Gap Junction Protein Beta-2 Gene Research Articles

Charcot-Marie-Tooth Disease with a Novel Variant in Gap Junction Protein Beta 1 Presenting with Visual Field Defects.

Pathogenic variants in Gap Junction Protein Beta 1 (GJB1) cause X-linked Charcot-Marie-Tooth (CMT) disease type 1 (CMTX1), which is a common hereditary motor and sensory neuropathy. A 45-year-old man presented with progressive muscle weakness, atrophy, sensory disturbance of all limbs from childhood, and visual field defects in both eyes at 40 years old. A segregation analysis revealed a novel variant, c.173C>A (p.P58H), in the GJB1 gene. Patients with variants at codon 58 in GJB1 showed clinically varied phenotypes, ranging from demyelinating neuropathy to cerebellar ataxia. This patient may represent one of the various clinical phenotypes of GJB1 variants.

Acute, Transient, Brain Lesions on Magnetic Resonance Imaging in X-linked Charcot-Marie-Tooth type 1 (P13-4.002)

<h3>Objective:</h3> NA <h3>Background:</h3> CMTX1 is an X-linked dominant form of hereditary sensorimotor polyneuropathy. It is caused by mutations in the gap junction protein beta 1(GJB1) gene on chromosome Xq13.1, which encodes connexin 32 protein. CNS can be affected and lead to transient or persistent CNS symptoms including dysarthria, dysphagia, hemiparesis or quadriparesis, ataxia, aphasia, and encephalopathy. <h3>Design/Methods:</h3> <h3>Case Report:</h3> A 22-year-old man presented with acute onset left facial droop, dysarthria and left upper extremity weakness. Two weeks prior he experienced a one-day episode of gastroenteritis. Neurological examination showed weakness in the left lower face, distal muscle weakness in toe extension, ankle dorsiflexion and hand intrinsic muscles, absent lower extremity reflexes, diminished vibration and temperature senses in length-dependent pattern, high-arched feet and hammertoes. Family history of early onset polyneuropathy, never genetically tested. Brain MRI showed marked and symmetric restricted diffusion lesions involving bilateral fronto-parietal white matter, corpus callosum and posterior limb of internal capsule without contrast enhancement. CSF analysis was unremarkable. The patient was given pulse steroid therapy for possible demyelinating disease, his symptoms completely resolved within 48 hours. Two prior similar symptoms, one was diagnosed as acute disseminated encephalomyelitis (ADEM) and treated with steroids. Brain MRI of these two episodes showed similar restricted diffusion abnormalities. Repeat brain MRI seven months after the second episode showed complete resolution of restricted diffusion lesions. Leukodystrophy genetic panel was negative. Genetic testing showed hemizygous pathogenic mutation c.491G&gt;A in GJB1 gene, associated with X-linked Charcot-Marie-Tooth disease - CMTX1. <h3>Results:</h3> NA <h3>Conclusions:</h3> Young patients with history of polyneuropathy presenting with acute CNS symptoms with bilateral white matter and corpus callosum lesions, CMTX1 should be included in the differential diagnosis. Upon confirmation of CMTX1 diagnosis, patient reassurance is important as well as education regarding potential provoking factors that lead to CNS involvement. <b>Disclosure:</b> Dr. Altarazi has nothing to disclose. Dr. Chen has nothing to disclose. Dr. Sankaraneni has nothing to disclose.

