Gap Junction Beta-2 Gene Research Articles

Silicon/Silver nanocomposite-based surface-enhanced Raman spectroscopy (SERS) biosensor for ultrasensitive direct detection of deafness mutations in real system

Surface-enhanced Raman scattering (SERS) is a promising emerging, highly sensitive technique for detecting biological samples. The current research aims to bring an effortless biosensor-based approach to detect and discriminate DNA mutations with their fingerprints for each deafness mutation within the GJB2 (gap junction beta 2) gene. Therefore, we developed silver (Ag) modified silicon-based SERS sensing platform to directly screen GJB2 gene mutations for UAE patients with hereditary hearing loss (HL). The prepared AgNPs@Si biosensor was utilized for establishing a silicon-based SERS biosensing protocol for further analyses toward label-free DNA deafness mutations screening. Furthermore, the comparative studies demonstrated the viability of the developed sensor to distinguish between the normal/mutant samples in the real-time system by investigating the DNA assignments and the peaks intensity. Noticeably, under 785 nm laser excitation distinguishable Raman peaks for cytosine bands (C) are enriched with normal DNA (DMF-34) at 780 cm−1, 1450 cm−1 and 1590 cm−1 whereas with the single nucleotide deletion of cytosine band for the mutant DNA correspondingly predicted with Quenched intensities at the parallel Raman peak positions. The sensitivity studies portrayed the limit of detection to be 1 fg/μL. Further their reproducibility studies evaluation conveyed with low values of % RSD as 10. By the end of this study, we expected to update the mutational profile of the GJB2 gene in the UAE population using the advanced simple SERS-based technique for further supplemental applications in terms of genetic counseling and prenatal diagnosis.

3D Chromatin Organization Involving MEIS1 Factor in the cis-Regulatory Landscape of GJB2.

The human genome is covered by 8% of candidate cis-regulatory elements. The identification of distal acting regulatory elements and an understanding of their action are crucial to determining their key role in gene expression. Disruptions of such regulatory elements and/or chromatin conformation are likely to play a critical role in human genetic diseases. Non-syndromic hearing loss (i.e., DFNB1) is mostly due to GJB2 (Gap Junction Beta 2) variations and DFNB1 large deletions. Although several GJB2 cis-regulatory elements (CREs) have been described, GJB2 gene regulation remains not well understood. We investigated the endogenous effect of these CREs with CRISPR (clustered regularly interspaced short palindromic repeats) disruptions and observed GJB2 expression. To decipher the GJB2 regulatory landscape, we used the 4C-seq technique and defined new chromatin contacts inside the DFNB1 locus, which permit DNA loops and long-range regulation. Moreover, through ChIP-PCR, we determined the involvement of the MEIS1 transcription factor in GJB2 expression. Taken together, the results of our study enable us to describe the 3D DFNB1 regulatory landscape.

Analysis of Genetic Variations in Connexin 26 ( GJB2 ) Gene among Nonsyndromic Hearing Impairment: Familial Study.

Objective The goal of this research was to investigate the gap junction beta 2 ( GJB2 ) gene mutations associated with nonsyndromic hearing loss individuals in North Karnataka, India. Materials and Methods For this study, patients with sensorineural genetic hearing abnormalities and a family history of deafness were included. A total of 35 patients from 20 families have been included in the study. The patient's DNA was isolated from peripheral blood samples. The GJB2 gene coding region was analyzed through Sanger sequencing. Results There is no changes in the first exon of the GJB2 gene. Nine different variants were recorded in second exon of the targeted gene. W24X and W77X are two nonsense mutations and three polymorphisms viz. R127H, V153I, and I33T were reported along with four 3′-UTR variants. A total (9/20) of 45% of families have been identified with mutations in the targeted gene. Conclusion GJB2 mutations were identified in 19 deaf-mute patients (19/35), and 13 patients were homozygous for the mutations identified in our study cohort. In our study, W24X mutation was found to be the pathogenic with a high percentage, prompting further evaluation of the other genes, along with the study of additional genetic or external causes in the families, which is essential.

Generation of two iPSC lines from siblings of a homozygous patient with hearing loss and a heterozygous carrier with normal hearing carrying p.G45E/Y136X mutation in GJB2

The gap junction beta-2 (GJB2) gene is the most common genetic cause of hereditary deafness worldwide. Among them, the G45E/Y136X mutation in GJB2 is the third most prevalent in Japan. In this study, we generated two induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) of siblings with moderate-to-severe hearing loss (patient) or normal hearing (genetic carrier) carrying a homozygous or heterozygous G45E/Y136X mutation in GJB2 gene, respectively. These iPSC lines showed the expression of pluripotency markers and could differentiate into three germ layers. These disease-specific iPSC lines will be a powerful tool for investigating the pathogenesis of GJB2-related deafness.

