The present study of KCNQ4 mutations was carried out to 1) determine the prevalence by unbiased population-based genetic screening, 2) clarify the mutation spectrum and genotype/phenotype correlations, and 3) summarize clinical characteristics. In addition, a review of the reported mutations was performed for better understanding of this deafness gene. The screening using 287 probands from unbiased Japanese autosomal dominant nonsyndromic hearing loss (ADNSHL) families identified 19 families with 7 different disease causing mutations, indicating that the frequency is 6.62% (19/287). While the majority were private mutations, one particular recurrent mutation, c.211delC, was observed in 13 unrelated families. Haplotype analysis in the vicinity of c.211delC suggests existence of a common ancestor. The majority of the patients showed all frequency, but high-frequency predominant, sensorineural hearing loss. The present study adds a new typical audiogram configuration characterized by mid-frequency predominant hearing loss caused by the p.V230E mutation. A variant at the N-terminal site (c. 211delC) showed typical ski-slope type audiogram configuration. Concerning clinical features, onset age was from 3 to 40 years old, and mostly in the teens, and hearing loss was gradually progressive. Progressive nature is a common feature of patients with KCNQ4 mutations regardless of the mutation type. In conclusion, KCNQ4 mutations are frequent among ADNSHL patients, and therefore screening of the gene and molecular confirmation of these mutations have become important in the diagnosis of these conditions.
Objectives: We sought to elucidate the gene expression profiles of the causative genes as well as the localization of the encoded proteins involved in hereditary hearing loss. Methods: Relevant articles (as of September 2014) were searched in PubMed databases, and the gene symbols of the genes reported to be associated with deafness were located on the Hereditary Hearing Loss Homepage using localization, expression, and distribution as keywords. Results: Our review of the literature allowed us to systematize the gene expression profiles for genetic deafness in the inner ear, clarifying the unique functions and specific expression patterns of these genes in the cochlea and vestibular endorgans. Conclusions:The coordinated actions of various encoded molecules are essential for the normal development and maintenance of auditory and vestibular function.
BackgroundAuditory neuropathy spectrum disorder (ANSD) is a unique form of hearing loss that involves absence or severe abnormality of auditory brainstem response (ABR), but also the presence of otoacoustic emissions (OAEs). However, with age, the OAEs disappear, making it difficult to distinguish this condition from other nonsyndromic hearing loss. Therefore, the frequency of ANSD may be underestimated. The aim of this study was to determine what portion of nonsyndromic hearing loss is caused by mutations of OTOF, the major responsible gene for nonsyndromic ANSD.MethodsWe screened 160 unrelated Japanese with severe to profound recessive nonsyndromic hearing loss (ARNSHL) without GJB2 or SLC26A4 mutations, and 192 controls with normal hearing.ResultsWe identified five pathogenic OTOF mutations (p.D398E, p.Y474X, p.N727S, p.R1856Q and p.R1939Q) and six novel, possibly pathogenic variants (p.D450E, p.W717X, p.S1368X, p.R1583H, p.V1778I, and p.E1803A).ConclusionsThe present study showed that OTOF mutations accounted for 3.2–7.3% of severe to profound ARNSHL patients in Japan. OTOF mutations are thus a frequent cause in the Japanese deafness population and mutation screening should be considered regardless of the presence/absence of OAEs.
BackgroundTonotopy is one of the most fundamental principles of auditory function. While gradients in various morphological and physiological characteristics of the cochlea have been reported, little information is available on gradient patterns of gene expression. In addition, the audiograms in autosomal dominant non syndromic hearing loss can be distinctive, however, the mechanism that accounts for that has not been clarified. We thought that it is possible that tonotopic gradients of gene expression within the cochlea account for the distinct audiograms.Methodology/Principal FindingsWe compared expression profiles of genes in the cochlea between the apical, middle, and basal turns of the mouse cochlea by microarray technology and quantitative RT-PCR. Of 24,547 genes, 783 annotated genes expressed more than 2-fold. The most remarkable finding was a gradient of gene expression changes in four genes (Pou4f3, Slc17a8, Tmc1, and Crym) whose mutations cause autosomal dominant deafness. Expression of these genes was greater in the apex than in the base. Interestingly, expression of the Emilin-2 and Tectb genes, which may have crucial roles in the cochlea, was also greater in the apex than in the base.Conclusions/SignificanceThis study provides baseline data of gradient gene expression in the cochlea. Especially for genes whose mutations cause autosomal dominant non syndromic hearing loss (Pou4f3, Slc17a8, Tmc1, and Crym) as well as genes important for cochlear function (Emilin-2 and Tectb), gradual expression changes may help to explain the various pathological conditions.
Objective Copy number variations (CNVs), a major cause of genetic hearing loss, most frequently involve the STRC gene, located on chr15q15.3 and causally related to autosomal recessive non-syndromic hearing loss (ARNSHL) at the DFNB16 locus. The interpretation of STRC sequence data can be challenging due to the existence of a virtually identical pseudogene, pSTRC that promotes complex genomic rearrangements in this genomic region. Targeted genomic enrichment with massively parallel sequencing (TGE+MPS) has emerged as the preferred method by which to provide comprehensive genetic testing for hearing loss. We aimed to identify CNVs in the STRC region using established and validated bioinformatics methods. Methods We used TGE+MPS to identify the genetic cause of hearing loss. CNV results were confirmed with customized array comparative genomic hybridization (array CGH). Results Three probands with progressive mild-to-moderate hearing loss were found among 40 subjects with ARNSHL to segregate homozygous STRC deletions and gene to pseudogene conversion. Array CGH showed that the deletions/conversions span multiple genes outside of the exons captured by TGE+MPS. Conclusion These data further validate the necessity to integrate the detection of both simple variant changes and complex genomic rearrangements in the clinical diagnosis of genetic hearing loss.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.