4‐octyl itaconate improves the viability of D66H cells by regulating the KEAP1‐NRF2‐GCLC/HO‐1 pathway

As a novel nuclear factor E2-related factor 2 (NRF2) activator, the itaconate has shown significant therapeutic potential for oxidative stress diseases. However, its role in Vohwinkel syndrome in relation to the gap junction protein beta 2 (GJB2) mutation is still unclear. This study aimed at investigating the effect of 4-octyl itaconate (OI) on HaCaT and D66H cells and clarify its potential mechanism in vitro. The optimal concentration and treatment time of OI on HaCaT cells and D66H cells were determined by CCK-8 and LDH experiments. The effect of OI on cell proliferation was detected by EdU staining and FACS analysis of PI, while the apoptosis was evaluated by TUNEL staining and FACS analysis of Annexin V. The ROS staining was performed, and the levels of SOD, MDA, GSH and GSH/GSSG were detected to evaluate the effect of OI on oxidative damage induced by D66H-type mutation. CO-IP, Western blot, immunofluorescence and qPCR analyses were employed to detect the activation of KEAP1-NRF2-GCLC/HO-1 pathway by OI. Finally, sh-NRF2 was used to confirm the activation of this pathway by OI. Results showed that OI could improve the cell viability decreased by GJB2 gene mutation by regulating the balance between cell growth and apoptosis induced by oxidative damage. Furthermore, this alleviation process was regulated by the KEAP1-NRF2-HO-1/GCLC pathway. In conclusion, OI could improve the viability of HaCaT and D66H cells via regulating the KEAP1-NRF2-GCLC/HO-1 pathway, which provided a wide spectrum of potential targets for effective therapeutic treatments of Vohwinkel syndrome in the clinic.

GJB2 mutations in Iranian Azeri population with autosomal recessive nonsyndromic hearing loss (ARNSHL): First report of c.238 C>A mutation in Iran.

ObjectiveAutosomal‐recessive nonsyndromic hearing loss (ARNSHL) is a heterogeneous genetic disorder. Mutations in the gap junction protein beta 2 (GJB2) gene, encoding connexin 26, are a significant cause of ARNSHL in different ethnic groups. This study aimed to identify the frequency and type of GJB2 mutations in the Iranian Azeri population.MethodsFifty unrelated families presenting ARNSHL in Ardabil Province, the northwest of Iran, were studied to determine the frequency and type of GJB2 mutations leading to ARNSHL. ARMS‐PCR screened all DNA samples to detect c.35delG; p. Gly12Val mutation. In addition, normal samples for c.35delG; p. Gly12Val were analyzed by direct sequencing for other GJB2 mutations.ResultOf the fifty families, 13 (26%) showed a GJB2 gene mutation, with c.35delG; p. Gly12Val mutation was the most prevalent one that occurred in eight (61.5%) out of the 13 families. Of the families, two were homozygous for c.358‐360delGAC; p. Glu120del mutation, and one was homozygous for c.290dupA; p. Tyr97Ter and c.299–300delAT; p. His100Arg mutations. Also, we detected a novel mutation, c.238C>A; p. Gln80lys, in one of the families.ConclusionOur findings are comparable to previous studies, indicating c.35d3lG; p. Gly12Val mutation in the GJB2 gene is the most common cause of GJB2‐related hearing loss in the Iranian Azeri population. Furthermore, our study highlights the significance of ARNSHL screening programs of live births based on local population data in Iran.

Gap Junction Protein Beta 2 Gene Variants and Non-Syndromic Hearing Impairment among Couples Referred For Prenatal Diagnosis in the Northeast of Iran.

Hearing impairment is a complex medical disorder which has genetic and non-genetic causes. Gap Junction Protein Beta 2 (GJB2) gene variant is a well-known disease-causing gene among patients with hearing impairment. The frequencies of genetic variants in the GJB2 gene are different in each population. This study aimed to discuss the GJB2 gene status in an Iranian population with hearing impairment who referred for prenatal testing. This cross-sectional study was conducted in a genetic laboratory affiliated with Mashhad Jahad Daneshgahi, Mashhad, Iran. A total number of 21 bilateral hearing impaired patients were enrolled in this study. The exons for target GJB2 gene were amplified by polymerase chain reaction after the confirmation of the hearing impairment and the exclusion of the acquired causes of hearing loss. The c.35delG and c.79G>A variants were the first and second most common variants in the study population, respectively. The mean age of the patients was 27.5 (8.7) years and 12 cases were male. There was no significant association between hearing impairment degree and age and heterozygosity status (P=0.376 and P=.074 respectively). The c.35delG and c.79G>A variants were determined as the first and second most common variants in the GJB2 gene, respectively. The mean age of 26 years in this study population indicates the late referral for the evaluation of the hearing difficulty. Furthermore, it highlights the further need to encourage families with a history of hearing impairment to engage in genetic counseling.