Molecular alteration in the Gap Junction Beta 2 (GJB2) gene associated with non-syndromic sensorineural hearing impairment.

Non-syndromic sensory neural hearing defect is one of the genetic diseases inherited from parents to offerings. The autosomal recessive form affects a large population worldwide and has become a major concern in the social and professional lives of many people. There are many factors and genes which are involved in hearing loss but the Gap Junction Beta 2 (GJB2) gene which encodes the connexin 26 protein, is a major cause of non-syndromic recessive deafness (NSRD). This study aims to record and analyze GJB2 gene mutations in the hearing-impaired population of North Karnataka, India. In this study, we included 368 congenitally hearing-impaired children from North Karnataka, India, under 18 years of age. After thorough clinical examinations, patient's history and proper audiological results, peripheral blood samples were collected and subjected to genetic analysis. We recorded that 54.8% of the NSRD cases have an autosomal recessive mutation in the coding region of the GJB2 gene. The frequency of W24X (25%) mutation was found to be high in the present study population. From this study we can suggest that, identifying this mutation in new-borns definitely helps in the early diagnosis of hearing loss.

Generation of two induced pluripotent stem cell lines from PBMCs of siblings carrying c.235delC mutation in the GJB2 gene associated with sensorineural hearing loss.

The gap junction beta-2 (GJB2) gene is the most common genetic cause of hereditary deafness worldwide. Especially, the 235delC mutation in GJB2 is most prevalent in East Asia. In this study, we generated two iPSC lines from PBMCs of siblings carrying homozygous 235delC mutation which exhibits an audiometric phenotype of profound hearing loss. These iPSC lines had normal karyotype, showed expression of pluripotency markers, and could differentiate into three germ layers. These disease specific iPSC lines may be useful for the construction of the disease models and for the elucidation of pathogenesis in GJB2-related deafness.

Screening of 35delG, W24X, W77X and Q124X Variants in connexin 26 gene associated with Non-Syndromic Hearing Impairment

Introduction: Hearing deficiency is the most common sensory incompetence that affects millions of people all over the world. Profound Deafness is a common disorder that occurs in 1:1000 neonates and the cause is hereditary. Gap Junction Beta2 (GJB2) gene which codes for connexion 26 protein is implicated in hearing. Mutation or defect in this gene leads to the most common form of the congenital disorder called Deaf Mutism (DM). The present study aims to screen the common variants associated with hearing impairment. Objective: To Screen common variants 35delG, W24X, W77X, and Q124X in connexin 26 gene of the North Karnataka population. Methods: 613 deaf-mute children from districts of North Karnataka were screened and 184 Non Syndromic Sensorineural Hearing-impaired children were included in the study. Genomic DNA was isolated using peripheral blood. Our gene of interest was amplified by Polymerase Chain Reaction (PCR) using target-specific primers. The PCR product was subjected to sequencing to analyze the mutations. Result: In our population prevalence of W24X, W77X variants were 25% & 5.4% respectively and 35 del G and Q124X mutations were absent. Along with this common variant, I33T (5.4%) and R127H (14.6%) were also observed. Conclusion: above findings suggests that Gap junction Beta 2 gene plays a crucial role in hearing impairment. Mutation analysis of the entire GJB2 gene in our population may help to define the etiology of deafness as well as the development of population-specific prenatal and perinatal genetic markers.

Recurrent episodes of reversible posterior leukoencephalopathy in three Chinese families with GJB1 mutations in X-linked Charcot-Marie-tooth type 1 disease: cases report

BackgroundThe X-linked form of Charcot-Marie-Tooth disease type 1 (CMTX1) is an inherited peripheral neuropathy that arises in patients with mutations in the gap-junction beta-1 gene (GJB1).Case presentationThree young male patients from Southern China with pes cavus experienced multiple episodes of transient central nervous system (CNS) dysfunction. Three patients all had reversible posterior leukoencephalopathy as detected by brain diffusion-weighted magnetic resonance imaging (MRI-DWI). Nerve conduction velocity (NCV) showed sensorimotor polyneuropathy with mixed demyelinating and axonal features. Genetic testing indicated a c.425G > A (p.Arg142Glu) or c.563 C > T (p.Thr188Ile) or c.103G > C (p.Val35Leu) mutation in GJB1. The unique feature of this report is the identification of two novel mutations: c.563 C > T and sc.103G > C of the GJB1 gene detected in two families respectively. Another unique feature is that peripheral neuropathy symptoms in the three patients were insidious and found at the onset of CNS symptoms.ConclusionsPosterior leukoencephalopathy is involved in CMTX1 patients. The white matter changes in MRI of CMTX1 patients are reversible and recover later than CNS symptoms.

