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1.
Rev Med Suisse ; 15(665): 1740-1745, 2019 Oct 02.
Artigo em Francês | MEDLINE | ID: mdl-31580017

RESUMO

The majority of early hearing disorders are of genetic origin. In view of the genetic heterogeneity, high-throughput sequencing analysis of a panel of genes involved in hearing loss is the most effective and economical approach, providing a diagnostic yield of around 40 % today. The determination of a molecular diagnosis makes it possible to: i) adapt the audiological care; ii) to search for possible somatic problems associated with so-called syndromic hearing loss; (iii) to avoid unnecessary additional examinations in isolated hearing loss; (iv) to establish accurate genetic counseling for relatives, or even to provide early diagnosis; and (v) to lay the foundation for potential future molecular hearing loss therapies in selected cases.


Assuntos
Perda Auditiva/genética , Criança , Surdez/diagnóstico , Surdez/genética , Surdez/terapia , Diagnóstico Precoce , Aconselhamento Genético , Perda Auditiva/diagnóstico , Perda Auditiva/terapia , Humanos , Terapia de Alvo Molecular , Síndrome
2.
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
3.
BMC Med Genet ; 20(1): 133, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31370824

RESUMO

BACKGROUND: Proximal symphalangism (SYM1; OMIM 185800), also called Cushing's symphalangism, is an infrequent autosomal dominant disease. An SYM1 patient typically features variable fusion of proximal interphalangeal joints in the hands and feet. METHODS: We recruited a four-generation Chinese non-consanguineous family with SYM1. We examined their hands and feet using X-rays to confirm fusion of proximal interphalangeal joints. We evaluated their audiology using standard audiometric procedures and equipment. Then, we identified genetic variants using whole exome sequencing and validated mutations using Sanger sequencing. Mutation pathogenicity was analyzed with bioinformatics. RESULTS: Radiographs revealed proximal-joint fusion of fingers and toes in the patients. Two elderly individuals (II:1 and II:4) exhibited slight hearing loss. Additionally, we detected a novel heterozygous missense mutation in exon 1 of NOG (NM_005450) c.124C > T, p.(Pro42Ser) in all patients. This c.124C > T mutation is highly conserved across multiple species and the p.(Pro42Ser) variation is potentially highly pathogenic. CONCLUSION: Our results suggest that heterozygous c.124C > T, p.(Pro42Ser) in NOG is a novel mutation that causes human SYM1 phenotype.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Proteínas de Transporte/genética , Articulações dos Dedos/anormalidades , Predisposição Genética para Doença/genética , Artropatias/congênito , Mutação de Sentido Incorreto , Sequência de Aminoácidos , Sequência de Bases , Éxons , Articulações dos Dedos/diagnóstico por imagem , Articulações dos Dedos/fisiopatologia , Pé/diagnóstico por imagem , Mãos/diagnóstico por imagem , Perda Auditiva/genética , Heterozigoto , Humanos , Artropatias/diagnóstico por imagem , Artropatias/genética , Artropatias/fisiopatologia , Modelos Moleculares , Linhagem , Fenótipo , Análise de Sequência de DNA , Análise de Sequência de Proteína , Sequenciamento Completo do Exoma
4.
J Craniofac Surg ; 30(5): 1506-1511, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31299755

