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Abstract Background The 235delC mutation of GJB2 gene is considered as a risk factor for the non-syndromic hearing loss (NSHL), and a significant difference in the frequency and distribution of the 235delC mutation has been described world widely. Methods A systematic review was performed by means of a meta-analysis to evaluate the influence of the 235delC mutation on the risk of NSHL. A literature search in electronic databases using keywords “235delC”, “GJB2” associated with “carrier frequency” was conducted to include all papers from January 1999 to June 2011. A total of 36 papers were included and there contained 13217 cases and 6521 controls derived from Oceania, American, Europe and Asian. Results A remarkable heterogeneity between these studies was observed. The combined results of meta-analysis showed that the 235delC mutant increased the risk of NSHL (OR = 7.9, 95%CI 4.77 ~ 13.11, P OR = 12.05, 95%CI 8.33~17.44, P OR = 10.36, 95%CI: 4.68~22.96, Z = 1.68, P >0.05). Conclusions The 235delC mutation of GJB2 gene increased the risk of NHSL in the East Asian and South-east Asian populations, but non-significantly associated with the NSHL susceptibility in Oceania and European populations, suggesting a significant ethnic specificity of this NSHL-associated mutation.

Objective: To explore the molecular genetic characterization of two Chinese families with aminoglycoside-induced and non-syndromic hearing loss (NSHL). Design:Clinical evaluations, sequence analysis of mitochondrial DNA (mtDNA) as well as two nuclear genes TRMU and MTO1 encoding mitochondrial proteins. Study sample: Two Chinese families with aminoglycoside-induced and NSHL. Results: Clinical evaluations revealed incomplete penetrance (28.6% vs. 40.0%) and variable phenotype of hearing losses between two families. When the effect of aminoglycosides was excluded, the penetrances were both 0%. Sequence analysis of mitochondrial genomes showed a homoplasmic 1494C > T mutation in the12S rRNA gene (MT-RNR1) in all maternal relatives, as well as distinct sets of mtDNA polymorphism belonging to Eastern Asian haplogroups D4j and D5a2, respectively. However, none of these mtDNA variants was highly evolutionarily conserved and implicated to have functional significance. No mutations were identified in either TRMU or MTO1 gene. Conclusions: Mitochondrial 1494C> T mutation is the molecular basis responsible for the NSHL of two families, and the use of aminoglycoside antibiotics can worsen the hearing of the mutation carriers. Our results indicate the importance of a systematic screening for the mitochondrial 1494C > T mutation in Chinese subjects in the prevention of aminoglycoside-induced and non-syndromic hearing loss. [ABSTRACT FROM AUTHOR]

Objective: To detect genetic cause of two Chinese siblings (patient 1 and 2) with Pendred syndrome. Design: Patients and their parents underwent clinical and genetic evaluations. To identify genetic mutations, sequencing of SLC26A4 was carried out. Study sample: Two siblings and their parents. Results: Clinical evaluations showed that patient 1 suffered from bilateral postlingual progressive sensorineural hearing loss with enlarged vestibular aqueduct and slight diffuse multinodular goiter with euthyroid, and patient 2 suffered from bilateral prelingual progressive sensorineural hearing loss with enlarged vestibular aqueduct and no goiter with euthyroid. Furthermore, the sequence analysis of SLC26A4 indicated that either of the two siblings presented a compound heterozygote for the c.919A>G mutation in the splice site of intron 7 and for the c.1548insC mutation in exon 14. Their mother was a heterozygous carrier of the splice site mutation in intron 7, and their father was a heterozygous carrier of the insertion mutation in exon 14. Conclusions: Mutation analysis identified a compound heterozygous mutation (c.919A>G/c.1548insC) in SLC26A4 in two Chinese siblings with Pendred syndrome. Also, c.1548insC was first reported in the Chinese population. Although the two siblings from the same family carried the same genotype, they presented different phenotypes. [ABSTRACT FROM AUTHOR]

ABSTRACT G protein‐coupled receptor‐associated sorting protein 2 (GPRASP2) has been identified as the causative gene for X‐linked recessive syndromic hearing loss (SHL) in our previous study. However, the role of GPRASP2 in auditory function remains unclear. The present study demonstrated that Gprasp2 overexpression in mouse organoids promoted the proliferation of supporting cells (SCs), which was mainly mediated by the Hedgehog signalling pathway. Meanwhile, GPRASP2 promoted hair cell (HC) formation from SCs via β‐catenin signalling. In addition, GPRASP2 deficiency resulted in increased lysosomal degradation of SMO protein, leading to decreased expression of β‐catenin and the Hedgehog pathway transcription factor GLI1. In neomycin‐treated mouse cochlear explant, the smoothened agonist (SAG) recured the HC loss and further facilitated AAV‐ie‐Gprasp2 to promote the proliferation of SCs and formation of HCs. Our results suggested that GPRASP2 could be a potential candidate for gene therapy in the regeneration of HCs. [ABSTRACT FROM AUTHOR]

Mutations in the GJB2 gene are responsible for up to 50% of cases of non-syndromic recessive hearing loss, with c.35delG, c.167delT and c.235delC being the predominant mutations in many world populations. However, a large number of rare mutations in this gene may also contribute to hearing loss. The aim of the present study was to conduct a clinical and molecular characterization of a Chinese family with non-syndromic hearing loss. Sequence analysis of the GJB2 gene led to the identification of a novel compound heterozygous mutation c.257C>G (p.T86R)/c.605ins46 in two profoundly deaf siblings whose hearing parents were each heterozygous, either for the c.257C>G (paternal) or for the c.605ins46 (maternal) mutations. Both c.257C>G and c.605ins46 are rare GJB2 mutations that have previously been reported to segregate with autosomal recessive hearing loss exclusively in East Asian populations. To study the pathogenic effect of the compound heterozygous mutation, a three-dimensional model was constructed and Anolea mean force potential energy was predicted for a bioinformatic structural analysis. HEK293 cells were used to study the pathogenic effect of mutant connexin 26 proteins. The results suggested that the c.257C>G (p.T86R)/c.605ins46 mutations in the GJB2 gene provides a novel molecular explanation for the role of the GJB2 gene in hearing loss.

