scholarly journals Identification of a Potential Founder Effect of a Novel PDZD7 Variant Involved in Moderate-to-Severe Sensorineural Hearing Loss in Koreans

2019 ◽  
Vol 20 (17) ◽  
pp. 4174 ◽  
Author(s):  
Sang-Yeon Lee ◽  
Jin Hee Han ◽  
Bong Jik Kim ◽  
Seung Ha Oh ◽  
Seungmin Lee ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Founder Effect ◽  
Hot Spot ◽  
Usher Syndrome ◽  
Pdz Domain ◽  
Missense Variant ◽  
Normal Hearing ◽  
Causative Gene ◽  
Str Markers ◽  
Korean Families

PDZD7, a PDZ domain-containing scaffold protein, is critical for the organization of Usher syndrome type 2 (USH2) interactome. Recently, biallelic PDZD7 variants have been associated with autosomal-recessive, non-syndromic hearing loss (ARNSHL). Indeed, we identified novel, likely pathogenic PDZD7 variants based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines from Korean families manifesting putative moderate-to-severe prelingual ARNSHL; these were c.490C>T (p.Arg164Trp), c.1669delC (p.Arg557Glyfs*13), and c.1526G>A (p.Gly509Glu), with p.Arg164Trp being a predominantly recurring variant. Given the recurring missense variant (p.Arg164Trp) from our cohort, we compared the genotyping data using six short tandem-repeat (STR) markers within or flanking PDZD7 between four probands carrying p.Arg164Trp and 81 normal-hearing controls. We observed an identical haplotype across three out of six STR genotyping markers exclusively shared by two unrelated hearing impaired probands but not by any of the 81 normal-hearing controls, suggesting a potential founder effect. However, STR genotyping, based on six STR markers, revealed various p.Arg164Trp-linked haplotypes shared by all of the affected subjects. In conclusion, PDZD7 can be an important causative gene for moderate to severe ARNSHL in Koreans. Moreover, at least some, if not all, p.Arg164Trp alleles in Koreans could exert a potential founder effect and arise from diverse haplotypes as a mutational hot spot.

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

Genes ◽  
2019 ◽  
Vol 10 (10) ◽  
pp. 744 ◽  
Author(s):  
Rika Yasukawa ◽  
Hideaki Moteki ◽  
Shin-ya Nishio ◽  
Kotaro Ishikawa ◽  
Satoko Abe ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Autosomal Dominant ◽  
Hot Spot ◽  
Missense Variant ◽  
Sensorineural Hearing ◽  
Sequencing Analysis ◽  
Causative Gene ◽  
Ethnic Populations ◽  
Next Generation Sequencing Analysis

TECTA is well known as a causative gene for autosomal dominant mid-frequency hearing loss observed in various populations. In this study, we performed next-generation sequencing analysis of a large Japanese hearing loss cohort, including eight hundred and twelve (812) subjects from unrelated autosomal dominant hearing loss families, to estimate the prevalence and phenotype-genotype correlations in patients with TECTA mutations. The prevalence of TECTA mutations in Japanese autosomal dominant sensorineural hearing loss families was found to be 3.2%. With regard to the type of hearing loss, the patients with mutations in the nidogen-like domain or ZA domain of TECTA showed varied audiograms. However, most of the patients with mutations in the ZP domain showed mid-frequency hearing loss. The rate of hearing deterioration in TECTA-associated hearing loss patients and in the normal hearing Japanese control population were the same and regression lines for each group were parallel. We carried out haplotype analysis for four families which had one recurring missense variant, c.5597C>T (p.Thr1866Met). Our results revealed four different haplotypes, suggesting that this mutation occurred independently in each family. In conclusion, TECTA variants represent the second largest cause of autosomal dominant sensorineural hearing loss in Japan. The hearing loss progression observed in the patients with TECTA mutations might reflect presbycusis. The c.5597C>T mutation occurred in a mutational hot spot and is observed in many ethnic populations.

scholarly journals Structure and Membrane Targeting of the PDZD7 Harmonin Homology Domain (HHD) Associated With Hearing Loss

2021 ◽  
Vol 9 ◽  
Author(s):  
Lin Lin ◽  
Huang Wang ◽  
Decheng Ren ◽  
Yitian Xia ◽  
Guang He ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Vision Loss ◽  
Biochemical Characterization ◽  
Usher Syndrome ◽  
Pdz Domain ◽  
Binding Pocket ◽  
Binding Mode ◽  
Lipid Binding ◽  
Membrane Targeting ◽  
Pdz Domains