RESUMO

Saethre-Chotzen syndrome (SCS) is an autosomal dominant condition defined by mutations affecting the TWIST1 gene on chromosome 7p21.1. Previous research has identified an elevated prevalence of intracranial hypertension and hearing impairment associated with this syndrome. This study aimed to investigate the influence of hearing history and presence of intracranial hypertension on language development in children with SCS.A retrospective study note analysis was performed for all patients with a confirmed TWIST1 gene abnormality who attended the Oxford Craniofacial Unit and underwent a language assessment over a 22-year period. Intracranial pressure monitoring, hearing status, and language outcomes were examined in detail.Thirty patients with genetically confirmed SCS and language assessment data were identified. Twenty-eight patients underwent surgical intervention; 10 presented with intracranial hypertension (5 prior to, and 5 after primary surgical intervention). Language data coinciding with the presentation of intracranial hypertension were available for 8 children. About 44% of children with intracranial hypertension presented with concurrent receptive and expressive language delay (n = 4/8). For both children (n = 2) with longitudinal language data available, the onset of intracranial hypertension reflected a concurrent decline in language skills. Audiometric data were available for 25 children, 80% (n = 20/25) had a history of hearing loss. About 50% of these had confirmed conductive hearing loss with middle ear effusion and the other 50% had presumed conductive hearing loss with middle ear effusion. About 100% of the children with available hearing data in our study had evidence of middle ear effusion in at least 1 ear. Results also indicated that 43% (n = 13/30) of the children presented with receptive and/or expressive language delay during childhood.Given the importance of hearing for language development and the preliminary findings of a potential decline in language skills in children during periods of intracranial hypertension, regular follow-up of hearing, language, and intracranial hypertension are indicated in children with SCS.


Assuntos
Acrocefalossindactilia/genética , Perda Auditiva/genética , Hipertensão Intracraniana/genética , Desenvolvimento da Linguagem , Proteínas Nucleares/genética , Proteína 1 Relacionada a Twist/genética , Acrocefalossindactilia/complicações , Audiometria/métodos , Criança , Pré-Escolar , Feminino , Perda Auditiva/complicações , Humanos , Hipertensão Intracraniana/complicações , Masculino , Mutação , Otite Média com Derrame/complicações , Estudos Retrospectivos
5.
BMC Med Genet ; 20(1): 118, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266487

RESUMO

BACKGROUND: Recessive mutations of coding regions and splice sites of the SLC26A4 gene cause hearing loss with enlargement of the vestibular aqueduct (EVA). Some patients also have a thyroid iodination defect that can lead to multinodular goiter as part of Pendred syndrome. A haplotype of variants upstream of SLC26A4, called CEVA, acts as a pathogenic recessive allele in trans to mutations affecting the coding regions or splice sites of SLC26A4. Our first hypothesis is that CEVA, acting as a pathogenic recessive allele, is correlated with a less severe phenotype than mutations affecting the coding regions and splice sites of SLC26A4. Our second hypothesis is that CEVA acts as a modifier of the phenotype in patients with EVA caused by mutations affecting the coding regions or splice sites of both alleles of SLC26A4 or EVA caused by other factors. METHODS: This was a prospective cohort study of 114 individuals and 202 ears with EVA. To test our first hypothesis, we compared the thyroid and auditory phenotypes of subjects with mutations affecting coding regions of both alleles of SLC26A4 with those of subjects carrying CEVA in trans to mutations affecting the coding regions. To test our second hypothesis, we compared the phenotypes associated with the presence versus absence of CEVA among subjects with no coding region mutations, as well as among subjects with mutations affecting coding regions of both alleles. RESULTS: Subjects carrying CEVA in trans to a mutation of SLC26A4 have a normal thyroid phenotype and less severe hearing loss in comparison to individuals with mutations affecting coding regions of both alleles of SLC26A4. In subjects with no mutant alleles of SLC26A4, hearing loss was more severe in subjects who carry the CEVA haplotype in comparison to non-carriers. There was no correlation of CEVA with the phenotype of subjects with mutations affecting coding regions of both alleles. CONCLUSIONS: CEVA, acting as a likely pathogenic recessive allele, is associated with a less severe phenotype than alleles with a mutation affecting the coding regions or splice sites of SLC26A4. CEVA may act as a genetic modifier in patients with EVA caused by other factors.