Analysis of GJB2 mutations and the clinical manifestation in a large Hungarian cohort.

Pathogenic variants of the gap junction beta 2 (GJB2) gene are responsible for about 50% of hereditary non-syndromic sensorineural hearing loss (NSHL). In this study, we report mutation frequency and phenotype comparison of different GJB2 gene alterations in Hungarian NSHL patients. The total coding region of the GJB2 gene was analyzed with Sanger or NGS sequencing for 239 patients with NSHL and 160 controls. Homozygous and compound heterozygous GJB2 mutations were associated with early onset serious clinical phenotype in 28 patients. In 24 patients, two deletion or nonsense mutations were detected in individuals with mainly prelingual NSHL. In compound heterozygous cases, a combination of deletion and missense mutations associated with milder postlingual NSHL. A further 25 cases harbored single heterozygous GJB2 mutations mainly associated with later onset, milder clinical phenotype. The most common mutation was the c.35delG deletion, with 12.6% allele frequency. The hearing loss was more severe in the prelingual groups. The mutation frequency of GJB2 in the investigated cohort is lower than in other European cohorts. The most serious cases were associated with homozygous and compound heterozygous mutations. In our cohort the hearing impairment and age of onset was not altered between in cases with only one heterozygous GJB2 mutation and wild type genotype, which may exclude the possibility of autosomal dominant inheritance. In early onset, severe to profound hearing loss cases, if the GJB2 analysis results in only one heterozygous alteration further next generation sequencing is highly recommended.

Intrathecal gene therapy in mouse models expressing CMT1X mutations.

Gap junction beta-1 (GJB1) gene mutations affecting the gap junction protein connexin32 (Cx32) cause the X-linked Charcot-Marie-Tooth disease (CMT1X), a common inherited neuropathy. Targeted expression of virally delivered Cx32 in Schwann cells following intrathecal injection of lentiviral vectors in the Cx32 knockout (KO) mouse model of the disease has led to morphological and functional improvement. To examine whether this approach could be effective in CMT1X patients expressing different Cx32 mutants, we treated transgenic Cx32 KO mice expressing the T55I, R75W or N175D CMT1X mutations. All three mutants were localized in the perinuclear compartment of myelinating Schwann cells consistent with retention in the ER (T55I) or Golgi (R75W, N175D) and loss of physiological expression in the non-compact myelin. Following intrathecal delivery of the GJB1 gene we detected the virally delivered wild-type (WT) Cx32 in non-compact myelin of T55I KO mice, but only rarely in N175D KO or R75W KO mice, suggesting dominant-negative effects of the R75W and N175D mutants but not of the T55I mutant on co-expressed WT Cx32. GJB1 treated T55I KO mice showed improved motor performance, lower ratios of abnormally myelinated fibers and reduction of inflammatory cells in spinal roots and peripheral nerves compared with mock-treated littermates. Either partial (N175D KO) or no (R75W KO) improvement was observed in the other two mutant lines. Thus, certain CMT1X mutants may interfere with gene addition therapy for CMT1X. Whereas gene addition can be used for non-interfering CMT1X mutations, further studies will be needed to develop treatments for patients harboring interfering mutations.

Diverse pattern of gap junction beta-2 and gap junction beta-4 genes mutations and lack of contribution of DFNB21, DFNB24, DFNB29, and DFNB42 loci in autosomal recessive nonsyndromic hearing loss patients in Hormozgan, Iran.

