ABSTRACT
Auditory neuropathy is sensorineural deafness where sound signals cannot be transmitted synchronously from the cochlea to the auditory center. Abnormal expression of vesicle glutamate transporter 3 (VGluT3) encoded by the SLC17a8 gene is associated with the pathophysiology of auditory neuropathy. Although several suspected pathogenic mutations of the SLC17a8 gene have been identified in humans, few studies have confirmed their pathogenicity. Here, we describe the effects of two known suspected pathogenic mutations (c.824C>A and c.616dupA) in the SLC17a8 gene coding VGluT3 protein and analyzed the potential pathogenicity of these mutations. The p.M206Nfs4 and p.A275D changes are caused by c.824C>A and c.616dupA mutations in the cytoplasmic loop, an important structure of VGluT3. To explore the potential pathogenic effects of c.824C>A and c.616dupA mutations, we performed a series of experiments on mRNA levels and protein expression in cell culture. The c.616dupA mutation in the SLC17a8 gene resulted in a significant decrease in transcriptional activity of mRNA, and the expression of VGluT3 was also reduced. The c.824C>A mutation in the SLC17a8 gene resulted in abnormal VGluT3, although this mutation did not affect the transcriptional activity of mRNA. Our results demonstrate that c.824C>A and c.616dupA mutations in the SLC17a8 gene could lead to pathological protein expression of VGluT3 and supported the potential pathogenicity of these mutations.
Subject(s)
Computational Biology/methods , Hearing Loss, Central/genetics , Mutation/genetics , Vesicular Glutamate Transport Proteins/genetics , Amino Acid Sequence , Gene Expression , HEK293 Cells , Hearing Loss, Central/metabolism , Humans , Protein Structure, Secondary , Vesicular Glutamate Transport Proteins/biosynthesis , Vesicular Glutamate Transport Proteins/chemistryABSTRACT
Breast cancer is one of the most common malignant cancers affecting females. Estrogen receptor (ER)-positive breast cancer is responsive to endocrine therapy. Although current therapies offer favorable prospects for improving survival, the development of resistance remains a severe problem. In this study, we explored the resistance mechanisms of ER-positive breast cancer to neoadjuvant endocrine therapy. Microarray data of GSE87411 contained 109 pairs of samples from Z1031 trial, including untreated samples and post-treated samples with neoadjuvant aromatase inhibitor (AI) therapy. The differentially expressed genes (DEGs) were obtained from two different comparisons: untreated samples versus post-treated samples with AIs, and post-treated samples sensitive versus resistant to AIs. Multiple bioinformatic methods were applied to evaluate biological function, protein-protein network and potential binding between target protein and aromatase inhibitor. Then, regulation of gene expression, DNA methylation and clinicopathological factors of breast cancer were further analyzed with TCGA data. From GSE87411 dataset, 30 overlapped DEGs were identified. Cell division was found to be the main function of overlapped DEGs by functional enrichment and gene ontology (GO) analysis. RAD51 recombinase (RAD51), a key protein of homologous recombination, was detected to interact with BReast CAncer genes 2 (BRCA2). Moreover, according to the docking simulation, RAD51 might potentially bind to AIs. Overexpressed RAD51 was associated with hypermethylation of BRCA2, resistance to AIs and poor overall survival of patients with ER-positive breast cancer. Furthermore, RAD51 was found to be a better indicator than MKI67 for predicting resistance in neoadjuvant setting. The results indicated that methylation of BRCA2 led to incomplete suppression on RAD51, which caused an increased expression of RAD51, subsequently AI-resistance and poor prognosis in ER-positive breast cancer. RAD51 could be a new candidate used as a predicative marker and therapeutic target in neoadjuvant endocrine treatment.