Usher syndrome (USH) is the leading cause of hereditary hearing–vision loss in humans. PDZ domain-containing 7 (PDZD7) has been reported to be a modifier of and contributor to USH. PDZD7 co-localizes with USH2 proteins in the inner ear hair cells and is essential for ankle-link formation and stereocilia development. PDZD7 contains three PDZ domains and a low-complexity region between the last two PDZ domains, which has been overlooked in the previous studies. Here we characterized a well-folded harmonin homology domain (HHD) from the middle region and solved the PDZD7 HHD structure at the resolution of 1.49 Å. PDZD7 HHD adopts the same five-helix fold as other HHDs found in Harmonin and Whirlin; however, in PDZD7 HHD, a unique α1N helix occupies the canonical binding pocket, suggesting a distinct binding mode. Moreover, we found that the PDZD7 HHD domain can bind lipid and mediate the localization of PDZD7 to the plasma membrane in HEK293T cells. Intriguingly, a hearing-loss mutation at the N-terminal extension region of the HHD can disrupt the lipid-binding ability of PDZD7 HHD, suggesting that HHD-mediated membrane targeting is required for the hearing process. This structural and biochemical characterization of the PDZD7 HHD region provides mechanistic explanations for human deafness-causing mutations in PDZD7. Furthermore, this structure will also facilitate biochemical and functional studies of other HHDs.

scholarly journals Haplotype Analysis of GJB2 Mutations: Founder Effect or Mutational Hot Spot?

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 250 ◽  
Author(s):  
Jun Shinagawa ◽  
Hideaki Moteki ◽  
Shin-ya Nishio ◽  
Yoshihiro Noguchi ◽  
Shin-ichi Usami
Keyword(s):  
Hearing Loss ◽  
Founder Effect ◽  
Hot Spot ◽  
Distribution Patterns ◽  
Gjb2 Gene ◽  
Founder Effects ◽  
Haplotype Data ◽  
Clock Analysis ◽  
Specific Haplotype ◽  
Gjb2 Mutations

The GJB2 gene is the most frequent cause of congenital or early onset hearing loss worldwide. In this study, we investigated the haplotypes of six GJB2 mutations frequently observed in Japanese hearing loss patients (i.e., c.235delC, p.V37I, p.[G45E; Y136X], p.R143W, c.176_191del, and c.299_300delAT) and analyzed whether the recurring mechanisms for each mutation are due to founder effects or mutational hot spots. Furthermore, regarding the mutations considered to be caused by founder effects, we also calculated the age at which each mutation occurred using the principle of genetic clock analysis. As a result, all six mutations were observed in a specific haplotype and were estimated to derive from founder effects. Our haplotype data together with their distribution patterns indicated that p.R143W and p.V37I may have occurred as multiple events, and suggested that both a founder effect and hot spot may be involved in some mutations. With regard to the founders’ age of frequent GJB2 mutations, each mutation may have occurred at a different time, with the oldest, p.V37I, considered to have occurred around 14,500 years ago, and the most recent, c.176_191del, considered to have occurred around 4000 years ago.

When Hearing Does Not Mean Understanding: On the Neural Processing of Syntactically Complex Sentences by Listeners With Hearing Loss

2021 ◽  
pp. 1-13
Author(s):  
Margreet Vogelzang ◽  
Christiane M. Thiel ◽  
Stephanie Rosemann ◽  
Jochem W. Rieger ◽  
Esther Ruigendijk
Keyword(s):  
Hearing Loss ◽  
Sentence Processing ◽  
Secondary Task ◽  
Sentence Comprehension ◽  
Inferior Frontal Gyrus ◽  
Normal Hearing ◽  
Cognitive Demands ◽  
Sentence Complexity ◽  
Complex Sentences ◽  
And Task

Purpose Adults with mild-to-moderate age-related hearing loss typically exhibit issues with speech understanding, but their processing of syntactically complex sentences is not well understood. We test the hypothesis that listeners with hearing loss' difficulties with comprehension and processing of syntactically complex sentences are due to the processing of degraded input interfering with the successful processing of complex sentences. Method We performed a neuroimaging study with a sentence comprehension task, varying sentence complexity (through subject–object order and verb–arguments order) and cognitive demands (presence or absence of a secondary task) within subjects. Groups of older subjects with hearing loss ( n = 20) and age-matched normal-hearing controls ( n = 20) were tested. Results The comprehension data show effects of syntactic complexity and hearing ability, with normal-hearing controls outperforming listeners with hearing loss, seemingly more so on syntactically complex sentences. The secondary task did not influence off-line comprehension. The imaging data show effects of group, sentence complexity, and task, with listeners with hearing loss showing decreased activation in typical speech processing areas, such as the inferior frontal gyrus and superior temporal gyrus. No interactions between group, sentence complexity, and task were found in the neuroimaging data. Conclusions The results suggest that listeners with hearing loss process speech differently from their normal-hearing peers, possibly due to the increased demands of processing degraded auditory input. Increased cognitive demands by means of a secondary visual shape processing task influence neural sentence processing, but no evidence was found that it does so in a different way for listeners with hearing loss and normal-hearing listeners.

