treatments. However, there is a lack of information on the precise contribution of epigenetic modifications in the auditory system, specifically regarding their correlation with development of inner ear (cochlea) and consequent hearing impairment. Current studies have suggested that epigenetic modifications influence differentiation, development, and protection of auditory hair cells in cochlea, and can lead to hair cell degeneration. The objective of this article is to review the existing literature and discuss the advancements made in understanding epigenetic modifications of inner ear sensory epithelial cells. The analysis of the emerging epigenetic mechanisms related to inner ear sensory epithelial cells development, differentiation, protection, and regeneration will pave the way to develop novel therapeutic strategies for hearing loss.


Assuntos
Células Ciliadas Auditivas/citologia , Células Ciliadas Auditivas/fisiologia , Perda Auditiva Neurossensorial/genética , Animais , Diferenciação Celular/genética , Surdez/genética , Orelha Interna/crescimento & desenvolvimento , Epigênese Genética , Células Ciliadas Auditivas Internas/citologia , Células Ciliadas Auditivas Internas/fisiologia , Perda Auditiva/genética , Humanos , Regeneração/genética
5.
Proc Natl Acad Sci U S A ; 117(33): 20070-20076, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32747562

RESUMO

The genetic characterization of a common phenotype for an entire population reveals both the causes of that phenotype for that place and the power of family-based, population-wide genomic analysis for gene and mutation discovery. We characterized the genetics of hearing loss throughout the Palestinian population, enrolling 2,198 participants from 491 families from all parts of the West Bank and Gaza. In Palestinian families with no prior history of hearing loss, we estimate that 56% of hearing loss is genetic and 44% is not genetic. For the great majority (87%) of families with inherited hearing loss, panel-based genomic DNA sequencing, followed by segregation analysis of large kindreds and transcriptional analysis of participant RNA, enabled identification of the causal genes and mutations, including at distant noncoding sites. Genetic heterogeneity of hearing loss was striking with respect to both genes and alleles: The 337 solved families harbored 143 different mutations in 48 different genes. For one in four solved families, a transcription-altering mutation was the responsible allele. Many of these mutations were cryptic, either exonic alterations of splice enhancers or silencers or deeply intronic events. Experimentally calibrated in silico analysis of transcriptional effects yielded inferences of high confidence for effects on splicing even of mutations in genes not expressed in accessible tissue. Most (58%) of all hearing loss in the population was attributable to consanguinity. Given the ongoing decline in consanguineous marriage, inherited hearing loss will likely be much rarer in the next generation.


Assuntos
Perda Auditiva/congênito , Perda Auditiva/genética , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Consanguinidade , Éxons , Feminino , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Oriente Médio , Mutação , Linhagem , Adulto Jovem
6.
BMC Med Genet ; 21(1): 151, 2020 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-32682410

RESUMO

BACKGROUND: Hearing loss is the most common sensory defect, and it affects over 6% of the population worldwide. Approximately 50-60% of hearing loss patients are attributed to genetic causes. Currently, more than 100 genes have been reported to cause non-syndromic hearing loss. It is possible and efficient to screen all potential disease-causing genes for hereditary hearing loss by whole exome sequencing (WES). METHODS: We collected 5 consanguineous pedigrees from Pakistan with hearing loss and applied WES in selected patients for each pedigree, followed by bioinformatics analysis and Sanger validation to identify the causal genes. RESULTS: Variants in 7 genes were identified and validated in these pedigrees. We identified single candidate variant for 3 pedigrees: GIPC3 (c.937 T > C), LOXHD1 (c.6136G > A) and TMPRSS3 (c.941 T > C). The remaining 2 pedigrees each contained two candidate variants: TECTA (c.4045G > A) and MYO15A (c.3310G > T and c.9913G > C) for one pedigree and DFNB59 (c.494G > A) and TRIOBP (c.1952C > T) for the other pedigree. The candidate variants were validated in all available samples by Sanger sequencing. CONCLUSION: The candidate variants in hearing-loss genes were validated to be co-segregated in the pedigrees, and they may indicate the aetiologies of hearing loss in such patients. We also suggest that WES may be a suitable strategy for hearing-loss gene screening in clinical detection.