Subject(s)
Antineoplastic Agents, Hormonal/pharmacology , Aromatase Inhibitors/pharmacology , Breast Neoplasms/genetics , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic , Rad51 Recombinase/metabolism , Receptors, Estrogen/metabolism , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Female , Gene Expression Profiling , Humans , Rad51 Recombinase/geneticsABSTRACT
OBJECTIVES: To analyze complications associated with minimally invasive cochlear implantation by comparing data from different centers, to discuss major reasons for complications, and to refine implantation techniques to decrease them. PATIENTS: Patients who underwent cochlear implantation at our center by the same surgeon (the corresponding author of this article) from March 2006 to March 2015 were enrolled. INTERVENTION: First, a retrospective analysis of the complications associated with minimally invasive cochlear implantation at our center was performed. Second, published reports from other centers that describe complications were reviewed. Differences between complications in our cohort and other studies were evaluated. MAIN OUTCOME MEASURE: Strategies for reducing complications were assessed and modifications in surgical protocol proposed accordingly. RESULTS: In total, 1,014 patients underwent 1,065 cochlear implantations. There were 28 complications (7 major, 21 minor) and only 2 reimplantations for the entire cohort, with no case of severe infection, flap necrosis, or device extrusion. The major complications were electrode misplacement, magnet displacement, implant failure secondary to trauma, and temporary cerebrospinal fluid leakage. The rates of major complications in our cohort were very low (0.6%) compared with those in the literature. CONCLUSION: Preoperative surgical planning based on individual patient anatomy and employment of soft surgical techniques can minimize surgical complications.
Subject(s)
Cerebrospinal Fluid Leak/etiology , Cochlear Implantation/adverse effects , Cochlear Implants/adverse effects , Prosthesis Failure , Adolescent , Adult , Aged , Cerebrospinal Fluid Leak/epidemiology , Cerebrospinal Fluid Leak/surgery , Child , Child, Preschool , Cochlear Implantation/methods , Equipment Failure , Female , Humans , Infant , Male , Middle Aged , Postoperative Complications/epidemiology , Postoperative Complications/surgery , Prevalence , Retrospective Studies , Young AdultABSTRACT
OBJECTIVE: Congenital absence of the oval window (CAOW) is a rare condition in which the stapes footplate fails to develop, resulting in a significant conductive hearing loss in the affected ear. The purpose of this study was to describe the surgical management and outcomes of patients with CAOW undergoing the oval window drill-out (OWD) procedure. MATERIALS AND METHODS: A retrospective chart review of patients with CAOW between 1996 and 2011 was performed. Clinical data of patients who underwent OWD were collected. Seventy-nine patients (103 ears) were confirmed using exploratory tympanotomy as having congenital stapes anomalies and CAOW without any anomalies of the tympanic membrane and external auditory canal. Demographic data, CT findings, operative findings, complications, and preoperative/postoperative audiometry data of patients who underwent OWD were collected. The preoperative and postoperative audiologic findings were analyzed in 42 patients (56 ears) with complete data. RESULTS: Hearing restoration surgery was aborted for various reasons in 14 cases. Six patients underwent revision operations for worsening hearing after their first surgery. The average preoperative 4 tone air conduction threshold was 67 dB; the average 6-month postoperative four tone air conduction threshold was 49 dB, and the average postoperative hearing gain was 18 dB. For the 56 ears, the average 4 tone air conduction threshold 6 months after surgery was significantly lower than the preoperative threshold. CONCLUSION: The oval window drill-out procedure is a viable operation for patients with congenital absence of the oval window, and it is important for surgeons to develop personalized treatment programs to improve patients' hearing with minimal complications.
Subject(s)
Ear, Middle/abnormalities , Ear, Middle/surgery , Hearing Loss, Conductive/surgery , Stapes Surgery/methods , Stapes/abnormalities , Adolescent , Adult , Audiometry , Child , Ear Canal/abnormalities , Ear Canal/surgery , Female , Hearing/physiology , Hearing Loss, Conductive/congenital , Hearing Loss, Conductive/physiopathology , Humans , Male , Retrospective Studies , Treatment Outcome , Tympanic Membrane/abnormalities , Tympanic Membrane/surgery , Young AdultABSTRACT
TECTA-related deafness can be inherited as autosomal-dominant nonsyndromic deafness (designated DFNA) or as the autosomal-recessive version. The α-tectorin protein, which is encoded by the TECTA gene, is one of the major components of the tectorial membrane in the inner ear. Using targeted DNA capture and massively parallel sequencing (MPS), we screened 42 genes known to be responsible for human deafness in a Chinese family (Family 3187) in which common deafness mutations had been ruled out as the cause, and identified a novel mutation, c.257-262CCTTTC>GCT (p. Ser86Cys; p. Pro88del) in exon 3 of the TECTA gene in the proband and his extended family. All affected individuals in this family had moderate down-sloping hearing loss across all frequencies. To our knowledge, this is the second TECTA mutation identified in Chinese population. This study demonstrates that targeted genomic capture, MPS, and barcode technology might broaden the availability of genetic testing for individuals with undiagnosed DFNA.