Detection of single-nucleotide polymorphism Gap junction protein Beta-2 genes in deaf schoolchildren of javanese population in Surabaya, Indonesia

Background: Genetic factors account for about 50%–75% responsible for hearing loss. The existence of single-nucleotide polymorphism (SNP) as genetic factors that affect hereditary hearing loss. The widely studied SNP was the gap junction protein beta-2 (GJB2) gene encoding the gap junction beta-2 protein (connexin26) that found in cochlea and required to convert sound waves into electrical nerve impulse. This study was aimed to detect the SNP GJB2 gene of hereditary hearing loss patients from Javanese population in Surabaya, Indonesia. Methods: The design of this study was a cross-sectional, analytic observational. The participant was taken randomly among the students from a deaf School in Surabaya. The questionnaire was completed by the parents of the deaf children. Blood sampling was taken from venous peripheral blood. DNA was extracted and amplified on GJB2 gene area by polymerase chain reaction (PCR). The positive results of PCR were processed further for sequencing. The sequencing results were analyzed to detect the GJB2 gene SNP with reference sequence/rs-80338939. Results: A total of 22 children participated in this study; all were profound sensorineural hearing loss (SNHL). The hereditary hearing loss was obtained with fewer in five children (22.73%), who had a history of hearing loss in their family. It was compared to 17 children (77.27%) who had no family history of hearing loss. It was found that the nucleotide variation in nucleotide number 8473 of GJB2 gene as much as 3 (13.64%) out of 22 children in hereditary hearing loss patients in Deaf School Type B Surabaya. Conclusions: This study did not found any SNP GJB2 gene (rs-80338939) of hereditary hearing loss patients from the Javanese population in Surabaya, Indonesia. There was the nucleotide substitution G to A in nucleotide number 8473 of GJB2 gene, which indicated the change of amino acid code genetic code table (valine) to amino acid code genetic code table (isoleucine). It may as the cause of SNHL.

Mutations in GJB2 as Major Causes of Autosomal Recessive Non-Syndromic Hearing Loss: First Report of c.299-300delAT Mutation in Kurdish Population of Iran.

Background and ObjectivesAutosomal recessive non-syndromic hearing loss (ARNSHL) with genetic origin is common (1/2000 births). ARNSHL can be associated with mutations in gap junction protein beta 2 (GJB2). To this end, this cohort investigation aimed to find the contribution of GJB2 gene mutations with the genotype-phenotype correlations in 45 ARNSHL cases in the Kurdish population.Subjects and MethodsGenomic DNA was extracted from a total of 45 ARNSHL families. The linkage analysis with 3 short tandem repeat markers linked to GJB2 was performed on 45 ARNSHL families. Only 9 of these families were linked to the DFNB1 locus. All the 45 families who took part were sequenced for confirmation linkage analysis (to perform a large project).ResultsA total of three different mutations were determined. Two of which [c.35delG and c.-23+1G>A (IVS1+1G>A)] were previously reported but (c.299-300delAT) mutation was novel in the Kurdish population. The homozygous pathogenic mutations of GJB2 gene was observed in nine out of the 45 families (20%), also heterozygous genotype (c.35delG/N)+(c.-23+1G>A/c.-23+1G>A) were observed in 4/45 families (8.8%). The degree of hearing loss (HL) in patients with other mutations was less severe than patients with c.35delG homozygous mutation (p<0.001).ConclusionsOur data suggest that GJB2 mutations constitute 20% of the etiology of ARNSHL in Iran; moreover, the c.35delG mutation is the most common HL cause in the Kurdish population. Therefore, these mutations should be included in the molecular testing of HL in this population.