Assuntos
Bócio Nodular/genética , Haplótipos , Perda Auditiva Neurossensorial/genética , Mutação , Fenótipo , Transportadores de Sulfato/genética , Aqueduto Vestibular/anormalidades , Aqueduto Vestibular/patologia , Adolescente , Adulto , Alelos , Audiometria , Criança , Pré-Escolar , Cromossomos Humanos Par 7/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Genótipo , Audição/genética , Perda Auditiva/genética , Heterozigoto , Homozigoto , Humanos , Masculino , Estudos Prospectivos , Sítios de Splice de RNA , Glândula Tireoide , Adulto Jovem
6.
Medicine (Baltimore) ; 98(25): e16128, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31232964

RESUMO

OBJECTIVE: The grainyhead-like-2 (GRHL2) genetic variants were reported in age-related hearing impairment (ARHI) susceptibility in several case-control studies. However, their conclusions are conflicting; it is difficult to precisely assess the disease risk associated with the variants. Therefore we conduct the meta-analysis to discover the association of GRHL2 polymorphisms and the risk of ARHI. METHODS: A related literature search was conducted in on-line databases, such as Wanfang database, China National Knowledge Infrastructure (CNKI), EMBASE, Web of Science, and PubMed (updated to August 30, 2018). We use Review Manager 5.0 and Stata SE 12.0 software to reckon the odds radio (OR), 95% confidence interval (CI) and P value in random- or fixed-effects model according to the I2 value in the heterogeneity test. RESULTS: 2762 cases and 2321 controls in 5 articles were provided data to the meta-analysis. The pooled ORs (95% CI) of the rs10955255 polymorphism were 1.26 (1.05-1.50, P = .01), 1.33 (1.07-1.65, P = .01), and 1.32 (1.12-1.55, P = .0007) in the allele, homozygote and recessive model separately. Besides, a significant association was detected between rs1981361 in mixed population and the ARHI risk in the allele, heterozygote, and dominant genetic model respectively. Then subgroup analyses was performed by ethnicity, for rs10955255 meaningful associations were detected for the allele model, homozygote model, dominant model and recessive model in the Caucasian population but no relations in any of the 5 genetic models in Asian population. CONCLUSION: The meta-analysis indicated that the rs10955255 polymorphism could be an important risk factor for ARHI, especially in the Caucasians. The rs1981361 polymorphism may be a risk factor for ARHI in Asians. Larger scale researches are needed to further bring the consequences up to date.


Assuntos
Fatores Etários , Proteínas de Ligação a DNA/genética , Perda Auditiva/genética , Fatores de Transcrição/genética , Estudos de Casos e Controles , Proteínas de Ligação a DNA/análise , Humanos , Polimorfismo de Nucleotídeo Único/fisiologia , Fatores de Risco , Fatores de Transcrição/análise
7.
Int J Pediatr Otorhinolaryngol ; 124: 99-105, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31176026

RESUMO

OBJECTIVES: Hearing loss (HL) is the most common sensory-neural disorder with excessive clinical and genetic heterogeneity, which negatively affects life quality. Autosomal recessive non-syndromic hearing loss (ARNSHL) is the most common form of the disease with no specific genotype-phenotype correlation in most of the cases. Whole exome sequencing (WES) is a powerful tool to overcome the problem of finding mutations in heterogeneous disorders. METHODS: A comprehensive clinical and pedigree examination was performed on a multiplex family from Khuzestan province suffering from hereditary HL. Direct sequencing of GJB2 and genetic linkage analysis of DFNB1A/B was accomplished. WES was utilized to find possible genetic etiology of the disease. Co-segregation analysis of the candidate variant was done. High resolution melting analysis was applied to detect variant status in 50 healthy matched controls. RESULTS: Clinical investigations suggested ARNSHL in the pedigree. The family was negative for DFNB1A/B. WES revealed a novel nonsense mutation, c.256G > T (p.Glu86*), in TMC1 segregating with the phenotype in the pedigree. The variant was absent in the controls. CONCLUSION: Here, we report successful application of WES to identify the molecular pathogenesis of ARNSHL in a large family. The novel nonsense TMC1 variant meets the criteria of being pathogenic according to the ACMG-AMP variant interpretation guideline.