Assuntos
Consanguinidade , Perda Auditiva/genética , Mutação/genética , Sequenciamento Completo do Exoma , Feminino , Perda Auditiva/diagnóstico , Humanos , Masculino , Paquistão , Linhagem , Reprodutibilidade dos Testes
7.
Acta otorrinolaringol. esp ; 71(3): 166-174, mayo-jun. 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-192632

RESUMO

INTRODUCCIÓN: La hipoacusia neurosensorial (HNS) es el déficit sensorial más prevalente en nuestro medio. La secuenciación genómica de nueva generación (NGS) permite obtener un diagnóstico etiológico en un alto porcentaje de pacientes. Nuestro estudio piloto muestra los resultados de la aplicación sistemática de la NGS en una Unidad de Hipoacusia Infantil, así como sus implicaciones en el manejo clínico de los pacientes y sus familiares. MATERIAL Y MÉTODO: Se incluyó a 27 pacientes diagnosticados de HNS entre 2014 y 2017 en los que se descartó una causa ambiental. El test genético consistió en un panel de genes analizados mediante NGS (panel OTOgenicsTM). Este panel ha sido diseñado para incluir genes asociados con hipoacusia neurosensorial o mixta, de inicio precoz o tardío, sindrómica y no sindrómica, independientemente de su patrón de herencia. RESULTADOS: Se obtuvo un diagnóstico genético en el 56% (15/27) de los pacientes (62% en el caso de las HNS bilaterales); 5/27 (19%) presentaron variantes patogénicas en el gen GJB2 y el resto variantes patogénicas o probablemente patogénicas en otros genes asociados con HNS aislada (PR2X2, TECTA y STRC), con HNS sindrómicas (CHD7, GATA3, COL4A5, MITF y SOX10) o con HNS sindrómicas y no sindrómicas (BSND, ACTG1 y CDH23). DISCUSIÓN: El diagnóstico etiológico de la HNS supone un desafío en la práctica clínica. Nuestra serie demuestra que es posible implementar el diagnóstico genético en la rutina asistencial y que esta información tiene implicaciones pronósticas y terapéuticas


INTRODUCTION: Sensorineural hearing loss (SNL) is the most prevalent sensory deficit in our environment. Next generation genomic sequencing (NGS) enables an aetiological diagnosis in a high percentage of patients. Our pilot study shows the results of the systematic application of NGS in a Childhood Hearing Loss Unit, as well as its implications for the clinical management of patients and their families. MATERIAL AND METHOD: We included 27 patients diagnosed with SNL between 2014 and 2017, in which an environmental cause was ruled out. The genetic test consisted of a panel of genes analyzed by NGS (OTOgenicsTM panel). This panel has been designed to include genes associated with sensorineural or mixed hearing loss, early onset or late, syndromic and non-syndromic, regardless of their inheritance pattern. RESULTS: A genetic diagnosis was obtained in 56% (15/27) of the patients (62% in the case of bilateral SNL). Of the patients, 5/27 (19%) presented pathogenic variants in the GJB2 gene and the rest pathogenic and / or probably pathogenic variants in other genes associated with isolated SNL (PR2X2, TECTA and STRC), with syndromic SNL (CHD7, GATA3, COL4A5, MITF and SOX10) or with syndromic and non-syndromic SNL (BSND, ACTG1 and CDH23). DISCUSSION: The aetiological diagnosis of SNL is a challenge in clinical practice. Our series demonstrates that it is possible to implement genetic diagnosis in the care routine and that this information has prognostic and therapeutic implications


Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Lactente , Pré-Escolar , Criança , Perda Auditiva/diagnóstico , Perda Auditiva/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Perda Auditiva/etiologia , DNA/genética , Variação Estrutural do Genoma/genética
9.
J Neurosci ; 40(20): 3915-3932, 2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32341094

