The Prevalence and Clinical Characteristics of TECTA-Associated Autosomal Dominant Hearing Loss

Yasukawa, Rika; Moteki, Hideaki; Nishio, Shin‐ya; Ishikawa, Kotaro; Abe, Satoko; Honkura, Yohei; Hyogo, Misako; Mihashi, Ryota; Ikezono, Tetsuo; Shintani, Tomoko; Ogasawara, Nagahisa; Shirai, Kyoko; Yoshihashi, Hiroshi; Ishino, Takashi; Otsuki, Koji; Ito, Tsukasa; Sugahara, Kazuma; Usami, Shin Ichi

doi:10.3390/genes10100744

Cited by 24 publications

(26 citation statements)

References 30 publications

(50 reference statements)

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“…The frequency of MYO6-associated hearing loss was 2.40% in the Japanese AD hearing loss patients. This frequency is compatible with our previous study (2.6%; 7/266) [20] and is lower than the most frequent ADSNHL gene (6.6% for KCNQ4 [26]) but comparable with other ADSNHL genes, such as 3.2% for TECTA [27], 2.5% for POU4F3 [28], and 2.5% for WFS1 [29]. Therefore, MYO6 is considered an important causative gene for Japanese patients with ADSNHL.…”

Section: Discussionsupporting

confidence: 91%

Clinical Characteristics and In Vitro Analysis of MYO6 Variants Causing Late-onset Progressive Hearing Loss

Oka

Day

Nishio

et al. 2020

Genes

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MYO6 is known as a genetic cause of autosomal dominant and autosomal recessive inherited hearing loss. In this study, to clarify the frequency and clinical characteristics of hearing loss caused by MYO6 gene mutations, a large-scale genetic analysis of Japanese patients with hearing loss was performed. By means of massively parallel DNA sequencing (MPS) using next-generation sequencing for 8074 Japanese families, we found 27 MYO6 variants in 33 families, 22 of which are novel. In total, 2.40% of autosomal dominant sensorineural hearing loss (ADSNHL) in families in this study (32 out of 1336) was found to be caused by MYO6 mutations. The present study clarified that most cases showed juvenile-onset progressive hearing loss and their hearing deteriorated markedly after 40 years of age. The estimated hearing deterioration was found to be 0.57 dB per year; when restricted to change after 40 years of age, the deterioration speed was accelerated to 1.07 dB per year. To obtain supportive evidence for pathogenicity, variants identified in the patients were introduced to MYO6 cDNA by site-directed mutagenesis and overexpressed in epithelial cells. They were then assessed for their effects on espin1-induced microvilli formation. Cells with wildtype myosin 6 and espin1 co-expressed created long microvilli, while co-expression with mutant constructs resulted in severely shortened microvilli. In conclusion, the present data clearly showed that MYO6 is one of the Genes 2020, 11, 273 2 of 14 genes to keep in mind with regard to ADSNHL, and the molecular characteristics of the identified gene variants suggest that a possible pathology seems to result from malformed stereocilia of the cochlear hair cells.

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Section: Discussionsupporting

confidence: 91%

Clinical Characteristics and In Vitro Analysis of MYO6 Variants Causing Late-onset Progressive Hearing Loss

Oka

Day

Nishio

et al. 2020

Genes

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“…On the other hand, vWFD domains containing the multimerization consensus site CGLC are essential for the multimer assembly of proteins expressed in the tectorial membrane (like α-tectorin, otogelin or otogelin-like protein) to form a lament and higher order structures. Although little is known about these domains in OTOGL, mutations in the vWFDs of TECTA have been clearly connected with hearing impairment [37,44]. Moreover, the shape of the audiometric curve observed in our proband is almost identical to the audiogram obtained from the compound heterozygous patient carrying mutations p.Gln520* and p.Arg925* reported by Bonnet et al [42].…”

Section: Discussionsupporting

confidence: 83%

“…Missense mutations in different Tecta domains are known to cause different phenotypes with distinct changes in the structure of the tectorial membrane. Mutations in the zona pellucida domain cause mid-frequency HL with a typical U-shaped or shallow U-shaped audiogram, whereas mutations in the zonadhesin-like domain comprising vWFD1, vWFD2 and trypsin inhibitor-like (TIL) repeats lead to high-frequency HL[35,37]. Our results are in agreement with the ndings of previous studies: four of our variants (p.Gly1858Glu,…”

supporting

confidence: 93%

“…Sound induces movement of these hair cells relative to the TM, de ects the stereocilia, and leads to uctuations in hair-cell membrane potential, transducing sound into electrical signals [30,31]. [37] identi ed the likely pathogenic p.Cys606Gly variant in the TIL1 domain in a proband with midfrequency HL. Variant p.Lys2150Asnfs*9 is located in the last exon and causes replacement of the last six amino acids and extension of the glycosylphosphatidylinositol (GPI) anchorage of TECTA protein by two amino acids.…”