An Evaluation of the Relationship between Retinal Nerve Fiber Thickness, Cochlear Nerve Thickness, the Level of Tinnitus, and Hearing Loss in Unilateral Tinnitus Patients

2021 ◽  
pp. 1-8
Author(s):  
Mustafa Avcu ◽  
Mehmet Metin ◽  
Raşit Kılıç ◽  
Muhammed Alpaslan
Keyword(s):  
Hearing Loss ◽  
Nerve Fiber ◽  
Normal Hearing ◽  
Cochlear Nerve ◽  
Significant Difference ◽  
The Relationship ◽  
Fiber Thickness ◽  
Moderate Hearing Loss ◽  
Group 1 ◽  
Retinal Nerve Fiber

Background: In this study, optic coherence tomography (OCT) examination was performed to check whether there was any interaction between ophthalmic axonal structures in unilateral tinnitus patients, and the relationship between optic nerve thickness and cochlear nerve thickness was evaluated. Objective: The aim of the study was to evaluate the relatioship between hearing loss, tinnitus, and nerve thicknesses. Study Design: Prospective study. Setting: Tertiary referral university hospital. Patients: The study included 88 patients with unilateral tinnitus, for which no organic cause could be found in physical examination, psychiatric evaluation, or with imaging methods. Study groups were formed of the tinnitus side and control groups were formed of the healthy side as follows: Group 1 (Non-tinnitus side normal hearing values – n = 30), Group 2 (non-tinnitus side minimal hearing loss – n = 27), Group 3 (non-tinnitus side moderate hearing loss – n = 31), Group 4 (tinnitus side normal hearing values – n = 25), Group 5 (tinnitus side minimal hearing loss – n = 25), and Group 6 (tinnitus side moderate hearing loss – n = 38). Intervention: Retinal nerve fiber layer (RNFL) thickness was evaluated with OCT, and the cochlear nerve cross-sectional area was evaluated with MRI. Main Outcome Measures: RNFL measurements were taken with OCT from the subfoveal area (RNFL-SF) and 1.5 mm temporal to the fovea (RNFL-T µm) and nasal (RNFL-N µm) sectors. On MRI, 3 measurements were taken along the nerve from the cerebellopontine angle as far as the internal auditory canal, and the mean value of these 3 measurements was calculated. Results: When the groups were evaluated in respect of cochlear nerve thickness, a significant difference was seen between Group 1 and both the groups with hearing loss and the tinnitus groups. In the subgroup analysis, a statistically significant difference was determined between Group 1 and Groups 3, 4, 5, and 6 (p = 0.013, p = 0.003, p < 0.001, and p < 0.001, respectively). When the groups were evaluated in respect of the RNFL-SF (µm), RNFL-T (µm), and RNFL-N (µm) values, the differences were determined to be statistically significant (p < 0.001 for all). In the correlation analysis, a negative correlation was determined between hearing loss and cochlear nerve diameter (r: −0.184, p = 0.014), and RNFL-N (r: −0.272, p < 0.001) and between tinnitus and cochlear nerve diameter (r: −0.536, p < 0.001), and RNFL-T (r: −0.222, p < 0.009). Conclusion: The study results clearly showed a relationship between cochlear nerve fiber thickness and hearing loss and the severity of tinnitus in cases with unilateral tinnitus and that there could be neurodegenerative factors in the disease etiology. A similar relationship seen with the RNFL supports the study hypothesis.

scholarly journals Susceptibility to Residual Inhibition Is Associated With Hearing Loss and Tinnitus Chronicity

2021 ◽  
Vol 25 ◽  
pp. 233121652098630
Author(s):  
S. Hu ◽  
L. Anschuetz ◽  
D. A. Hall ◽  
M. Caversaccio ◽  
W. Wimmer
Keyword(s):  
Hearing Loss ◽  
Narrow Band ◽  
Acoustic Stimulation ◽  
Normal Hearing ◽  
Short Term ◽  
Factors Associated ◽  
Band Noise ◽  
Comparator Group ◽  
Residual Inhibition ◽  
Subject Comparison

