Sensorineural hearing loss is a common deficit and mainly occurs due to genetic factors. Recently, copy number variants (CNVs) in the STRC gene have also been recognized as a major cause of genetic hearing loss. We investigated the frequency of STRC deletions in the Japanese population and the characteristics of associated hearing loss. For CNV analysis, we employed a specialized method of Ion AmpliSeqTM sequencing, and confirmed the CNV results via custom array comparative genomic hybridization. We identified 17 probands with STRC homozygous deletions. The prevalence of STRC homozygous deletions was 1.7% in the hearing loss population overall, and 4.3% among mild-to-moderate hearing loss patients. A 2.63% carrier deletion rate was identified in both the hearing loss and the control population with normal hearing. In conclusion, our results show that STRC deletions are the second most common cause of mild-to-moderate hearing loss after the GJB2 gene, which accounts for the majority of genetic hearing loss. The phenotype of hearing loss is congenital and appears to be moderate, and is most likely to be stable without deterioration even after the age of 50. The present study highlights the importance of the STRC gene as a major cause of mild-to-moderate hearing loss.
A variant in a transcription factor gene, POU4F3, is responsible for autosomal dominant nonsyndromic hereditary hearing loss, DFNA15. To date, 14 variants, including a whole deletion of POU4F3, have been reported to cause HL in various ethnic groups. In the present study, genetic screening for POU4F3 variants was carried out for a large series of Japanese hearing loss (HL) patients to clarify the prevalence and clinical characteristics of DFNA15 in the Japanese population. Massively parallel DNA sequencing of 68 target candidate genes was utilized in 2,549 unrelated Japanese HL patients (probands) to identify genomic variations responsible for HL. The detailed clinical features in patients with POU4F3 variants were collected from medical charts and analyzed. Novel 12 POU4F3 likely pathogenic variants (six missense variants, three frameshift variants, and three nonsense variants) were successfully identified in 15 probands (2.5%) among 602 families exhibiting autosomal dominant HL, whereas no variants were detected in the other 1,947 probands with autosomal recessive or inheritance pattern unknown HL. To obtain the audiovestibular configuration of the patients harboring POU4F3 variants, we collected audiograms and vestibular symptoms of the probands and their affected family members. Audiovestibular phenotypes in a total of 24 individuals from the 15 families possessing variants were characterized by progressive HL, with a large variation in the onset age and severity with or without vestibular symptoms observed. Pure-tone audiograms indicated the most prevalent configuration as mid-frequency HL type followed by high-frequency HL type, with asymmetry observed in approximately 20% of affected individuals. Analysis of the relationship between age and pure-tone average suggested that individuals with truncating variants showed earlier onset and slower progression of HL than did those with non-truncating variants. The present study showed that variants in POU4F3 were a common cause of autosomal dominant HL.
The boundary of gene expression of transcription factors often plays a role in making a signaling center in development. In the otic vesicle, Gbx2 is expressed in the dorso-medial region including the endolymphatic duct, and Otx2 in the ventral region. Fgf10 is expressed between their expression boundaries, and the cochleovestibular ganglion develops close to the medial side of the Fgf10 expressing domain. Similar expression patterns are observed in the central nervous system, where Otx2 and Gbx2 expression abut at the mid-hindbrain boundary, and the repressive interaction between Otx2 and Gbx2 defines the mid-hindbrain boundary. These analogous expression patterns raise a question about the role of the interaction between Gbx2 and Otx2 in the otic vesicle. To address this, we misexpressed Gbx2 and Otx2 to the otic epithelium. Ectopic Gbx2 expression could repress Otx2 expression and vice versa. In addition, Fgf10 expression was repressed and cochlear ganglion formation was interfered with. Moreover, endolymphatic duct was severely hypomorphic in the Otx2 misexpressing embryos. These results suggest that the interaction between Gbx2 and Otx2 in developing inner ear defines Fgf10 expression domain to induce the cochlear ganglion. It is also suggested that Gbx2 expression is important for the formation of the endolymphatic duct.
Under resting conditions, the lengths of the closed area of the ETs in PET groups are clearly shorter than in groups without PET based on sitting position CT scans in resting condition. Among the symptoms and clinical test findings including the ET function test results, the presence of tympanic membrane movement induced by respiration, the high degree of EAC pressure change in TTAG, as well as the positive results of sonotubometry are significantly correlated with the positive findings of sitting CT revealing the open ET.
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