RESUMO

Loss of sensory hair cells causes permanent hearing and balance deficits in humans and other mammals, but for nonmammals such deficits are temporary. Nonmammals recover hearing and balance sensitivity after supporting cells proliferate and differentiate into replacement hair cells. Evidence of mechanical differences between those sensory epithelia and their supporting cells prompted us to investigate whether the capacity to activate YAP, an effector in the mechanosensitive Hippo pathway, correlates with regenerative capacity in acceleration-sensing utricles of chickens and mice of both sexes. After hair cell ablation, YAP accumulated in supporting cell nuclei in chicken utricles and promoted regenerative proliferation, but YAP remained cytoplasmic and little proliferation occurred in mouse utricles. YAP localization in supporting cells was also more sensitive to shape change and inhibition of MST1/2 in chicken utricles than in mouse utricles. Genetic manipulations showed that in vivo expression of the YAP-S127A variant caused robust proliferation of neonatal mouse supporting cells, which produced progeny that expressed hair cell markers, but proliferative responses declined postnatally. Expression of YAP-5SA, which more effectively evades inhibitory phosphorylation, resulted in TEAD-dependent proliferation of striolar supporting cells, even in adult utricles. Conditional deletion of LATS1/2 kinases abolished the inhibitory phosphorylation of endogenous YAP and led to striolar proliferation in adult mouse utricles. The findings suggest that damage overcomes inhibitory Hippo signaling and facilitates regenerative proliferation in nonmammalian utricles, whereas constitutive LATS1/2 kinase activity suppresses YAP-TEAD signaling in mammalian utricles and contributes to maintaining the proliferative quiescence that appears to underlie the permanence of sensory deficits.SIGNIFICANCE STATEMENT Loud sounds, ototoxic drugs, infections, and aging kill sensory hair cells in the ear, causing irreversible hearing loss and balance deficits for millions. In nonmammals, damage evokes shape changes in supporting cells, which can divide and regenerate hair cells. Such shape changes are limited in mammalian ears, where supporting cells develop E-cadherin-rich apical junctions reinforced by robust F-actin bands, and the cells fail to divide. Here, we find that damage readily activates YAP in supporting cells within balance epithelia of chickens, but not mice. Deleting LATS kinases or expressing YAP variants that evade LATS-mediated inhibitory phosphorylation induces proliferation in supporting cells of adult mice. YAP signaling eventually may be harnessed to overcome proliferative quiescence that limits regeneration in mammalian ears.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteínas de Ciclo Celular/fisiologia , Células Ciliadas Auditivas/fisiologia , Regeneração Nervosa/genética , Regeneração Nervosa/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Animais Recém-Nascidos , Proteínas de Ciclo Celular/genética , Proliferação de Células , Embrião de Galinha , Galinhas , Deleção de Genes , Variação Genética , Perda Auditiva/genética , Fator de Crescimento de Hepatócito/antagonistas & inibidores , Estimulador Tireóideo de Ação Prolongada , Camundongos , Camundongos Knockout , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Sáculo e Utrículo/efeitos dos fármacos , Especificidade da Espécie , Proteínas Supressoras de Tumor/genética
10.
BMC Med Genet ; 21(1): 68, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32234020

RESUMO

BACKGROUND: The TWNK gene encodes the twinkle protein, which is a mitochondrial helicase for DNA replication. The dominant TWNK variants cause progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, while the recessive variants cause mitochondrial DNA depletion syndrome 7 and Perrault syndrome 5. Perrault syndrome is characterized by sensorineural hearing loss in both males and females and gonadal dysfunction in females. Patients with Perrault syndrome may present early-onset cerebellar ataxia, whereas middle-age-onset cerebellar ataxia caused by TWNK variants is rare. CASE PRESENTATION: A Japanese female born to consanguineous parents presented hearing loss at age 48, a staggering gait at age 53, and numbness in her distal extremities at age 57. Neurological examination revealed sensorineural hearing loss, cerebellar ataxia, decreased deep tendon reflexes, and sensory disturbance in the distal extremities. Laboratory tests showed no abnormal findings other than a moderate elevation of pyruvate concentration levels. Brain magnetic resonance imaging revealed mild cerebellar atrophy. Using exome sequencing, we identified a homozygous TWNK variant (NM_021830: c.1358G>A, p.R453Q). CONCLUSIONS: TWNK variants could cause middle-age-onset cerebellar ataxia. Screening for TWNK variants should be considered in cases of cerebellar ataxia associated with deafness and/or peripheral neuropathy, even if the onset is not early.