Background:We aimed to determine the contribution of four DFNB loci and mutation analysis of gap junction beta-2 (GJB2) and GJB4 genes in autosomal recessive nonsyndromic hearing loss (ARNSHL) in South of Iran.Materials and Methods:A total of 36 large ARNSHL pedigrees with at least two affected subjects were enrolled in the current study. The GJB2 and GJB4 genes mutations were screened using direct sequencing method. The GJB2 and GJB4 negative families were analyzed for the linkage to DFNB21, DFNB24, DFNB29, and DFNB42 loci by genotyping the corresponding STR markers using polymerase chain reaction-PAGE method.Results:We found a homozygous nonsense mutation W77X and a homozygous missense mutation C169W in 5.55% of studied families in GJB2 and GJB4 genes, respectively. Five heterozygous mutations including V63G, A78T, and R127H in GJB2 gene, and R103C and R227W in GJB4 gene were detected. We identified two novel variations V63G in GJB2 and R227W in GJB4. In silico analysis predicted that both novel variations are deleterious mutations. We did not unveil any linkage between DFNB21, DFNB24, DFNB29, and DFNB42 loci and ARNSHL among studied families.Conclusion:This is the first report of GJB2 and GJB4 mutations from Hormozgan population. According to the previous publications regarding GJB2 and GJB4 mutations, the distribution of the mutations is different from other parts of Iran that should be considered in primary health-care programs. Further investigations are needed to evaluate the contribution of other loci in ARNSHL subjects in South of Iran.

The role of alternative GJB2 transcription in screening for neonatal sensorineural deafness in Austria

Conclusion: Alterations within a novel putative Exon 1a within the gap junction beta 2 (GJB2) gene may play a role in the development of genetic hearing impairment in Austria.Objectives: Mutations in the GJB2 gene are the most common cause of hereditary sensorineural deafness. Genome-wide screening for alternative transcriptional start sites in the human genome has revealed the presence of an additional GJB2 exon (E1a). This study tested the hypothesis of whether alternative GJB2 transcription involving E1a may play a role in the development of congenital sensorineural deafness in Austria.Methods: GJB2 E1a and flanking regions were sequenced in randomized normal hearing control subjects and three different patient groups with non-syndromic hearing impairment (NSHI), and bioinformatic analysis was performed. Statistical analysis of disease association was carried out using the Cochran-Armitage test for trend.Results: A single change 2410 bp proximal to the translational start site (c.-2410T > C, rs7994748, NM_004004.5:c.-23 + 792T > C) was found to be significantly associated with the common c.35delG GJB2 mutation (p = .009). c.35delG in combination with c.-2410CC occurred at a 6.9-fold increased frequency compared to the control group. Additionally, one patient with idiopathic congenital hearing loss was found to be homozygous c.-2410CC.

Three novel mutations and genetic epidemiology analysis of the Gap Junction Beta 1 (GJB1) gene among Hungarian Charcot-Marie-Tooth disease patients

Pathogenic variants of the gap junction beta 1 (GJB1) gene are responsible for the Charcot-Marie-Tooth neuropathy X type 1 (CMTX1). In this study, we report the mutation frequency of GJB1 in 210 Hungarian CMT patients and the phenotype comparison between male and female CMTX1 patients. Altogether, 13 missense substitutions were found in the GJB1 gene. Among them, 10 have been previously described as pathogenic variants (p.Arg15Trp, p.Val63Ile, p.Leu89Val, p.Ala96Gly, p.Arg107Trp, p.Arg142Gln, p.Arg164Trp, p.Arg164Gln, p.Pro172Ala and p.Asn205Ser), while 3 were novel, likely pathogenic alterations (p.Val13Glu, p.Glu186Gly, p.Met194Ile). These variants were not present in controls and were predicted as disease causing by in silico analysis. The frequency of the variants was 6.7% in our cohort which refers to a common cause of hereditary neuropathy among Hungarian patients. In addition to the classical phenotype, CNS involvement was proved in 26.1% of the CMTX1 patients. GJB1 pathogenic alterations were found mainly in males but we also detected them in female probands. The statistical analysis of CMTX1 patients revealed a significant difference between the two genders regarding the age of onset, Charcot-Marie-Tooth neuropathy and examination scores.

GJB2 Mutation Spectrum and Genotype-Phenotype Correlation in 1067 Han Chinese Subjects with Non-Syndromic Hearing Loss.