A novel compound heterozygous mutation in the GJB2 gene is associated with non-syndromic hearing loss in a Chinese family.

Autosomal recessive (AR) non-syndromic hearing loss (NSHL) is the most common form of hereditary deafness. Mutations in the gap junction protein beta 2 (GJB2) gene encoding connexin 26 (Cx26) account for about 50% of cases of ARNSHL. In the current study, a combination of exome sequencing and Sanger sequencing in a Chinese Dong family with ARNSHL allowed identification of a novel compound heterozygous mutation c.240G>C(p. Q80H)/C.109G>A(p.V37I) in exon 2 of the GJB2 gene, which co-segregated with the disease phenotype in this family and was not evident in 100 healthy controls. Bioinformatic analysis revealed that the two mutations in the GJB2 gene were probably pathogenic. Results indicated that the compound heterozygous variants, p.Q80H and p.V37I, in the GJB2 gene are associated with ARNSHL. The Q80H variant was initially identified in patients of Dong Chinese origin with NSHL. The current results broaden the spectrum of GJB2 mutations responsible for NSHL and have important implications for molecular diagnosis, treatment, and genetic counseling for this family.

Prevalence of GJB2 Mutations in Affected Individuals from United Arab Emirates with Autosomal Recessive Nonsyndromic Hearing Loss.

Mutations in the gap junction protein beta 2 (GJB2) gene are responsible for more cases of nonsyndromic recessive hearing loss than any other gene. The purpose of our study was to evaluate the prevalence of GJB2 mutations among affected individuals from United Arab Emirates (UAE). There were 50 individuals diagnosed with hereditary hearing loss and 120 healthy individuals enrolled in the study. The Sanger sequencing method was used to screen the GJB2 coding region in all affected individuals. The c.-1G>A variant was determined by the polymerase chain reaction-restriction fragment length polymorphism method in normal individuals. Nine cases with bi-allelic mutations and three cases with mono-allelic mutations were detected in 12 out of 50 patients (24%). The homozygous mutation c.35delG was identified as the cause of hearing loss in six participants (12%). The mutation c.506G>A was identified in three affected individuals (6%). The allelic frequency (14%) and low percentage of individuals that were homozygous (2%) for the c.35delG mutation suggest that there are other genes responsible for nonsyndromic deafness in the UAE population. The results reported here are a preliminary step in collecting epidemiological data regarding autosomal recessive nonsyndromic hearing loss related to GJB2 gene mutations among the UAE population. The c.35delG mutation of the GJB2 gene is the most frequently seen causative mutation in the UAE and is followed by the p.Cys169Tyr mutation.

Long Term Speech Perception Outcomes of Cochlear Implantation in Gap Junction Protein Beta 2 Related Hearing Loss

Background and ObjectivesThe mutation of the gap junction protein beta 2 (GJB2) gene is the predominant cause of autosomal recessive non-syndromic hearing loss. The purpose of this study was to evaluate the speech perception outcome after cochlear implantation according to the presence of a GJB2 mutation.Subjects and MethodsDuring the period from March 2004 to February 2005, 38 patients underwent cochlear implantation at Asan Medical Center. Genetic factors and speech perception were evaluated in all subjects, and the patients were grouped according to the presence of a GJB2 mutation. The two groups were carefully matched according to the age at cochlear implantation. We analyzed four mutations in the GJB2 gene: 35delG, 167delT, 235delC, and E114G. Speech perception outcomes were measured using the open set, 1 and 2 syllables, the comprehension test, the Meaningful Auditory Integration Scale, the categories of auditory performance, and the Speech Intelligibility Rating scores. The evaluations were performed before the operation, 6 and 12 months thereafter, and then annually up to nine years after cochlear implantation.ResultsFifteen patients had bi-allelic GJB2 mutations (11 with E114G and 4 with 235delC), whereas the remaining 23 had wild type alleles. For the age-matched analysis, 14 patients were selected and divided into two groups of 7 subjects each: GJB2 mutation and no mutation (i.e., deafness of unknown origin). Overall, all patients showed improvement of speech perception outcome after cochlear implantation. There was no difference in the improvement between patients with and without GJB2 mutations at the 5-year and 9-year follow up. The pattern of improvement throughout the duration of the follow-up also showed no difference between the two groups.ConclusionsSimilar outcomes of speech perception are expected after cochlear implantation in pediatric patients with or without GJB2 mutation.