Assuntos
Perda Auditiva/genética , Proteínas de Membrana/genética , Feminino , Estudos de Associação Genética , Ligação Genética , Perda Auditiva Neurossensorial/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Irã (Geográfico) , Masculino , Mutação , Linhagem , Fenótipo , Sequenciamento Completo do Exoma
8.
Genet Test Mol Biomarkers ; 23(6): 423-427, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31063410

RESUMO

Aim: The aim of this study was to report a novel POU Class 3 Homeobox 4 (POU3F4) variant and to provide further guidance on genetic counseling for incomplete partition (IP) type III families in the Korean population by showing two new contrasting cases in terms of genotypes and inheritance. Materials and Methods: Two consecutively recruited hearing-impaired probands with seemingly nonsyndromic features and their biological mothers were included in this study. Sanger sequencing and quantitative polymerase chain reaction (PCR) assays were performed for POU3F4. Results: A novel frameshift variant of POU3F4, c.852delC (p.Ile285Serfs*3), was identified in one of the patients. This mutation is predicted to truncate the protein within the POU homeodomain, resulting in the complete loss of the last nucleus localization signal. The proband's biological mother was also shown to be a carrier of this c.852delC (p.Ile285Serfs*3) mutant allele. A de novo genomic deletion on chromosome Xq21.2 was confirmed in another subject via quantitative PCR. This subject's biological mother, however, was not a carrier of this deletion. This indicates that the large upstream deletion of POU3F4 in the second proband occurred de novo. This finding is compatible with the previously proposed tendency for a high de novo rate of large genomic deletions involving the X-linked deafness-2 (DFNX2) locus. Conclusion: This study adds a novel, probably pathogenic POU3F4 truncation variant to the literature and provides guidance toward effective genetic counseling for IP III subjects based on more frequent de novo occurrence of POU3F4 deletions than POU3F4 point variants.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/genética , Perda Auditiva Neurossensorial/genética , Fatores do Domínio POU/genética , Adulto , Criança , Surdez/genética , Família , Feminino , Mutação da Fase de Leitura/genética , Aconselhamento Genético/métodos , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Genótipo , Perda Auditiva/genética , Perda Auditiva Neurossensorial/metabolismo , Humanos , Masculino , Mutação , Linhagem , República da Coreia
9.
Gene ; 709: 65-74, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31129248

RESUMO

BACKGROUND: Autosomal recessive non-syndromic hearing loss (ARNSHL) is a highly heterogeneous genetic disease. PDZD7 is a new ARNSHL associated gene. Until now, nine PDZD7 biallelic mutation families with ARNSHL have been reported. Here we report a case of Chinese patient with ARNSHL linked to novel mutations in PDZD7 genes. METHOD: The pathogenic mutations were detected by whole exome sequencing for hereditary deafness-related genes of both the proband and his parents. We used kinship detection, mutational hazard prediction, genotype-phenotype correlation analysis and variation screening for potential pathogenic mutations. Re-sequencing was used to confirm the mutations by Sanger sequence. Real time quantitative PCR (RT-qPCR) was used to analyze the PDZD7 gene expression. Population-based screening for variation frequency, evolutionary conservation comparisons, pathogenicity evaluation, and protein structure prediction were conducted to assess the pathogenicity of the novel mutations of PDZD7 gene. RESULTS: We determined three variants of the PDZD7 gene that contributed to the deafness of the patient (PDZD7 c.192G > A, p. Met64Ile; c.1648C > T p. Gln550* and c.2341_2352delCGCAGCCGCAGCp. Arg781_Ser 784del). Pathogenic analysis in accordance with the ACMG/AMP Standards and Guidelines identified two novel mutations as Likely Pathogenic. The expression level of PDZD7 gene in the patient was decreased compared to the normal control (P < 0.001). CONCLUSION: Three mutations in PDZD7 gene linked to ARNSHL were identified in a Chinese pedigree. The findings expand not only our knowledge of genetic causes of ARNSHL, but also PDZD7 genes mutation spectrum of the disease. They will aid personalized genetic counseling, molecular diagnostics and clinical management of this condition.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Proteínas de Transporte/genética , Genes Recessivos , Perda Auditiva/genética , Mutação , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Criança , Surdez/genética , Família , Estudos de Associação Genética , Predisposição Genética para Doença , Perda Auditiva/etnologia , Heterozigoto , Humanos , Masculino , Linhagem
10.
BMC Med Genet ; 20(1): 84, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101089