Residual inhibition, that is, the temporary suppression of tinnitus loudness after acoustic stimulation, is a frequently observed phenomenon that may have prognostic value for clinical applications. However, it is unclear in which subjects residual inhibition is more likely and how stable the effect of inhibition is over multiple repetitions. The primary aim of this work was to evaluate the effect of hearing loss and tinnitus chronicity on residual inhibition susceptibility. The secondary aim was to investigate the short-term repeatability of residual inhibition. Residual inhibition was assessed in 74 tinnitus subjects with 60-second narrow-band noise stimuli in 10 consecutive trials. The subjects were assigned to groups according to their depth of suppression (substantial residual inhibition vs. comparator group). In addition, a categorization in normal hearing and hearing loss groups, related to the degree of hearing loss at the frequency corresponding to the tinnitus pitch, was made. Logistic regression was used to identify factors associated with susceptibility to residual inhibition. Repeatability of residual inhibition was assessed using mixed-effects ordinal regression including poststimulus time and repetitions as factors. Tinnitus chronicity was not associated with residual inhibition for subjects with hearing loss, while a statistically significant negative association between tinnitus chronicity and residual inhibition susceptibility was observed in normal hearing subjects (odds ratio: 0.63; p = .0076). Moreover, repeated states of suppression can be stably induced, reinforcing the use of residual inhibition for within-subject comparison studies.

scholarly journals A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans

2021 ◽  
Author(s):  
Barbara Vona ◽  
Neda Mazaheri ◽  
Sheng-Jia Lin ◽  
Lucy A. Dunbar ◽  
Reza Maroofian ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Amino Acid ◽  
Rna Splicing ◽  
Stop Codon ◽  
Missense Variant ◽  
Homozygosity Mapping ◽  
Deafness Gene ◽  
Expression Studies ◽  
Hearing Function

AbstractDeafness, the most frequent sensory deficit in humans, is extremely heterogeneous with hundreds of genes involved. Clinical and genetic analyses of an extended consanguineous family with pre-lingual, moderate-to-profound autosomal recessive sensorineural hearing loss, allowed us to identify CLRN2, encoding a tetraspan protein, as a new deafness gene. Homozygosity mapping followed by exome sequencing identified a 14.96 Mb locus on chromosome 4p15.32p15.1 containing a likely pathogenic missense variant in CLRN2 (c.494C > A, NM_001079827.2) segregating with the disease. Using in vitro RNA splicing analysis, we show that the CLRN2 c.494C > A variant leads to two events: (1) the substitution of a highly conserved threonine (uncharged amino acid) to lysine (charged amino acid) at position 165, p.(Thr165Lys), and (2) aberrant splicing, with the retention of intron 2 resulting in a stop codon after 26 additional amino acids, p.(Gly146Lysfs*26). Expression studies and phenotyping of newly produced zebrafish and mouse models deficient for clarin 2 further confirm that clarin 2, expressed in the inner ear hair cells, is essential for normal organization and maintenance of the auditory hair bundles, and for hearing function. Together, our findings identify CLRN2 as a new deafness gene, which will impact future diagnosis and treatment for deaf patients.

Measurements of Loudness Growth in 1/2-Octave Bands for Children and Adults With Normal Hearing

1999 ◽  
Vol 8 (1) ◽  
pp. 40-46 ◽  
Author(s):  
Melisa R. Ellis ◽  
Michael K. Wynne
Keyword(s):  
Hearing Loss ◽  
Hearing Aids ◽  
Hearing Aid ◽  
Age Groups ◽  
Lower Boundary ◽  
Normal Hearing ◽  
Boundary Values ◽  
Simple Modification ◽  
Point Data ◽  
Loudness Growth

The loudness growth in 1/2-octave bands (LGOB) procedure has been shown previously to provide valid estimates of loudness growth for adults with normal hearing and those with hearing loss (Allen, Hall, & Jeng, 1990), and it has been widely incorporated into fitting strategies for adult hearing aid users by a hearing aid manufacturer. Here, we applied a simple modification of LGOB to children and adults with normal hearing and then compared the loudness growth functions (as obtained from end-point data) between the two age groups. In addition, reliability data obtained within a single session and between test sessions were compared between the two groups. Large differences were observed in the means between the two groups for the lower boundary values, the upper boundary values, and the range between boundaries both within and across all frequencies. The data obtained from children also had greater variance than the adult data. In addition, there was more variability in the data across test sessions for children. Many test-retest differences for children exceeded 10 dB. Adult test-retest differences were generally less than 10 dB. Although the LGOB with the modifications used in this study may be used to measure loudness growth in children, its poor reliability with this age group may limit its clinical use for children with hearing loss. Additional work is needed to explore whether loudness growth measures can be adapted successfully to children and whether these measures contribute worthwhile information for fitting hearing aids to children.

Sign in / Sign up

Export Citation Format

Share Document