Identification of a novel homozygous mutation in transmembrane channel like 1 (TMC1) gene, one of the second-tier hearing loss genes after GJB2 in India.

Background & objectives:Hearing impairment is a common and heterogeneous sensory disorder in humans. Among about 90 genes, which are known to be associated with hearing impairment, mutations in the GJB2 (gap junction protein beta 2) gene are the most prevalent in individuals with hereditary hearing loss. Contribution of the other deafness-causing genes is relatively poorly understood. Here, we present our findings on two families with transmembrane channel like 1 (TMC1) gene variants of the 47 families with nonsyndromic hearing loss (NSHL) studied.Methods:Forty seven families including 26 consanguineous families with at least two hearing impaired children and one normal hearing child and 21 non-consanguineous families having at least three hearing impaired children and one normal hearing child were enrolled for this study. Genetic linkage studies were carried out in 41 families that were GJB2 (Connexin 26) negative. Seven polymorphic short tandem repeat markers at the DFNB7/11 locus were studied employing fluorescently labelled markers.Results:A novel homozygous missense mutation c.1283C>A (p.Ala428Asp) was identified co-segregating with hearing loss. This change results in substitution of a highly conserved polar alanine to a charged aspartic acid and is predicted to be deleterious. In addition, a previously reported nonsense mutation, p.R34X in TMC1, was found.Interpretation & conclusions:While mutations in TMC1 are not as common a cause of NSHL as those in GJB2, TMC1 should be considered for diagnostic investigations in cases of NSHL in GJB2-negative families.

Mutation Analysis of Gap Junction Protein Beta 1 and Genotype-Phenotype Correlation in X-linked Charcot-Marie-Tooth Disease in Chinese Patients.

Background:Among patients with Charcot–Marie–Tooth disease (CMT), the X-linked variant (CMTX) caused by gap junction protein beta 1 (GJB1) gene mutation is the second most frequent type, accounting for approximately 90% of all CMTX. More than 400 mutations have been identified in the GJB1 gene that encodes connexin 32 (CX32). CX32 is thought to form gap junctions that promote the diffusion pathway between cells. GJB1 mutations interfere with the formation of the functional channel and impair the maintenance of peripheral myelin, and novel mutations are continually discovered.Methods:We included 79 unrelated patients clinically diagnosed with CMT at the Department of Neurology of the Chinese People's Liberation Army General Hospital from December 20, 2012, to December 31, 2015. Clinical examination, nerve conduction studies, and molecular and bioinformatics analyses were performed to identify patients with CMTX1.Results:Nine GJB1 mutations (c.283G>A, c.77C>T, c.643C>T, c.515C>T, c.191G>A, c.610C>T, c.490C>T, c.491G>A, and c.44G>A) were discovered in nine patients. Median motor nerve conduction velocities of all nine patients were < 38 m/s, resembling CMT Type 1. Three novel mutations, c.643C>T, c.191G>A, and c.610C>T, were revealed and bioinformatics analyses indicated high pathogenicity.Conclusions:The three novel missense mutations within the GJB1 gene broaden the mutational diversity of CMT1X. Molecular analysis of family members and bioinformatics analyses of the afflicted patients confirmed the pathogenicity of these mutations.

Role of Specificity Protein-1 and Activating Protein-2 Transcription Factors in the Regulation of the Gap Junction Protein Beta-2 Gene in the Epididymis of the Rat.