Subject(s)
Deafness/genetics , Extracellular Matrix Proteins/genetics , Mutation , Asian People/genetics , Audiometry, Pure-Tone , China , DNA Mutational Analysis , Deafness/physiopathology , Female , GPI-Linked Proteins/genetics , Humans , Male , Pedigree , Pregnancy , Prenatal DiagnosisABSTRACT
BACKGROUND: Inherited genetic defects play an important role in congenital hearing loss, contributing to about 60% of deafness occurring in infants. Hereditary nonsyndromic hearing loss is highly heterogeneous, and most patients with a presumed genetic etiology lack a specific molecular diagnosis. METHODS: By whole exome sequencing, we identified responsible gene of family 4794 with autosomal recessively nonsyndromic hearing loss (ARNSHL). We also used DNA from 56 Chinese familial patients with ARNSHL (autosomal recessive nonsyndromic hearing loss) and 108 ethnicity-matched negative samples to perform extended variants analysis. RESULTS: We identified MYO15A c.IVS25+3G>A and c.8375 T>C (p.V2792A) as the disease-causing mutations. Both mutations co-segregated with hearing loss in family 4794, but were absent in the 56 index patients and 108 ethnicity-matched controls. CONCLUSIONS: Our results demonstrated that the hearing loss of family 4794 was caused by novel compound heterozygous mutations in MYO15A.
Subject(s)
Exome , Genes, Recessive , Hearing Loss/genetics , Heterozygote , Mutation , Myosins/genetics , Sequence Analysis , Adult , Animals , Base Sequence , China , DNA/genetics , Female , Hearing Loss/physiopathology , Hearing Tests , Humans , Male , Molecular Sequence Data , Myosins/chemistry , Pedigree , Sequence Homology, Amino Acid , Sequence Homology, Nucleic AcidABSTRACT
Hereditary nonsyndromic hearing loss is highly heterogeneous and most patients with a presumed genetic etiology lack a specific diagnosis. It has been estimated that several hundred genes may be associated with this sensory deficit in humans. Here, we identified compound heterozygous mutations in the TMC1 gene as the cause of recessively inherited sensorineural hearing loss by using whole-exome sequencing in a family with two deaf siblings. Sanger sequencing confirmed that both siblings inherited a missense mutation, c.589G>A p.G197R (maternal allele), and a nonsense mutation, c.1171C>T p.Q391X (paternal allele), in TMC1. We also used DNA from 50 Chinese familial patients with ARNSHL and 208 ethnicity-matched negative samples to perform extended variants analysis. Both variants co-segregated in family 1953, which had the hearing loss phenotype, but were absent in 50 patients and 208 ethnicity-matched controls. Therefore, we concluded that the hearing loss in this family was caused by novel compound heterozygous mutations in TMC1.