RESUMO

BACKGROUND: Progressive bilateral sensorineural deafness in postlingual period may be linked to many different etiologies including genetic factors. Identification of the exact deafness cause may, therefore, be quite challenging. Here we present a family with late-onset hearing loss as an autosomal dominant trait caused by a novel EYA4 mutation. CASE PRESENTATION: Forty-four years old female proband clinically investigated for progressive hearing loss and occasional dizziness with positive family history for deafness was subject to molecular-genetic testing. Patient's DNA sample was analyzed by whole exome sequencing. We identified a novel missense variant c.804G > C located at the last base pair of exon 10 in EYA4. Candidate variant was confirmed by Sanger sequencing in the proband and her family members. In silico prediction tools and co-segregation analysis were used to indicate pathogenicity of the identified variant. To confirm our hypothesis, we performed minigene assay to demonstrate if the transcript of exon 10 in EYA4 is present. We provide evidence that this mutation in vitro compromises donor site functionality and causes exon 10 skipping and frameshift that most likely results in nonsense-mediated mRNA decay. The onset of moderate to severe hearing loss in the family ranged from 10 to 40 years. The normal cardiac phenotype was confirmed by ECG and echocardiography. CONCLUSIONS: We identified a novel EYA4 mutation associated with adult-onset autosomal dominant sensorineural hearing loss. This report extends the knowledge of spectrum of EYA4 mutations and demonstrates the pathogenicity of a variant affecting specific position in the gene. A comprehensive review of known EYA4 mutations is also given and their impact on cardiac phenotype is discussed. Our findings highlight the importance of genetic testing and complex clinical assessment in patients with familial progressive hearing loss.


Assuntos
Genes Dominantes , Perda Auditiva/genética , Transativadores/genética , Idade de Início , Feminino , Humanos , Pessoa de Meia-Idade , Eslováquia
11.
Int J Pediatr Otorhinolaryngol ; 123: 141-145, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31102969

RESUMO

OBJECTIVES: Branchio-Oto (BO) syndrome is one of the common syndromic forms of hearing loss. In this study, we aimed to characterize the clinical and genetic features of BO syndrome in two Chinese Han deaf families. METHODS: The auditory and other BO-related clinical features of Family 1809 and Family 1974 were summarized. Targeted next-generation sequencing in 144 known deafness genes was performed in the probands. Co-segregation of the pathogenic mutations and the phenotype was confirmed by Sanger sequencing in the family members. RESULTS: Interfamilial and intrafamilial variations can be observed in the clinical phenotypes of BO syndrome in Family 1809 and 1974. A novel c.1493_1494insAT (p.Ile498PhefsTer*3) mutation and a previous reported c.967-2A>G mutation in EYA1 were identified as the pathogenic cause in Family 1974 and 1809, respectively. CONCLUSION: Our results supported the heterogeneity of the genetic and phenotypic spectrum of BO syndrome. The recurrent c.967-2A>G in different ethnical groups suggested that it is a hot-spot mutation.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Síndrome Brânquio-Otorrenal/genética , Perda Auditiva/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação/genética , Proteínas Nucleares/genética , Proteínas Tirosina Fosfatases/genética , Sequência de Bases , Síndrome Brânquio-Otorrenal/complicações , China , Feminino , Perda Auditiva/complicações , Humanos , Masculino , Linhagem , Fenótipo
12.
Artigo em Chinês | MEDLINE | ID: mdl-30991779