In prepubertal rats, connexin 26 (GJB2) is expressed between adjacent columnar cells of the epididymis. At 28 days of age, when columnar cells differentiate into adult epithelial cell types, Gjb2 mRNA levels decrease to barely detectable levels. There is no information on the regulation of GJB2 in the epididymis. The present study characterized regulation of the Gjb2 gene promoter in the epididymis. A single transcription start site at position −3829 bp relative to the ATG was identified. Computational analysis revealed several TFAP2A, SP1, and KLF4 putative binding sites. A 1.5-kb fragment of the Gjb2 promoter was cloned into a vector containing a luciferase reporter gene. Transfection of the construct into immortalized rat caput epididymal (RCE-1) cells indicated that the promoter contained sufficient information to drive expression of the reporter gene. Deletion constructs showed that the basal activity of the promoter resides in the first −230 bp of the transcriptional start site. Two response elements necessary for GJB2 expression were identified: an overlapping TFAP2A/SP1 site (−136 to −126 bp) and an SP1 site (−50 bp). Chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assays confirmed that SP1 and TFAP2A were bound to the promoter. ChIP analysis of chromatin from young and pubertal rats indicated that TFAP2A and SP1 binding decreased with age. SP1 and TFAP2A knockdown indicated that SP1 is necessary for Gjb2 expression. DNA methylation did not appear to be involved in the regulation of Gjb2 expression. Results indicate that SP1 and TFAP2A regulate Gjb2 promoter activity during epididymal differentiation in rat.

Compound heterozygous GJB2 mutations associated to a consanguineous Han family with autosomal recessive non-syndromic hearing loss

Conclusion: This study demonstrates that the gap junction protein beta-2 gene (GJB2) p.R32C and p.L79Cfs*3 variants are associated to a consanguineous family with autosomal recessive non-syndromic hearing loss (ARNSHL). The p.R32C variant is found for the first time in the NSHL patients of Han Chinese origin. The finding sheds new light on the accurate genetic diagnosis and counseling for the family. Objective: ARNSHL is a highly heterogeneous genetic disease. ARNSHL usually displays non-progressive congenital or pre-lingual deafness. In this study, the aim is to detect the disease-causing mutation(s) in a Han family with ARNSHL. Methods: A consanguineous Han family with ARNSHL was enrolled. Two hundred ethnicity-matched unrelated subjects without any hearing impairments were used as normal controls. Exome sequencing and Sanger sequencing were applied to identify the causative mutation in the ARNSHL family. Results: Compound heterozygous variants c.94C > T (p.R32C) and c.235delC (p.L79Cfs*3) in the GJB2 gene were identified in the two patients of the ARNSHL family, and the heterozygous GJB2 c.94C > T and c.235delC variants were identified in his unaffected father and mother, respectively. The two variants in the GJB2 gene were absent in the 200 unrelated controls.

The Prevalence of Gap Junction Protein Beta 2 (GJB2) Mutations in Non Syndromic Sensorineural Hearing Loss in Çukurova Region.

To date, studies in all populations showed that mutations in the gene of Gap junction protein beta 2 (GJB2) play an important role in non-syndromic autosomal recessive congenital hearing loss. The aim of this study was to evaluate GJB2 gene of patients with hearing loss in our region using deoxyribonucleic acid (DNA) sequencing method and to demonstrate region-specific mutation and polymorphism distribution. Patients who had bilateral severe sensorineural non-syndromic hearing loss identified by audiologic evaluation were included. Peripheral blood samples were collected and the GJB2 gene exon1 and exon 2 regions were amplified by polymerase chain reaction (PCR). Obtained PCR products were sequenced by the DNA sequence analysis method (SeqFinder Sequencing System; ABI 3130; Foster City, CA, USA) and analyzed using the SeqScape software. Of the 77 patients, 16 had homozygous or heterozygous mutation. The mutation of 35delG, which is known as the most frequent mutation of GJB2 gene, was also the most frequently seen mutation at a ratio of 5.5% in patients with hearing loss in our region; this was followed by the V27I mutation. As this is the first study conducted by sequence analysis in our region, it was worth to be presented in terms of showing the distribution of mutation.