Subject(s)
Asian People/genetics , Hearing Loss, Sensorineural/genetics , Heterozygote , Membrane Proteins/genetics , Membrane Proteins/metabolism , Pedigree , Adolescent , Amino Acid Sequence , Animals , Base Sequence , DNA Mutational Analysis , Exome/genetics , Female , Hearing Loss, Sensorineural/pathology , Hearing Loss, Sensorineural/physiopathology , Humans , Male , Membrane Proteins/chemistry , Mice , Molecular Sequence Data , Polymorphism, Genetic , Rats , Siblings , Young AdultABSTRACT
In most studies, sensorineural hearing loss is reported as a single-gene disease with autosomal dominant or autosomal recessive or with X-linked or maternal inheritance. It is uncommon that the hearing impairment is caused by a combined inheritance model including genomic and mitochondrial models. Here, we report six patients with sensorineural hearing loss caused by co-existing mutations in GJB2 or SLC26A4 and the mitochondrial gene. And there was no significant difference in hearing phenotypes between the six patients and the controls. The results indicate the complicated genetic etiology of, and may impact the diagnostic strategy for, hereditary hearing impairment. All patient siblings will carry mitochondrial DNA A1555G or C1494T mutations, and 25% of siblings may carry the same homozygous or compound heterozygote mutations in GJB2 or SLC26A4. Although this combined inheritance is not common in the Chinese deaf population (0.10%), our findings will have great impact in genetic counseling and risk prediction for deafness.
Subject(s)
Deafness/genetics , Genome, Mitochondrial , Models, Genetic , Cohort Studies , Connexin 26 , Connexins , Female , Genotype , Humans , Male , Pedigree , PhenotypeABSTRACT
BACKGROUND: Most studies of the molecular etiology of sensorineural hearing loss have described deafness as a monogenic disease encompassing double-allele mutations for patients with autosomal recessive deafness. Here, we report the first case of autosomal recessive genetic deafness in an enlarged vestibular aqueduct syndrome (EVAS) patient with biallelic mutations in two deafness genes. METHODS: Temporal computed tomography (CT), complete physical and otoscopic examinations, and an audiological study, including tympanometry, pure-tone audiometry or auditory steady-state response (ASSR), were carried out. Exon 2 of GJB2 and the coding exons of SLC26A4 were sequenced. RESULTS: A patient with an enlarged vestibular aqueduct was found to carry c.1229C>T/c.1079C>T compound heterozygous mutations in SLC26A4.This individual also carried c.257C>G/c.299-300delAT compound heterozygous mutations in GJB2. As a result, the recurrent risk of the patient's siblings increased significantly from 25% for typical autosomal recessive deafness to 43.75%. CONCLUSIONS: The findings of the present study challenge the traditional diagnostic strategy in which testing is generally considered complete upon identification of a double-allele mutation within one gene, with significant implications for genetic counseling and risk prediction. Our results suggest that, with advances in sequencing technology, it will be possible and necessary to test all known deafness genes in the near future, as this will likely allow more accurate genetic counseling of patients.
Subject(s)
Connexins/genetics , Hearing Loss, Sensorineural/genetics , Membrane Transport Proteins/genetics , Alleles , Child , Connexin 26 , Hearing Loss, Sensorineural/diagnosis , Humans , Male , Mutation , Sulfate Transporters , Vestibular Aqueduct/abnormalitiesABSTRACT
Aberrant internal carotid artery (ICA) in the middle ear is a rare, dangerous vascular anomaly and conservative follow-up was usually adopted in most reported cases. Here we report the case of an 8-year-old girl with symptoms of objective pulsatile tinnitus and conductive hearing loss in the right ear. Otoscopic examination, computed tomography, and conventional angiography were performed. An aberrant ICA combined with a 'third mobile window' was suspected preoperatively and confirmed at exploratory surgery of the middle ear. The aberrant ICA was treated, and the pulsatile tinnitus disappeared and hearing recovered after the surgery. This case suggests that surgery is practical to relieve troublesome tinnitus and hearing loss in appropriate cases with aberrant ICA.