Mutations in Gap Junction Beta 2 (GJB2) have been reported to be a major cause of non-syndromic hearing loss in many populations worldwide. The spectrums and frequencies of GJB2 variants vary substantially among different ethnic groups, and the genotypes among these populations remain poorly understood. In the present study, we carried out a systematic and extended mutational screening of GJB2 gene in 1067 Han Chinese subjects with non-syndromic hearing loss, and the resultant GJB2 variants were evaluated by phylogenetic, structural and bioinformatic analysis. A total of 25 (23 known and 2 novel) GJB2 variants were identified, including 6 frameshift mutations, 1 nonsense mutation, 16 missense mutations and 2 silent mutations. In this cohort, c.235delC is the most frequently observed pathogenic mutation. The phylogenetic, structural and bioinformatic analysis showed that 2 novel variants c.127G>T (p.V43L), c.293G>C (p.R98P) and 2 known variants c. 107T>C (p.L36P) and c.187G>T (p.V63L) are localized at highly conserved amino acids. In addition, these 4 mutations are absent in 203 healthy individuals, therefore, they are probably the most likely candidate pathogenic mutations. In addition, 66 (24 novel and 42 known) genotypes were identified, including 6 homozygotes, 20 compound heterozygotes, 18 single heterozygotes, 21 genotypes harboring only polymorphism(s) and the wild type genotype. Among these, 153 (14.34%) subjects were homozygous for pathogenic mutations, 63 (5.91%) were compound heterozygotes, and 157 (14.71%) carried single heterozygous mutation. Furthermore, 65.28% (141/216) of these cases with two pathogenic mutations exhibited profound hearing loss. These data suggested that mutations in GJB2 gene are responsible for approximately 34.96% of non-syndromic hearing loss in Han Chinese population from Zhejiang Province in eastern China. In addition, our results also strongly supported the idea that other factors such as alterations in regulatory regions, additional genes, and environmental factors may contribute to the clinical manifestation of deafness.

Bioinformatic Analysis of GJB2 Gene Missense Mutations.

Gap junction beta 2 (GJB2) gene is the most commonly mutated connexin gene in patients with autosomal recessive and dominant hearing loss. According to Ensembl (release 74) database, 1347 sequence variations are reported in the GJB2 gene and about 13.5% of them are categorized as missense SNPs or nonsynonymous variant. Because of the high incidence of GJB2 mutations in hearing loss patients, revealing the molecular effect of GJB2 mutations on protein structure may also provide clear point of view regarding the molecular etiology of deafness. Hence, the aim of this study is to analyze structural and functional consequences of all known GJB2 missense variations to the Cx26 protein by applying multiple bioinformatics methods. Two-hundred and eleven nonsynonymous variants were collected from Ensembl release 74, Leiden Open Variation Database (LOVD) and The Human Gene Mutation Database (HGMD). A number of bioinformatic tools were utilized for predicting the effect of GJB2 missense mutations at the sequence, structural, and functional levels. Some of the mutations were found to locate highly conserved regions and have structural and functional properties. Moreover, GJB2 mutations were also found to affect Cx26 protein at the molecular level via loss or gain of disorder, catalytic site, and post-translational modifications, including methylation, glycosylation, and ubiquitination. Findings, presented here, demonstrated the application of bioinformatic algorithms to predict the effects of mutations causing hearing impairment. I expect, this type of analysis will serve as a start point for future experimental evaluation of the GJB2 gene mutations and it will also be helpful in evaluating other deafness-related gene mutations.

Hearing loss associated with an unusual mutation combination in the gap junction beta 2 (GJB2) gene in a Chinese family

ObjectiveTo assess the molecular etiology of nonsyndromic sensorineural hearing loss (NSHL) in members of an affected Chinese family. MethodsCommon hearing-related genes including gap junction beta 2 (GJB2), SLC26A4, mitochondrial DNA 12S rRNA, GJB3 and GJB6 were examined in a family consisting of a normal hearing father, an NSHL-affected mother, one normal-hearing child and three NSHL-affected children. Specific primers were used in polymerase chain reactions to amplify the coding regions of the above genes from the peripheral blood DNA from each family member, and the genes were analyzed by direct sequencing. The subjects were evaluated for phenotypic characterization using audiometric testing and radiological examination of the inner ear. ResultsPathogenic mutations in the GJB2 gene were identified. The affected mother showed a heterozygous G→A transition at nucleotide 232, resulting in an alanine to threonine substitution at codon 78 (p.A78T), and the normal hearing father had a c.35insG insertion mutation. The three affected children displayed heterozygosity for the GJB2 mutations, showing a previously unreported combination of c.35insG and c.232G>A. ConclusionsThe GJB2 mutations account for a significant proportion of NSHL in affected individuals worldwide. Genetic and audiological data analysis of a Chinese family with NSHL revealed a novel c.35insG/c.232G>A compound heterozygous state. Our results highlight the complexity of the GJB2 genotypes and phenotypes.