RESUMO

Objective: To detect 20 common deafness gene mutations in non-syndromic hearing loss patients in China using the melting curve method, and analyze and summarize the mutation data to explore the clinical value of this method. Methods: The real-time fluorescence PCR melting curve method was used to detect 20 common mutations of four deafness genes(GJB2,GJB3,SLC26A4 and mtDNA) in 492 patients with non-syndromic hearing loss recruited between March 2014 and September 2016 from the Otolaryngology Department of Xiangya Hospital, Central South University(283 males and 209 females, the age ranged from 1 to 48 years old). The Sanger sequencing method was used to compare the sensitivity, specificity, positive predictive value, negative predictive value, and total coincidence rate of the deafness mutation detected by the real-time fluorescence PCR melting curve method. Results: A total of 492 samples were detected. 193 wild-type samples, 93 homozygous mutant samples, 145 heterozygous mutant samples, 59 composite heterozygous mutant samples and 2 samples with unknown mutations were detected using the real-time fluorescence PCR melting curve method within the range of 20 gene mutations, whichwere identical to the Sanger sequencing results.The two samples were detected as unknown mutations by the real-time fluorescent PCR melting curve method were confirmed by Sanger sequencing, including a composite heterozygous mutant sample and a homogenous mutation sample. GJB2 c.235delC and SLC26A4 c.919-2 A>G were the most common hotspot mutations in this study, followed by mtDNA m.1555 A>G. Compared with the Sanger sequencing method, the sensitivity, specificity, positive predictive value, negative predictive value, and total coincidence rate of the real-time fluorescence PCR melting curve method were 100%, the Youden's index was 1.0, and the Kappa value was 1. Conclusions: The real-time fluorescence PCR melting curve method is suitable for the detection of deafness gene mutations. It has the advantages in terms of simple, rapid, high sensitivity and strong specificity and can accurately detect the 20 gene mutations of 4 common deafness genes in Chinese population, which is expected to be used for the clinical detection of deafness genes in the future.


Assuntos
Perda Auditiva/genética , Mutação/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Adolescente , Adulto , Criança , Pré-Escolar , China , Análise Mutacional de DNA/métodos , Surdez/genética , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Transportadores de Sulfato/genética , Adulto Jovem
13.
BMC Med Genet ; 20(1): 60, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30953472

RESUMO

BACKGROUND: MYO15A variants are responsible for human non-syndromic autosomal recessive deafness (DFNB3). The majority of MYO15A variants are associated with a congenital severe-to-profound hearing loss phenotype, except for MYO15A variants in exon 2, which cause a milder auditory phenotype, suggesting a genotype-phenotype correlation of MYO15A. However, MYO15A variants not in exon 2 related to a milder phenotype have also been reported, indicating that the genotype-phenotype correlation of MYO15A is complicated. This study aimed to provide more cases of MYO15A variation with diverse phenotypes to analyse this complex correlation. METHODS: Fifteen Chinese autosomal recessive non-syndromic hearing loss (ARNSHL) individuals with MYO15A variants (8 males and 7 females) from 14 unrelated families, identified by targeted gene capture of 127 known candidate deafness genes, were recruited. Additionally, we conducted a review of the literature to further analyses all reported MYO15A genotype-phenotype relationships worldwide. RESULTS: We identified 16 novel variants and 12 reported pathogenic MYO15A variants in 15 patients, two of which presented with a milder phenotype. Interestingly, one of these cases carried two reported pathogenic variants in exon 2, while the other carried two novel variants not in exon 2. Based on our literature review, MYO15A genotype-phenotype correlation analysis showed that almost all domains were reported to be correlated with a milder phenotype. However, variants in the N-terminal domain were more likely to cause a milder phenotype. Using next-generation sequencing (NGS), we also found that the number of known MYO15A variants with milder phenotypes in Southeast Asia has increased in recent years. CONCLUSION: Our work extended the MYO15A variant spectrum, enriched our knowledge of auditory phenotypes, and tried to explore the genotype-phenotype correlation in different populations in order to investigate the cause of the complex MYO15A genotype-phenotype correlation.