Subject(s)
Carotid Artery, Internal/abnormalities , Hearing Loss, Conductive/etiology , Tinnitus/etiology , Tomography, X-Ray Computed/methods , Vascular Malformations/complications , Acoustic Impedance Tests/methods , Audiometry, Pure-Tone , Carotid Artery, Internal/diagnostic imaging , Child , Female , Follow-Up Studies , Hearing Loss, Conductive/diagnosis , Humans , Magnetic Resonance Angiography/methods , Otologic Surgical Procedures/methods , Otoscopy/methods , Risk Assessment , Tinnitus/diagnosis , Treatment Outcome , Vascular Malformations/diagnostic imaging , Vascular Malformations/surgeryABSTRACT
CONCLUSIONS: Intraoperative computed tomography (iCT)-guided cochlear implantation is practical and effective for correct electrode placement in the cochlea of patients with congenital inner ear and/or complex middle ear malformation. OBJECTIVES: The operation in patients with inner ear and/or complex middle ear malformation including abnormal facial nerve course is difficult. This study evaluated the efficacy of cochlear implantation under the guidance of iCT to insure correct electrode placement. METHODS: This was a prospective interventional case series. Ten patients with severe to profound sensorineural hearing loss due to ear malformations were enrolled, and iCT was used to confirm the right placement of electrodes. RESULTS: Intraoperative CT was performed three times in one patient, twice in two, and once in the others. Interruption of the surgical process for each iCT until resumption of surgery was 9.64 ± 0.63 min. iCT revealed incorrectly positioned cochlear implants in two patients, which were immediately corrected. There were no reoperations due to misplacement of electrodes. iCT helped locate the cochlea in the middle ear of one patient with an abnormal facial nerve course. The overall intervention rate based on iCT findings was 30%. LEVEL OF EVIDENCE: level 4.
Subject(s)
Cochlear Implantation/methods , Deafness/surgery , Ear, Inner/abnormalities , Ear, Middle/abnormalities , Hearing Loss, Sensorineural/congenital , Hearing Loss, Sensorineural/surgery , Surgery, Computer-Assisted/methods , Tomography, X-Ray Computed/methods , Adult , Child , Child, Preschool , China , Deafness/congenital , Deafness/diagnostic imaging , Deafness/physiopathology , Ear, Inner/diagnostic imaging , Ear, Inner/physiopathology , Ear, Inner/surgery , Ear, Middle/diagnostic imaging , Ear, Middle/physiopathology , Ear, Middle/surgery , Electrodes, Implanted , Facial Nerve/abnormalities , Facial Nerve/physiopathology , Facial Nerve/surgery , Female , Hearing Loss, Sensorineural/diagnostic imaging , Hearing Loss, Sensorineural/physiopathology , Humans , Infant , Male , Postoperative Complications/diagnostic imaging , Postoperative Complications/physiopathology , TelemetryABSTRACT
BACKGROUND: Thirty thousand infants are born every year with congenital hearing impairment in mainland China. Racial and regional factors are important in clinical diagnosis of genetic deafness. However, molecular etiology of hearing impairment in the Tibetan Chinese population living in the Tibetan Plateau has not been investigated. To provide appropriate genetic testing and counseling to Tibetan families, we investigated molecular etiology of nonsyndromic deafness in this population. METHODS: A total of 114 unrelated deaf Tibetan children from the Tibet Autonomous Region were enrolled. Five prominent deafness-related genes, GJB2, SLC26A4, GJB6, POU3F4, and mtDNA 12S rRNA, were analyzed. Inner ear development was evaluated by temporal CT. A total of 106 Tibetan hearing normal individuals were included as genetic controls. For radiological comparison, 120 patients, mainly of Han ethnicity, with sensorineural hearing loss were analyzed by temporal CT. RESULTS: None of the Tibetan patients carried diallelic GJB2 or SLC26A4 mutations. Two patients with a history of aminoglycoside usage carried homogeneous mtDNA 12S rRNA A1555G mutation. Two controls were homozygous for 12S rRNA A1555G. There were no mutations in GJB6 or POU3F4. A diagnosis of inner ear malformation was made in 20.18% of the Tibetan patients and 21.67% of the Han deaf group. Enlarged vestibular aqueduct, the most common inner ear deformity, was not found in theTibetan patients, but was seen in 18.33% of the Han patients. Common molecular etiologies, GJB2 and SLC26A4 mutations, were rare in the Tibetan Chinese deaf population. CONCLUSION: The mutation spectrum of hearing loss differs significantly between Chinese Tibetan patients and Han patients. The incidence of inner ear malformation in Tibetans is almost as high as that in Han deaf patients, but the types of malformation vary greatly. Hypoxia and special environment in plateau may be one cause of developmental inner ear deformity in this population.