Objective: Three genes including the OTOF, the DFNB59 and the DIAPH3 have been implicated previously in human non-syndromic auditory neuropathy. In this study, we aim to investigate whether DIAPH3 gene or the known deafness loci of 25 cloned autosomal dominant deafness (DFNA) genes contribute to the nonsyndromic hearing loss of a Chinese pedigree with dominantly inherited auditory neuropathy (AN)., Method: Nine members of the kernal pedigree in this family were selected. Genomic DNA was isolated from the peripheral leukocytes of the subjects using the Puregene DNA Isolation Kits. Firstly, the 5'UTR of DIAPH3 gene was PCR amplified in all subjects. Then, the DNA fragments spanning the entire coding regions of DIAPH3, GJB2 and GJB3 genes, and 50 exons in other 23 cloned DFNA genes were amplified using specific primers. Each fragment was purified and analyzed by direct sequencing. The resultant sequence data were compared with the standard sequence to identify deafness-associated mutations., Result: PCR amplifications were successfully conducted. We failed to detect the presence either of c. --172G > A mutation in the 5'UTR that have been reported, or any other deafness-associated mutations in the whole DIAPH3 gene, by sequence analysis. We also did not find any known deafness-causing mutations among the 25 cloned DFNA genes., Conclusion: The DIAPH3 gene, and the known deafness loci of 25 cloned DFNA genes seem not contribute to the pathogenesis of this Chinese AN family in this study, which suggesting new gene(s) involvement.

Objective: To investigate the relationship of mitochondrial DNA mutations with inherited deafness in a maternally inherited pedigree with non-syndromic deafness., Methods: The diagnosis was validated by hearing tests. Blood samples were collected from 18 maternal members of the family and 53 controls including 6 paternal members, 7 spouses and 40 unrelated individuals. DNA was extracted from the leukocytes in blood samples. The gene fragments of mitochondrial DNA 12S rRNA, tRNA(Ser(UCN)) and GJB2 gene were amplified by polymerase chain reaction(PCR). PCR products were analyzed by sequencing. Computerized 12S rRNA secondary structure modeling was carried out to characterize the mutation found in the family., Results: A novel mitochondrial DNA 12S rRNA 709 G to A transition was detected from all maternal members including 8 patients with hearing loss and other 10 symptom-free maternal members. Non-maternal members and other controls did not carry this mutation. In addition, the tRNA(Ser(UCN))A7445G, 12S rRNA A1555G and GJB2 gene mutations were not observed in the study. Computerized modeling showed that this mutation changed the eighth and ninth loop-stem structure of the 12S rRNA secondary structure., Conclusion: In this family, 8 deaf patients carried the mitochondrial DNA 12S rRNA 709 G to A mutation, which is highly conservative in healthy adults. It was confirmed that the mitochondrial DNA 12S rRNA gene G709A was associated with non-syndromic inherited hearing loss. The other 10 maternal members carried the mutation, but they did not suffer from deafness, which might suggest that the G709A mutation may cause hearing impairment in combination with a synergistic effect of some other nuclear modifier genes.

Acetylation and deacetylation are the main post-translational modifications of histones. Increased deacetylation is associated with carcinogenesis, but the individual histone deacetylase (HDAC) responsible for this increase remains elusive. This study was designed to investigate the role of histone deacetylase 1 during tumorigenesis in MCF-7 human breast cancer cells. Anti-sense RNA was used to downregulate HDAC1 expression. RT-PCR analysis confirmed the efficiency of the anti-sense RNA, revealing that anti-sense RNA effectively downregulated HDAC1. The MTT assay showed that the proliferation of MCF-7 cells was inhibited and that cell activity was decreased. Cell cycle analysis identified cell cycle phase variations, with cells mainly arrested in the G1 and G2 phase. The anti-sense RNA of HDAC1 induced the inhibition of proliferation and cell cycle arrest in MCF-7 cells, suggesting it might have therapeutic applications as an antitumor agent in breast cancer.

Objective: To investigate if the DFNB59 gene contributes to the hearing loss of a Chinese pedigree with dominantly inherited auditory neuropathy (AN)., Method: Nine members in four generations of the family were selected for this study. Genomic DNA was isolated from the peripheral leukocytes of the patients using the pure gene DNA isolation kits. Firstly, the subjects DNA fragment was PCR amplified using specific primers corresponding to exon 2 and 4 of the DFNB59 gene. Each fragment was purified and subsequently analyzed by direct sequencing in an applied biosystems 3730 automated DNA sequencer. The whole coding sequence of DFNB59 gene of one family patient were then PCR amplified and submitted for sequence analysis as described above. The resultant sequence data were compared with the standard sequence to identify deafness-associated mutations., Result: PCR amplifications were successfully conducted in all the subjects. We failed to detect the presence either of mutations T54I and R183W in the exon 2 and exon 4 that have been reported, or any other deafness-associated mutations in the whole DFNB59 gene, by sequence analysis., Conclusion: The DFNB59 gene seems not contribute to the pathogenesis of this Chinese AN family, which suggesting new gene(s) involvement.