Assuntos
Ataxia Cerebelar/genética , DNA Helicases/genética , Proteínas Mitocondriais/genética , Ataxia Cerebelar/complicações , Ataxia Cerebelar/diagnóstico , Consanguinidade , Feminino , Marcha Atáxica/complicações , Marcha Atáxica/diagnóstico , Marcha Atáxica/genética , Disgenesia Gonadal 46 XX/diagnóstico , Disgenesia Gonadal 46 XX/genética , Perda Auditiva/complicações , Perda Auditiva/diagnóstico , Perda Auditiva/genética , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Homozigoto , Humanos , Japão , Transtornos de Início Tardio/diagnóstico , Transtornos de Início Tardio/genética , Pessoa de Meia-Idade , Mutação , Linhagem
11.
Sci China Life Sci ; 63(8): 1227-1239, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32189241

RESUMO

Aminoacyl-tRNA synthetases (aaRSs) are ubiquitously expressed, essential enzymes, synthesizing aminoacyl-tRNAs for protein synthesis. Functional defects of aaRSs frequently cause various human disorders. Human KARS encodes both cytosolic and mitochondrial lysyl-tRNA synthetases (LysRSs). Previously, two mutations (c.1129G>A and c.517T>C) were identified that led to hearing impairment; however, the underlying biochemical mechanism is unclear. In the present study, we found that the two mutations have no impact on the incorporation of LysRS into the multiple-synthetase complex in the cytosol, but affect the cytosolic LysRS level, its tertiary structure, and cytosolic tRNA aminoacylation in vitro. As for mitochondrial translation, the two mutations have little effect on the steady-state level, mitochondrial targeting, and tRNA binding affinity of mitochondrial LysRS. However, they exhibit striking differences in charging mitochondrial tRNALys, with the c.517T>C mutant being completely deficient in vitro and in vivo. We constructed two yeast genetic models, which are powerful tools to test the in vivo aminoacylation activity of KARS mutations at both the cytosolic and mitochondrial levels. Overall, our data provided biochemical insights into the potentially molecular pathological mechanism of KARS c.1129G>A and c.517T>C mutations and provided yeast genetic bases to investigate other KARS mutations in the future.


Assuntos
Aminoacilação/genética , Citoplasma/genética , Perda Auditiva/genética , Mitocôndrias/genética , RNA de Transferência de Lisina/metabolismo , Aminoacil-tRNA Sintetases/genética , Sequência de Bases , Domínio Catalítico , Regulação da Expressão Gênica , Perda Auditiva/metabolismo , Humanos , Modelos Moleculares , Mutação , Biossíntese de Proteínas , Conformação Proteica , Proteínas Recombinantes/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Transfecção
12.
Artigo em Inglês | MEDLINE | ID: mdl-32183210

RESUMO

Limited studies have assessed the relation between telomere length and risk of hearing loss; moreover, they have reported equivocal associations. In the first case-control study, the subjects were chosen from the general population of Zhejiang province in order to assess the association between leucocyte telomere length and risk of hearing loss from 2016 to 2018. A total of 817 cases (55.93 ± 8.99 years) and 817 age-, sex- and residential city-matched controls (55.91 ± 9.03 years) were included for analysis. In the multivariable models, individuals in the top quartile of relative telomere length (RTL) had an odds ratio (OR) for hearing loss of 0.53 (95% confidence intervals [CI], 0.38-0.74) compared to those in the bottom quartile, and specifically, the OR was 0.45 (95% CI, 0.28-0.73) in females. In females, the risk of hearing loss decreased by 46% as RTL doubling increased; the standard deviation of RTL was associated with a 29% decrease in hearing loss risk. Additional analysis showed significant difference between participants in the female mild hearing loss group and corresponding controls. These results suggest that telomere length is associated with hearing loss in the general population, particularly in females with mild hearing loss. Telomere length might be a potential predictive biomarker of hearing loss at early stage.


