How Transmembrane Inner Ear (TMIE) plays role in the auditory system: A mystery to us.

Different cellular mechanisms contribute to the hearing sense, so it is obvious that any disruption in such processes leads to hearing impairment that greatly influences the global economy and quality of life of the patients and their relatives. In the past two decades, transmembrane inner ear (TMIE) protein has received a great deal of research interest because its impairments cause hereditary deafness in humans. This evolutionarily conserved membrane protein contributes to a fundamental complex that plays role in the maintenance and function of the sensory hair cells. Although the critical roles of the TMIE in mechanoelectrical transduction or hearing procedures have been discussed, there are little to no review papers summarizing the roles of the TMIE in the auditory system. In order to fill this gap, herein, we discuss the important roles of this protein in the auditory system including its role in mechanotransduction, olivocochlear synapse, morphology and different signalling pathways; we also review the genotype-phenotype correlation that can per se show the possible roles of this protein in the auditory system.

Role of GJB2 and GJB6 in Iranian Nonsyndromic Hearing Impairment: From Molecular Analysis to Literature Reviews.

Background: Hearing impairment (HI) is a heterogeneous disorder. GJB2 and GJB6 genes are typically the first line of genetic screening before proceeding to any massive parallel sequencing. We evaluated the clinical utility of GJB2 and GJB6 testing in the Iranian population. Methods: GJB2 and GJB6 were sequenced. PubMed and Google Scholar were searched for Iranian publications on deletions in the DFNB1 locus. Results: We detected mutations of GJB2 in 16.5%, and no mutations of GJB6. Literature review revealed no reports of mutations of GJB6 in the Iranian population. Conclusion: This data and literature reviews indicate that GJB6 is not commonly responsible for Iranian nonsyndromic HI. Hence, the clinical utility of GJB6 genetic analysis as a first line for HI evaluation does not have the same utility as GJB2. The study is consistent with recent studies emphasizing the role of ethnicity in the selection of HI genetic testing strategy.

Assessment of Human Leukocyte Antigen Differences between Smokers with Reinke's Edema and Those with Laryngeal Cancer.

Introduction: The present study aimed to assess human leukocyte antigen (HLA) typing differences between smokers with Reinke's edema and those with laryngeal squamous cell carcinoma (SCC). Materials and Methods: The HLA class I, II alleles were examined in 76 unrelated Iranian patients using low-resolution polymerase chain reaction with the sequence-specific primer (PCR-SSP) method. Results: The frequency of the HLA-A*36 allele and HLA-B*35 was significantly higher in patients with SCC. The frequency of HLA-DRB1*01 alleles in Reinke's edema was significantly higher, as compared to that in others. In the volunteer group, HLA-DRB1*13 and HLA-DRB1*15 were significantly higher. Conclusions: As evidenced by the obtained results, HLA-A*36 was significantly higher in SCC, as compared to that in volunteers and Reinke's edema patients. It can be concluded that being positive for HLA-A*36 increases the chance of SCC by three times. This result should be further investigated in cohort studies conducted on larger samples. Furthermore, HLA-A*24 was significantly higher in the volunteer group, as compared to that in other groups. The HLADRB1*01 was remarkably higher in Reinke's edema, as compared to that in SCC.

Randomized Clinical Trial Comparing Bucket Handle and Cartilage Tympanoplasty Techniques for the Reconstruction of Subtotal or Anterior Tympanic Membrane Perforation.

OBJECTIVE: The purpose of the study is to compare the clinical outcome of the two techniques of Bucket Handle Tympanoplasty and Cartilage Tympanoplasty in achieving success in graft survival as well as acceptable auditory results. 60 patients who suffered chronic otitis media with anterior perforation of the tympanic membrane were chosen. The patients were randomly assigned using Block Randomization Method of two groups including patients who underwent Bucket Handle Tympanoplasty (n = 30) or those that underwent Cartilage Tympanoplasty (n = 30). The patients were followed up for 1, 3, 6, and 12 months postoperatively. RESULTS: The mean PTA was lower in Bucket Handle Tympanoplasty group as case group compared to Cartilage Tympanoplasty group as the control (P = 0.023). No significant statistical differences had identified passing through the time, in terms of PTA outcome (P Value = 0.547) and SRT outcome (P Value = 0.352), between Bucket Handle Tympanoplasty group and the Cartilage Tympanoplasty group. In total, postoperative tympanic membrane perforation was found in 10.0% of patients in Cartilage Tympanoplasty group and 13.3% in Bucket Handle Tympanoplasty group with no difference (P = 0.500). CONCLUSIONS: Hearing improvements in both methods were similar. REGISTRATION NUMBER: The trial is registered with IRCT2016022626773N1.

Identification of a new mutation in an Iranian family with hereditary multiple osteochondromas.

BACKGROUND: Hereditary multiple osteochondromas (HMO), previously named hereditary multiple exostoses (HME), is an autosomal dominant skeletal disorder characterized by the growth of multiple osteochondromas and is associated with bony deformity, skeletal growth reduction, nerve compression, restriction of joint motion, and premature osteoarthrosis. HMO is genetically heterogeneous, localized on at least three chromosomal loci including 8q24.1 (EXT1), 11p11-p13 (EXT2), and 19p (EXT3). The median age of diagnosis is 3 years; almost all affected individuals are diagnosed by age 12. The risk for malignant degeneration to osteochondrosarcoma increases with age, although the lifetime risk of malignant degeneration is low (~1%). METHODS AND RESULTS: This study was performed on an Iranian family with nine affected individuals from three consecutive generations. Here, the proband was an affected woman who received genetic counseling prior to pregnancy. All exons of the three genes were examined in the proband using polymerase chain reaction and sequencing methods (the last member of this family is a male with severe deformities and lesions, especially around his large joints). Exon 4 of EXT1 (c.1235 G>A) was changed in affected individuals. This mutation alters tryptophan to a premature stop codon on amino acid position 412 (p.Trp412x). CONCLUSION: The outcome of this study has extended the genotypic spectrum of Iranian patients with HMO, revealing a way for improving detection and genetic counseling in carriers.