G.P.86 X-linked Charcot–Marie–Tooth disease with c.22A>C missense mutation in the GJB1 gene in Koreans

<h2>Abstract</h2> X-linked Charcot–Marie–Tooth disease (CMT1X) is caused by gap junction beta 1 (GJB1) gene mutations, which encodes the connexin 32. Connexin 32 is an integral transmembrane protein expressed in peripheral nerve myelin. The frequency of CMT1X varies among different ethnic groups. The frequency in Koreans is low compared with those in Europeans. Herein we present one CMT1X patient with missense mutation in the GJB1 gene. The 27-year-old male presented with complaints of slowly progressive weakness beginning in the distal leg muscles. He had walked with waddling gait ever since he had started walking at 2years of age. He felt a weak hand grip around 8years of age. He could not run and have numbness on toe tips after 18years old. The family history revealed a more severe disease phenotype in affected males compared with affected females. Physical examination showed pes cavus, wasting of muscles below knee, and intrinsic hand muscle atrophy. Neurological examination demonstrated predominantly distal muscle weakness in the lower and upper limbs, decreased pinprick sensation in stocking-glove pattern, and areflexia. Electrophysiological study revealed sensori-motor polyneuropathy, but did not suggest sufficient evidence of demyelination or axonal degeneration. Gene analysis identified c.22A>C Missense Mutation in the GJB1 gene. We report a CMT1X patient having typical X-linked dominant inheritance and missense mutation in the GJB1 gene.

Identification of a p.R143Q dominant mutation in the gap junction beta-2 gene in three Chinese patients with different hearing phenotypes

Conclusions: p.R143Q mutation in GJB2 can cause mild to profound bilateral sensorineural hearing impairment. Although not common in Chinese patients with hearing loss, it is important to identify the specific phenotype and genotype correlations of the dominant mutation in GJB2. Objective: Mutations in the GJB2 gene are the most common cause of nonsyndromic autosomal recessive sensorineural hearing loss. A few mutations in GJB2 have also been reported to cause dominant nonsyndromic or syndromic hearing loss. However, dominant mutation in GJB2 is not common in Chinese populations. Methods: Three patients with hearing impairment from Chinese families are reported here. Temporal CT scan, complete physical (including skin and hair) and otoscopic examinations, and an audiological study, including tympanometry, auditory brainstem response (ABR), auditory steady-state response (ASSR), and 40 Hz auditory event-related potential (40 Hz-AERP), were carried out. The two exons of GJB2, the coding exons of SLC26A4, and mitochondrial 12S rRNA were sequenced. Results: Sequencing of GJB2 in two patients showed a heterozygous c.428G>A (p.R143Q) mutation, and the third patient was identified with c.299delAT and c.428G>A compound heterozygous mutation. Sequence analysis of the coding exons of SLC26A4 and mitochondrial 12S rRNA was performed but no sequence aberration or deletion was found.

C042 Auditory brainstem implantation outcomes: Longitudinal study results

To assess the molecular etiology of nonsyndromic sensorineural hearing loss (NSHL) in members of an affected Chinese family.Common hearing-related genes including gap junction beta 2 (GJB2), SLC26A4, mitochondrial DNA 12S rRNA, GJB3 and GJB6 were examined in a family consisting of a normal hearing father, an NSHL-affected mother, one normal-hearing child and three NSHL-affected children. Specific primers were used in polymerase chain reactions to amplify the coding regions of the above genes from the peripheral blood DNA from each family member, and the genes were analyzed by direct sequencing. The subjects were evaluated for phenotypic characterization using audiometric testing and radiological examination of the inner ear.Pathogenic mutations in the GJB2 gene were identified. The affected mother showed a heterozygous G → A transition at nucleotide 232, resulting in an alanine to threonine substitution at codon 78 (p.A78T), and the normal hearing father had a c.35insG insertion mutation. The three affected children displayed heterozygosity for the GJB2 mutations, showing a previously unreported combination of c.35insG and c.232G>A.The GJB2 mutations account for a significant proportion of NSHL in affected individuals worldwide. Genetic and audiological data analysis of a Chinese family with NSHL revealed a novel c.35insG/c.232G>A compound heterozygous state. Our results highlight the complexity of the GJB2 genotypes and phenotypes.

GJB1 gene mutations in suspected inflammatory demyelinating neuropathies not responding to treatment

It is generally accepted that while inflammatory demyelinating neuropathies often cause patchy demyelination resulting in conduction block, temporal dispersion and variation in conduction velocities, demyelinating hereditary neuropathies such as Charcot–Marie–Tooth...