Assuntos
Perda Auditiva , Telômero , Estudos de Casos e Controles , China/epidemiologia , Feminino , Perda Auditiva/epidemiologia , Perda Auditiva/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
13.
Medicine (Baltimore) ; 99(13): e19373, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32221064

RESUMO

Mutations in mitochondrial DNA, especially in 12S rRNA gene, are the most important causes for hearing loss. In particular, the A1555G and C1494T mutations have been found to be associated with both aminoglycoside-induced and non-syndromic hearing loss in many families worldwide. To determine the frequency of C1494T mutation in deaf patients, in the current study, we screened this mutation in 655 patients with non-syndromic hearing loss and 300 control subjects. After PCR amplification of mitochondrial 12S rRNA gene and direct sequence analysis, we found that there were 2 patients carrying the C1494T mutation; however, this mutation was not detected in 300 healthy subjects. Further genetic counseling suggested that only 1 patient had an obvious family history of hearing impairment. Clinical evaluation showed that 3 of 10 matrilineal relatives suffered from hearing loss, with different age at onset of hearing loss. Molecular analysis revealed the presence of homoplasmic 12S rRNA C1494T and ND5 T12338C mutations, together with a set of polymorphisms belonging to human mitochondrial haplogroup F2. Interestingly, T12338C mutation resulted in the replacement of the first amino acid, a translation-initiating methionine with a threonine, shortening 2 amino acids of ND5 polypeptide. Moreover, this mutation is located in 2 nucleotides adjacent to the 3' end of the mt-tRNALeu(CUN) gene. Therefore, this mutation may alter ND5 mRNA metabolism and the processing of RNA precursors. Thus, the combination of T12338C and C1494T mutations may contribute to deafness expression in this family. Taken together, our data suggested that the C1494T mutation was the molecular basis for hearing loss, screening for the mitochondrial DNA pathogenic mutations was recommended for early detection, prevention, and diagnosis of mitochondrial deafness.


Assuntos
Perda Auditiva/genética , RNA Ribossômico/genética , Adulto , Idade de Início , China , DNA Mitocondrial/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Hum Genet ; 139(4): 521-530, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32002660

RESUMO

Newborn hearing screening is not designed to detect delayed-onset prelingual hearing loss or aminoglycoside-antibiotic-induced ototoxicity. Cases with severe to profound hearing loss have been reported to have been missed by newborn hearing screens. The aim of this study was to evaluate the efficacy of concurrent hearing and genetic screening in the general population and demonstrate its benefits in practice. Enrolled newborns received concurrent hearing and genetic screens between September 1, 2015 and January 31, 2018. Of the 239,636 eligible infants (median age, 19 months), 548 (0.23%) had prelingual hearing loss. Genetic screening identified 14 hearing loss patients with positive genotypes and 27 patients with inconclusive genotypes who had passed the hearing screens. In addition, the genetic screen identified 0.23% (570/239,636) of the newborns and their family members as at-risk for ototoxicity, which is undetectable by hearing screens. In conclusion, genetic screening complements newborn hearing screening by improving the detection of infants at risk of hereditary hearing loss and ototoxicity, and by informing genotype-based clinical management for affected infants and their family members. Our findings suggest that the practice should be further validated in other populations and rigorous cost-effectiveness analyses are warranted.


Assuntos
Testes Genéticos , Perda Auditiva , Triagem Neonatal , Feminino , Perda Auditiva/diagnóstico , Perda Auditiva/genética , Testes Auditivos , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos
15.
Artigo em Chinês | MEDLINE | ID: mdl-32074743