Assuntos
Genes Recessivos , Genótipo , Perda Auditiva/genética , Miosinas/genética , Fenótipo , Adolescente , Adulto , Pré-Escolar , China , Grupos Étnicos , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Cell Mol Biol (Noisy-le-grand) ; 65(3): 84-88, 2019 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-30942159

RESUMO

The aim of this study was to identify the novel missense eya4 mutation which cause autosomal dominant non syndromic hearing loss In a Chinese family. Hearing loss is the most common sensory deficit in humans, but the middle-frequency sensorineural hearing loss (MFSNHL) is rare among hereditary non-syndromic hearing loss, and EYA4 is one of the genes reported to be associated with MFSNHL. A genetic analysis of a Chinese family with autosomal dominant non­syndromic progressive hearing impairment was conducted and assessed. Targeted exome sequencing, conducted using DNA samples of an affected member in this family, revealed a novel heterozygous missense mutation c.1855T>G in exon 20 of EYA4, causing amino-acid (aa) substitution Gly for Trp at a conserved position aa-619. The p.W619G mutation related to hearing loss in this Chinese family was validated by Sanger sequencing. Bioinformatic analysis confirmed the pathogenic effects of this mutation. We identified the novel missense mutation c.1855T>G (p.W619G) in EYA4 causing autosomal dominant non-syndromic hearing impairment in the selected Chinese family.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Genes Dominantes , Perda Auditiva/genética , Mutação de Sentido Incorreto/genética , Transativadores/genética , Adulto , Idoso , Simulação por Computador , Exoma/genética , Família , Feminino , Loci Gênicos , Humanos , Masculino , Pessoa de Meia-Idade , Software
15.
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
16.
Gene ; 703: 83-90, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-30898719

RESUMO

Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system has ushered in a new era of gene therapy. In this study, we aimed to demonstrate precise CRISPR/Cas9-mediated genome editing of the splicing mutation c.919-2A > G in intron 7 of the SLC26A4 gene, which is the second most common causative gene of congenital hearing loss. We designed candidate single-guide RNAs (sgRNAs) aimed to direct the targeting of Staphylococcus aureus Cas9 to either exon 7 or exon 8 of SLC26A4. Several of the designed sgRNAs showed targeting activity, with average indel efficiencies ranging from approximately 14% to 25%. The usage of dual sgRNAs delivered both into Neuro2a cells and primary mouse embryonic fibroblasts resulted in the successful removal of large genomic fragments within the target locus. We subsequently evaluated genome editing in the presence of artificial donor templates to induce precise target modification via homology-directed repair. Using this approach, two different donor plasmids successfully introduced silent mutations within the c.919-2A region of Slc26a4 without evident off-target activities. Overall, these results indicate that CRISPR/Cas9-mediated correction of mutations in the Slc26a4 gene is a feasible therapeutic option for restoration of hearing loss.


Assuntos
Proteína 9 Associada à CRISPR/metabolismo , Marcação de Genes/métodos , Perda Auditiva/congênito , Staphylococcus aureus/metabolismo , Transportadores de Sulfato/genética , Animais , Proteínas de Bactérias/metabolismo , Sistemas CRISPR-Cas , Linhagem Celular , Éxons , Edição de Genes , Terapia Genética , Perda Auditiva/genética , Humanos , Camundongos
17.
Nat Commun ; 10(1): 1117, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30850599

RESUMO

Sensory hair cells, the mechanoreceptors of the auditory and vestibular systems, harbor two specialized elaborations of the apical surface, the hair bundle and the cuticular plate. In contrast to the extensively studied mechanosensory hair bundle, the cuticular plate is not as well understood. It is believed to provide a rigid foundation for stereocilia motion, but specifics about its function, especially the significance of its integrity for long-term maintenance of hair cell mechanotransduction, are not known. We discovered that a hair cell protein called LIM only protein 7 (LMO7) is specifically localized in the cuticular plate and the cell junction. Lmo7 KO mice suffer multiple cuticular plate deficiencies, including reduced filamentous actin density and abnormal stereociliar rootlets. In addition to the cuticular plate defects, older Lmo7 KO mice develop abnormalities in inner hair cell stereocilia. Together, these defects affect cochlear tuning and sensitivity and give rise to late-onset progressive hearing loss.