A novel mutation in GJB1 (c.212T>G) in a Chinese family with X-linked Charcot–Marie–Tooth disease

Gap junction protein beta 1 (GJB1) gene mutations lead to X-linked Charcot–Marie–Tooth (CMTX) disease. We investigated a Chinese family with CMTX and identified a novel GJB1 point mutation. Clinical and electrophysiological features of the pedigree were examined, and sequence alterations of the coding region of GJB1 that encode connexin32 were determined by direct sequencing. Sequence alignment of the mutation site was performed using Clustal W. Mutation effects were analysed using PolyPhen-2, SIFT and Mutation Taster software. The three-dimensional structures of the mutant and wild-type proteins were predicted by modeling with SWISS MODEL online software. The affected family members displayed typical Charcot–Marie–Tooth phenotypes, but phenotypic heterogeneity was observed. Nerve conduction velocities of all affected patients were slow. Sequencing of GJB1 revealed a heterozygous T>G missense mutation at nucleotide 212 in the proband, the proband’s mother and the proband’s daughter. The affected male sibling of the proband displayed a hemizygous missense mutation with T>G transition at the identical position on the GJB1 gene. This mutation resulted in an amino acid change from isoleucine to serine that was predicted to lead to tertiary structural alterations that would disrupt the function of the GJB1 protein. A novel point mutation in GJB1 was detected, expanding the spectrum of GJB1 mutations known to be associated with CMTX.

Distortion-product otoacoustic emissions at ultra-high frequencies in parents of individuals with autosomal recessive hearing loss

To evaluate the cochlear function of parents of individuals with autosomal recessive gene Gap Junction Protein Beta-2 hearing loss by ultra-high frequencies distortion-product otoacoustic emissions (DPOAEs), compared with responses of a control group matched for age and gender. We studied 56 subjects aged from 20 to 58 years, divided into two groups. The study group comprised 28 parents of hearing-impaired patients due to autosomal recessive inheritance, 14 females aged 20.0-55.0 years (mean 32.8 years) and 14 males aged 20.0-58.0 years (mean 35.2 years). Control group was composed of normal hearing individuals, 14 males and 14 females age-matched to the study group. The subjects underwent tests for audiometry, tympanometry, and DPOAE in the frequency range of 9.000-16.000 Hz. We found 64.3% of normal results of DPOAE in the study group compared to 91.1% in the control. There were significant differences between groups in the ears and DPOAE responses, and the mean level of response was in 10 dBNPS in study group and 14 dBNPS in the control. The Pearson's correlation between age and DPOAE in ultra-high frequencies showed no statistical significance. DPOAE at ultra-high frequencies were able to identify individuals from both groups, suggesting that heterozygous individuals for the Gap Junction Protein Beta-2 gene mutation may have damage to the cochlear function before clinical manifestation in audiometry.

Non-Syndromic Autosomal Recessive Deafness in Gaza Strip: A Study of Five GJB2 Gene Mutations