RESUMO

Objective: To analyze the physiological basics for changes of cerebral functions in patients with congenital hereditary hearing loss (CHHL), by using voxel-based morphometry (VBM). Methods: From June 2016 to June 2017, we recruited volunteers from Yangzhou Special Education School and CHHL patients from the Department of Otorhinolaryngology, Subei People's Hospital as a case group with a total of 14 cases (8 males and 6 females), with an average age from 10 to 18 (13.13 ± 0.39). At the same time,patients with no ear diseases were recruited as a control group, a total of 23 cases (10 males and 13 females), with an average age from 10 to18 (13.50 ± 0.49). Brain scanning with resting state functional magnetic resonance imaging was performed on all subjects, and 3D T1WI was collected and processed by the analyzing software. Two sample t-tests were conducted with alphasim correction at the threshold level of P<0.001. Different morphologies of cerebral cortex were identified between patients with CHHL and their normal controls retrospectively. Results: Compared to their normal controls, patients with CHHL had no significant difference in terms of brain volume, gray matter volume, white matter volume, and cerebrospinal fluid volume ((1 397.53±103.98)cm(3) vs. (1 439.45±128.84)cm(3), (765.19±60.27)cm(3) vs. (800.139±77.64)cm(3), (392.89±40.38)cm(3) vs. (414.54±49.22)cm(3), (314.17±25.81)cm(3) vs. (296.47±51.42)cm(3), all P>0.05). However, compared to their normal controls, patients with CHHL had significantly increased (P<0.001) gray matter in the following cerebral gyri: right temporal pole: middle temporal gyrus, right inferior temporal gyrus, left middle occipital gyrus, right inferior parietal gyrus, and left middle frontal gyrus, left superior occipital gyrus, right superior frontal gyrus, and left superior frontal gyrus. Furthermore, compared to their normal controls, patients with CHHL had significantly decreased (P<0.001) gray matter in the following cerebral gyri: left parahippocampal gyrus, right fusiform gyrus, right middle frontal gyrus, left inferior temporal gyrus, right middle occipital gyrus, left insula, right inferior frontal gyrus, left precentral gyrus, and right superior parietal gyrus. Conclusions: Patients with CHHL show global changes in cerebral cortex not limited to auditory associated cerebral areas. This suggests that adaptable reshaping of global brain structures and functions has occurred in patients with CHHL.


Assuntos
Encéfalo/anatomia & histologia , Perda Auditiva/congênito , Adolescente , Encéfalo/diagnóstico por imagem , Criança , China , Feminino , Substância Cinzenta/diagnóstico por imagem , Perda Auditiva/genética , Humanos , Imagem por Ressonância Magnética , Masculino , Estudos Retrospectivos , Substância Branca/diagnóstico por imagem
16.
FASEB J ; 34(1): 1136-1149, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914662

RESUMO

Usher syndrome (USH) is the most frequent form of combined hereditary deafness-blindness, characterized by hearing loss and retinitis pigmentosa, with or without vestibular dysfunction. PDZD7 is a PDZ domain-containing scaffold protein that was suggested to be a USH modifier and a contributor to digenic USH. In the inner ear hair cells, PDZD7 localizes at the ankle region of the stereocilia and constitutes the so-called ankle-link complex together with three other USH proteins Usherin, WHRN, and ADGRV1. PDZD7 gene is subjected to alternative splicing, which gives rise to two types of PDZD7 isoforms, namely the long and short isoforms. At present, little is known which specific isoform is involved in ankle-link formation and stereocilia development. In this work, we showed that PDZD7 long isoform, but not short isoforms, localizes at the ankle region of the stereocilia. Moreover, we established Pdzd7 mutant mice by introducing deletions into exon 14 of the Pdzd7 gene, which causes potential premature translational stop in the long isoform but leaves short isoforms unaffected. We found that lack of PDZD7 long isoform affects the localization of other ankle-link complex components in the stereocilia. Consequently, Pdzd7 mutant mice showed stereocilia development deficits and hearing loss as well as reduced mechanotransduction (MET) currents, suggesting that PDZD7 long isoform is indispensable for hair cells. Furthermore, by performing yeast two-hybrid screening, we identified a PDZD7 long isoform-specific binding partner PIP5K1C, which has been shown to play important roles in hearing and might participate in the function and/or transportation of PDZD7.