Assuntos
Células Ciliadas Auditivas/fisiologia , Audição/fisiologia , Proteínas com Domínio LIM/deficiência , Fatores de Transcrição/deficiência , Actinas/metabolismo , Animais , Cóclea/fisiologia , Modelos Animais de Doenças , Células Ciliadas Auditivas/ultraestrutura , Células Ciliadas Auditivas Internas/fisiologia , Células Ciliadas Auditivas Internas/ultraestrutura , Audição/genética , Perda Auditiva/etiologia , Perda Auditiva/genética , Perda Auditiva/fisiopatologia , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Microscopia Eletrônica de Varredura , Estereocílios/genética , Estereocílios/fisiologia , Estereocílios/ultraestrutura , Fatores de Transcrição/genética , Fatores de Transcrição/fisiologia
18.
Medicine (Baltimore) ; 98(12): e14860, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30896630

RESUMO

Hearing loss is a highly heterogeneous disease presented with various phenotypes. Genetic testing of disease-causing mutations plays an important role in precise diagnosis and fertility guidance of heredity hearing loss. Here we reported an effective method employing target enrichment and BGISEQ-500 platform to detect clinically relevant alterations for heredity hearing patients in a single assay.In this study, we designed an array based chip, containing 127 genes related to hearing loss. Then we conducted targeted next-generation sequencing toward 58 patients to make a precise diagnosis using BGISEQ-500 platform.We successfully detected disease-causing mutations in 77.59% (45/58) of the patients with hearing loss. Finally, a total of 62 disease-causing mutations were identified, including 31 missense, 17 Indel, 11 splicing, 2 synonymous, and 1 copy number variant. 58.06% (36/62) of which has never been reported before.To our knowledge, this is the first report using BGISEQ-500 platform to investigate both syndromic and nonsyndromic hearing loss in the Chinese population. The results showed that this method can greatly assist and enhance hearing loss diagnosis and improve molecular diagnostics outcome.


Assuntos
Perda Auditiva/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Adolescente , Criança , Pré-Escolar , China , Variações do Número de Cópias de DNA , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Adulto Jovem
19.
BMC Med Genet ; 20(1): 43, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894143

RESUMO

BACKGROUND: To investigate the clinical features and the underlying causal gene of a family with hereditary late-onset deafness in Inner Mongolia of China, and to provide evidence for the early genetic screening and diagnosis of this disease. METHODS: Family data were collected to draw a pedigree. Audiological testing and physical examination of the family members were conducted following questionnaire. Genomic DNA was extracted from peripheral blood of 5 family members (3 patients and 2 normal control) and subjected to whole genome sequencing for identifying deafness casual genes. The pathogenic variant in the deafness gene was further confirmed by Sanger sequencing. RESULTS: The family is composed of a total of 6 generations, with 53 traceable individuals. In this family,19 of them were diagnosed with post lingual deafness with the age of onset between 10 and 40 years, displaying delayed and progressive hearing loss. Patients with hearing loss showed bilateral symmetry and mild to severe sensorineural deafness. The pattern of deafness inheritance in this family is autosomal dominant. Whole genome sequencing identified a novel pathogenic frameshift mutation, c.158_159delAA (p.Gln53Arg fs*100) in the gene OSBPL2 (Oxysterol-binding protein-related protein 2, NM_144498.2), which is absent from genomic data of 201 unrelated normal subjects. This pathogenic variant was further validated by Sanger sequencing, and was found to co-segregate in this family. CONCLUSIONS: Whole genome sequencing identified a two-nucleotide deletion in OSBPL2 (c.158_159delAA) as the pathogenic variant for deafness in the family. Our finding expands the mutational spectrum of OSBPL2 and contributes to the pathogenic variant list in genetic counseling for deafness screening.


Assuntos
Mutação da Fase de Leitura , Perda Auditiva/congênito , Perda Auditiva/genética , Receptores de Esteroides/genética , Sequenciamento Completo do Genoma/métodos , Adulto , Idade de Início , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Mongólia , Linhagem , Fenótipo
20.
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
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