Association of genetic variations in the mitochondrial DNA control region with presbycusis.

BACKGROUND: The prominent role of mitochondria in the generation of reactive oxygen species, cell death, and energy production contributes to the importance of this organelle in the intracellular mechanism underlying the progression of the common sensory disorder of the elderly, presbycusis. Reduced mitochondrial DNA (mtDNA) gene expression and coding region variation have frequently been reported as being associated with the development of presbycusis. The mtDNA control region regulates gene expression and replication of the genome of this organelle. To comprehensively understand of the role of mitochondria in the progression of presbycusis, we compared variations in the mtDNA control region between subjects with presbycusis and controls. METHODS: A total of 58 presbycusis patients and 220 control subjects were enrolled in the study after examination by the otolaryngologist and audiology tests. Variations in the mtDNA control region were investigated by polymerase chain reaction and Sanger sequencing. RESULTS: A total of 113 sequence variants were observed in mtDNA, and variants were detected in 100% of patients, with 84% located in hypervariable regions. The frequencies of the variants, 16,223 C>T, 16,311 T>C, 16,249 T>C, and 15,954 A>C, were significantly different between presbycusis and control subjects. CONCLUSION: The statistically significant difference in the frequencies of four nucleotide variants in the mtDNA control region of presbycusis patients and controls is in agreement with previous experimental evidence and supports the role of mitochondria in the intracellular mechanism underlying presbycusis development. Moreover, these variants have potential as diagnostic markers for individuals at a high risk of developing presbycusis. The data also suggest the possible presence of changes in the mtDNA control region in presbycusis, which could alter regulatory factor binding sites and influence mtDNA gene expression and copy number.

The potential role for use of mitochondrial DNA copy number as predictive biomarker in presbycusis.

OBJECTIVES: Age-related hearing impairment, or presbycusis, is the most common communication disorder and neurodegenerative disease in the elderly. Its prevalence is expected to increase, due to the trend of growth of the elderly population. The current diagnostic test for detection of presbycusis is implemented after there has been a change in hearing sensitivity. Identification of a pre-diagnostic biomarker would raise the possibility of preserving hearing sensitivity before damage occurs. Mitochondrial dysfunction, including the production of reactive oxygen species and induction of expression of apoptotic genes, participates in the progression of presbycusis. Mitochondrial DNA sequence variation has a critical role in presbycusis. However, the nature of the relationship between mitochondrial DNA copy number, an important biomarker in many other diseases, and presbycusis is undetermined. METHODS: Fifty-four subjects with presbycusis and 29 healthy controls were selected after ear, nose, throat examination and pure-tone audiometry. DNA was extracted from peripheral blood samples. The copy number of mitochondrial DNA relative to the nuclear genome was measured by quantitative real-time polymerase chain reaction. RESULTS: Subjects with presbycusis had a lower median mitochondrial DNA copy number than healthy subjects and the difference was statistically significant (P=0.007). Mitochondrial DNA copy number was also significantly associated with degree of hearing impairment (P=0.025) and audiogram configuration (P=0.022). CONCLUSION: The findings of this study suggest that lower mitochondrial DNA copy number is responsible for presbycusis through alteration of mitochondrial function. Moreover, the significant association of mitochondrial DNA copy number in peripheral blood samples with the degree of hearing impairment and audiogram configuration has potential for use as a standard test for presbycusis, providing the possibility of the development of an easy-to-use biomarker for the early detection of this condition.

Association of nuclear and mitochondrial genes with audiological examinations in Iranian patients with nonaminoglycoside antibiotics-induced hearing loss.

Mitochondrial DNA mutations play an important role in causing sensorineural hearing loss. The purpose of this study was to determine the association of the mitochondrial genes RNR1, MT-TL1, and ND1 as well as the nuclear genes GJB2 and GJB6 with audiological examinations in nonfamilial Iranians with cochlear implants, using polymerase chain reaction, DNA sequencing, and RNA secondary structure analysis. We found that there were no novel mutations in the mitochondrial gene 12S rRNA (MT-RNR1) in patients with and without GJB2 mutation (GJB2(+) and GJB2(-), respectively), but a total of six polymorphisms were found. No mutations were observed in tRNA(Leu) (() (UUR) ()) (MT-TL1). Furthermore, eight polymorphisms were found in the mitochondrial ND1 gene. Additionally, no mutations were observed in the nuclear GJB6 gene in patients in the GJB2(-) and GJB2(+) groups. The speech intelligibility rating and category of auditory perception tests were statistically assessed in patients in the GJB2(-) and GJB2(+) groups. The results indicated that there was a significant difference (P<0.05) between the categories of auditory perception score in the GJB2(-) group compared to that in the GJB2(+) group. Successful cochlear implantation was observed among individuals with GJB2 mutations (GJB2(+)) and mitochondrial polymorphisms compared to those without GJB2 mutations (GJB2(-)). In conclusion, the outcome of this study suggests that variation in the mitochondrial and nuclear genes may influence the penetrance of deafness. Therefore, further genetic and functional studies are required to help patients in making the best choice for cochlear implants.