Assuntos
Proteínas de Transporte/química , Proteínas de Transporte/genética , Perda Auditiva/genética , Síndromes de Usher/genética , Processamento Alternativo , Animais , Cóclea/metabolismo , Modelos Animais de Doenças , Éxons , Feminino , Deleção de Genes , Células HEK293 , Células Ciliadas Auditivas , Humanos , Masculino , Mecanotransdução Celular , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Varredura , Mutação , Isoformas de Proteínas , Estereocílios/química
17.
Biochem Biophys Res Commun ; 523(3): 692-698, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31948760

RESUMO

Age-related hearing loss (ARHL) is a neurodegenerative disease associated with an aged population. ARHL is influenced by biological factors such as aging, sex difference, and atherosclerosis. The mechanisms of ARHL caused by atherosclerosis have not been previously determined in apolipoprotein E knockout (ApoE KO) male mice. To investigate the onset and cause of the hearing loss, ApoE KO male mice were treated with a western diet (ApoE KO-WD) for 16 weeks. The lipid profile, atherosclerotic plaques throughout the aorta, and auditory brainstem response (ABR) thresholds were measured in the ApoE KO-WD male mice. The expression of S100 calcium-binding protein B (S100B), a neuronal damage biomarker, was also observed. Reactive oxygen species (ROS) and apoptosis rates were detected in the cochlea of the ApoE KO male mice. Atherosclerotic plaques on the aorta and ABR thresholds were significantly increased in the ApoE KO-WD male mice at 24 weeks of age. ABR thresholds had a statistically significant positive correlation with the area of atherosclerotic plaques (r = 0.783, p = 0.013) in male mice at 24 weeks of age. S100B protein expression and the dihydroethidium (DHE) reaction to ROS in the cochlear spiral ganglion neurons (SGNs) were significantly increased in the ApoE KO and ApoE KO-WD male mice. Cells positive for active caspase-3 and terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) in the SGNs were significantly increased in ApoE KO-WD male mice indicating an increased rate of cellular apoptosis. In conclusion, ROS in the SGNs were activated by increased S100B expression in ApoE KO-WD male mice, and this resulted in an increased apoptosis rate. Thus, hearing loss began at 16 weeks in ApoE KO-WD male mice. Our results suggest that the ApoE KO-WD male mice are a suitable animal model for studying ARHL associated with exacerbated atherosclerosis.


Assuntos
Apolipoproteínas E/genética , Apoptose , Dieta Ocidental/efeitos adversos , Perda Auditiva/etiologia , Gânglio Espiral da Cóclea/patologia , Envelhecimento , Animais , Modelos Animais de Doenças , Perda Auditiva/genética , Perda Auditiva/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/patologia , Gânglio Espiral da Cóclea/citologia
18.
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
19.
J Appl Genet ; 61(1): 51-65, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31912450

RESUMO

Hereditary hearing loss (HHL) is a neurosensory disorder that affects every 1/500 newborns worldwide and nearly 1/3 people over the age of 65. Congenital deafness is inherited as monogenetic or polygenic disorder. The delicacy, tissue heterogeneity, deep location of the inner ear down the brainstem, and minute quantity of cells present in cochlea are the major challenges for current therapeutic approaches to cure deafness. Targeted genome editing is considered a suitable approach to treat HHL since it can target defective molecular components of auditory transduction to restore normal cochlear function. With the advent of CRISPR/Cas9 technique, targeted genome editing and biomedical research have been revolutionized. The robustness and simplicity of this technology lie in its design and delivery methods. It can directly deliver a complex of Cas9 endonuclease and single guide RNA (sgRNA) into zygote using either vector-mediated stable transfection or transient delivery of ribonucleoproteins complexes. This strategy induces DNA double strand breaks (DSBs) at target site followed by endogenous DNA repairing mechanisms of the cell. CRISPR/Cas9 has been successfully used in model animals to edit hearing genes like calcium and integrin-binding protein 2, myosin VIIA, Xin-actin binding repeat containing 2, leucine-zipper and sterile-alpha motif kinase Zak, epiphycan, transmembrane channel-like protein 1, and cadherin 23. This review discusses the utility of lipid-mediated transient delivery of Cas9/sgRNA complexes, an efficient way to restore hearing in humans, suffering from HHL. Notwithstanding, challenges like PAM requirement, HDR efficiency, off-target activity, and optimized delivery systems need to be addressed.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/terapia , Perda Auditiva/genética , Perda Auditiva/terapia , Animais , Biomarcadores , Modelos Animais de Doenças , Regulação da Expressão Gênica , Técnicas de Transferência de Genes , Predisposição Genética para Doença , Terapia Genética , Vetores Genéticos/genética , Células Ciliadas Auditivas/fisiologia , Humanos , Camundongos , Ligação Proteica , Interferência de RNA , Regeneração , Ribonucleoproteínas/metabolismo , Transfecção/métodos , Resultado do Tratamento
20.
Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi ; 54(12): 881-887, 2019 Dec 07.
Artigo em Chinês | MEDLINE | ID: mdl-31887812