Section: Discussionmentioning

confidence: 99%

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Comprehensive molecular-genetic analysis of mid-frequency sensorineural hearing loss

Pavlenkova

Varga

Borecka

et al. 2021

Preprint

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The genetic heterogeneity of sensorineural hearing loss (SNHL) is a major hurdle to the detection of disease-causing variants. We aimed to identify underlying causal genes associated with mid-frequency hearing loss (HL), which contributes to less than about 1% of SNHL cases, by whole exome sequencing (WES). Thirty families segregating mid-frequency SNHL, in whom biallelic GJB2 mutations had been previously excluded, were selected from among 851 families in our DNA repository of SNHL. DNA samples from the probands were subjected to WES analysis and searched for candidate variants associated with SNHL. We were able to identify the genetic aetiology in six probands (20%). In total, we found three pathogenic and three likely pathogenic variants in four genes COL4A5, OTOGL, TECTA, TMPRSS3). One proband was a compound heterozygote for a pathogenic variant and a variant of uncertain significance (VUS) in MYO15A gene. To date, MYO15A and TMPRSS3 have not yet been described in association with mid-frequency SNHL. In eight additional probands, eight candidate VUS variants were detected in five genes (DIAPH1, MYO7A, TECTA, TMC1, TSPEAR). Seven of these 16 variants have not yet been published or mentioned in the available databases. The most prevalent gene was TECTA, identified in 23% of all tested families. Furthermore, we confirmed the hypothesis that a substantive portion of cases with this conspicuous audiogram shape is a consequence of a genetic disorder.

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“…Etiological studies have shown that genetic causes are the most common etiology of deafness, and approximately two-thirds of congenital/early-onset sensorineural hearing loss in developed countries is estimated to be due to genetic causes (Morton and Nance 2006). Recent studies have indicated that a significant portion of late-onset hearing loss is also due to genetic causes (Kitano et al 2017;Kobayashi et al 2018;Shinagawa et al 2020a;Yasukawa et al 2019;Oka et al 2020;Miyajima et al 2020). A series of etiological studies has demonstrated genetic disorders to be a common cause of all types of sensorineural hearing loss, but there has been no detailed genetic epidemiological data covering a wide range of ages.…”

Section: Genetic Epidemiology Based On Genetic Testingmentioning

confidence: 99%

The genetic etiology of hearing loss in Japan revealed by the social health insurance-based genetic testing of 10K patients

Usami

Nishio

2021

Hum Genet

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Etiological studies have shown genetic disorders to be a major cause of sensorineural hearing loss, but there are a limited number of comprehensive etiological reports based on genetic analysis. In the present study, the same platform using a diagnostic DNA panel carrying 63 deafness genes and the same filtering algorithm were applied to 10,047 samples obtained from social health insurance-based genetic testing of hearing loss. The most remarkable result obtained in this comprehensive study was that the data first clarified the genetic epidemiology from congenital/early-onset deafness to late-onset hearing loss. The overall diagnostic rate was 38.8%, with the rate differing for each age group; 48.6% for the congenital/early-onset group (~5y.o.), 33.5% for the juvenile/young adult-onset group, and 18.0% for the 40+ y.o. group. Interestingly, each group showed a different kind of causative gene. With regard to the mutational spectra, there are certain recurrent variants that may be due to founder effects or hot spots. A series of haplotype studies have shown many recurrent variants are due to founder effects, which is compatible with human migration. It should be noted that, regardless of differences in the mutational spectrum, the clinical characteristics caused by particular genes can be considered universal. This comprehensive review clarified the detailed clinical characteristics (onset age, severity, progressiveness, etc.) of hearing loss caused by each gene, and will provide useful information for future clinical application, including genetic counseling and selection of appropriate interventions.

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The Prevalence and Clinical Characteristics of TECTA-Associated Autosomal Dominant Hearing Loss

Cited by 24 publications

References 30 publications

Clinical Characteristics and In Vitro Analysis of MYO6 Variants Causing Late-onset Progressive Hearing Loss

Clinical Characteristics and In Vitro Analysis of MYO6 Variants Causing Late-onset Progressive Hearing Loss

Comprehensive molecular-genetic analysis of mid-frequency sensorineural hearing loss

The genetic etiology of hearing loss in Japan revealed by the social health insurance-based genetic testing of 10K patients

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