Hearing loss is a common, pan-ethnic and highly heterogeneous sensory disorder with an incidence of around 1 in 1000 infants. Genetic causes are thought to be responsible for more than 60% of the cases with the majority of non-syndromic hearing impairment being inherited in an autosomal recessive pattern. The gene that is most frequently mutated in autosomal recessive non-syndromic hearing loss (ARNSHL) is gap junction protein beta-2 (GJB2) which codes for connexin 26 (Cx26). Cx26 plays a key role in potassium homeostasis, which is essential for sound transduction. The aim of this study was to determine the common GJB2 gene mutations in 70 patients suffering from ARNSHL in Gaza strip. The patients were screened for five GJB2 gene mutations namely, c.35delG, c.167delT, c.-23+1G>A, c.229T>C (p.Trp77Arg) and c.235delC. Study results revealed that GJB2 mutations account for at least 35.7% of the ARNSHL with mutant allele frequency of 0.4%. The most frequently encountered mutation was c.35delG which accounted for 35.7% of the ARNSHL cases in either homozygous (34.3%) or heterozygous (1.4%) form and represented about 80.5% of all the detected mutations. The second most frequent mutation was c.235delC which was found only in heterozygous form. The third mutation was c.-23+1G>A which was identified in only one subject (1.4%) in a compound heterozygous form along with c.35delG. The c.167delT and p.Trp77Arg mutations were not observed in our patients. We conclude that there is a significant contribution of GJB2 mutations to congenital ARNSHL in the Palestinian population of Gaza strip. Screening for GJB2 mutations particularly, c.35delG, c.235delC and c.-23+1G>A should be offered to ARNSHL patients to confirm diagnosis of their congenital deafness, to deliver proper genetic counseling for the affected individuals and their families and to help them benefit from prenatal and pre-implantation genetic diagnosis.

Cochlear implantation effect on deaf children with gap junction protein beta 2 gene mutation

Background The popularization and promotion of gene diagnosis technology makes it possible to detect deafness genes for children with congenital hearing impairment, and the proportion of gap junction protein beta 2 (GJB2) gene mutations in cochlear implant patients is 26.5%. We did follow-up evaluation on auditory rehabilitation effect for all 31 deaf children with GJB2 gene mutation after cochlear implantation to provide a reference for such patients. Methods Application of “the genetic deafness gene chip detection kit” and “gene complete sequence analysis” were applied to conduct detection on common genetic deafness gene mutation hotspots of the hearing impaired children with cochlear implantation. To conduct auditory rehabilitation effect evaluation on all 31 cases of patients with GJB2 genetic deafness after 3, 6 and 12 months of the operation respectively. The single factor repeated measure analysis of variance (ANOVA) was applied to analysis whether there were significant difference among the results of initial consonant of a Chinese syllable recognition at 3 different stages after the operation, the results of vowel of a Chinese syllable recognition at 3 different stages after the operation, and the results of two-syllable recognition at 3 different stages after the operation. Results The 235delC is the high-incidence mutational site in 31 cases of patients with GJB2 genetic deafness, and the total detection rate is up to 90.3% (28/31). There were significant differences in the initial consonant and the vowel of a Chinese syllable recognition rate, and the two-syllable recognition rates at 3, 6, and 12 months after the operation (P &lt;0.01). Conclusion Cochlear implantation is a safe and effective measure for auditory reconstruction, enabling patients with GJB2 hereditary severe sensorineural deafness to achieve auditory speech recognition effectively.

Novel connexin 30 and connexin 26 mutational spectrum in patients with progressive sensorineural hearing loss

Mutations in the gap junction protein beta-2 gene ('GJB2') are known to be responsible for mild to profound congenital and late-onset hearing loss. This study aimed to investigate the molecular basis of progressive hearing loss compared with non-progressive hearing loss. Following clinical otorhinolaryngological evaluation, a genetic analysis was performed in a cohort of 72 patients with progressive sensorineural hearing loss. Pathological genotypes were established in 16 patients (22.2 per cent). Six different gap junction protein beta-2 gene mutations were detected in 15 patients, with the c.35delG mutation responsible for 56 per cent of the mutated alleles. A novel gap junction protein beta-6 gene ('GJB6') mutation (p.Met203Val) was observed in one patient with mild progressive hearing loss. Analyses of gap junction protein beta-2 and -6 genes revealed that similar pathological genotypes, occurring with similar frequencies, were responsible for progressive hearing loss, compared with reported genotypes for non-progressive hearing loss patients. Thus, genotype cannot be used to differentiate non-progressive from progressive hearing loss cases; in this study, patients both with and without an established pathological genotype had a similar clinical course.