RESUMO

Objective: To screen, diagnose and follow up the abnormal mutation in the gene screening of neonatal deafness. Methods: A total of 24161 newborns born in Zhuhai Maternal and Child Health Hospital from February 1, 2015 to January 31, 2008 were screened for hearing and deafness genes, and audiological screening, diagnosis and 1-3 years follow-up were carried out for the newborns with positive gene screening. Results: There were 991 cases of deafness gene mutation (533 males and 458 females), and the rate of abnormal mutation was 4.10%(991/24 161). Among them, 921 cases were single heterozygous mutation, 130 cases were failed in primary hearing screening, 11 cases were failed in secondary hearing screening, 8 cases were abnormal in audiological diagnosis finally. In these 8 cases, 3 were diagnosed as otitis media and passed audiological follow-up after cure, 2 cases of single ear sensorineural injury caused by high-risk factors, passed after close audiological follow-up, and the other 3 cases were closely audiological follow-up while none of them were successfully sequenced. All of them were moderate to severe sensorineural deafness, 1 case was heterozygous mutation at 3 loci of GJB2(c.235delC,c.408C>A,c.134G>A), 1 case was heterozygous mutation at 2 loci of GJB2(c.235delC, c.109G>A), and 1 case was single heterozygous mutation of GJB2(c.235delC). The remaining 913 cases who passed the primary screening, secondary screening or hearing diagnosis were followed up for 1 to 3 years. Three cases of multiple heterozygous mutation were found in gene screening(2 cases were SLC26A4 2168A>G, IVS7-2A>G, 1 case was GJB2 c.176_191del 16bp, c.299_300del AT), all of them passed both primary and secondary hearing screening. In these 3 cases, the final audiological diagnosis was moderate sensorineural deafness in both ears, with no improvement in the follow-up of 1-3 years. There were 9 monogenic homozygous mutations, 7 failed in primary hearing screening, 3 failed in secondary hearing screening and also failed in audiological diagnosis and 1-3 years' audiological follow-up, all of whom were GJB2 c.235 del C homozygous mutations, and one of whom had a definite family history of deafness. The remaining 6 cases of homozygous mutation diagnosed by primary screening, secondary screening or hearing diagnosis were GJB2 c109G>A homozygous mutation, and passed the 1-3 years' hearing follow-up. 58 children with mtDNA mutations, including 2 with 12S rRNA 1494C>T homozygous mutation, 47 with 1555A>G homozygous mutation, and 9 with 1555A>G heterozygous mutation, all passed the primary or secondary hearing screening, and were instructed to ban ototoxic drugs for the whole life, and passed the 1-3 years' hearing follow-up. Conclusions: The audiological follow-up of children with monogenic heterozygous mutations in deafness gene screening is generally normal. In case of abnormality, the influencing factors such as otitis media should be excluded at first. In case of unexplained moderate to severe sensorineural deafness, the whole-gene sequencing should be performed to find possible pathogenic factors. The children with homozygous mutation or compound heterozygous mutation in gene screening, most of whom show different degrees of hearing loss, should be followed up for a long time, and provide parents with scientific and reasonable genetic counseling according to the mutation genes and loci,. The hearing of drug-induced deafness gene carriers is normal after birth. Parents should be advised to strengthen prevention and follow-up is generally enough.


Assuntos
Análise Mutacional de DNA , Surdez , Perda Auditiva , Pré-Escolar , China , Conexina 26 , Conexinas , Feminino , Seguimentos , Testes Genéticos , Perda Auditiva/diagnóstico , Perda Auditiva/genética , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Triagem Neonatal
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