ELMOD3, a novel causative gene, associated with human autosomal dominant nonsyndromic and progressive hearing loss

2018 ◽  
Vol 137 (4) ◽  
pp. 329-342 ◽  
Author(s):  
Wu Li ◽  
Jie Sun ◽  
Jie Ling ◽  
Jiada Li ◽  
Chufeng He ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Autosomal Dominant ◽  
Progressive Hearing Loss ◽  
Causative Gene

scholarly journals NCOA3 identified as a new candidate to explain autosomal dominant progressive hearing loss

2020 ◽  
Author(s):  
Rodrigo Salazar da Silva ◽  
Vitor Lima Goes Dantas ◽  
Leandro Ucela Alves ◽  
Ana Carla Batissoco ◽  
Jeanne Oiticica ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Autosomal Dominant ◽  
Snp Array ◽  
Large Family ◽  
Sensory Function ◽  
Causative Mutation ◽  
Linkage Data ◽  
Potential Candidate ◽  
Mineral Density ◽  
Progressive Hearing Loss

Abstract Hearing loss is a frequent sensory impairment in humans and genetic factors account for an elevated fraction of the cases. We have investigated a large family of five generations, with 15 reported individuals presenting non-syndromic, sensorineural, bilateral and progressive hearing loss, segregating as an autosomal dominant condition. Linkage analysis, using SNP-array and selected microsatellites, identified a region of near 13 cM in chromosome 20 as the best candidate to harbour the causative mutation. After exome sequencing and filtering of variants, only one predicted deleterious variant in the NCOA3 gene (NM_181659, c.2810C > G; p.Ser937Cys) fit in with our linkage data. RT-PCR, immunostaining and in situ hybridization showed expression of ncoa3 in the inner ear of mice and zebrafish. We generated a stable homozygous zebrafish mutant line using the CRISPR/Cas9 system. ncoa3−/− did not display any major morphological abnormalities in the ear, however, anterior macular hair cells showed altered orientation. Surprisingly, chondrocytes forming the ear cartilage showed abnormal behaviour in ncoa3−/−, detaching from their location, invading the ear canal and blocking the cristae. Adult mutants displayed accumulation of denser material wrapping the otoliths of ncoa3−/− and increased bone mineral density. Altered zebrafish swimming behaviour corroborates a potential role of ncoa3 in hearing loss. In conclusion, we identified a potential candidate gene to explain hereditary hearing loss, and our functional analyses suggest subtle and abnormal skeletal behaviour as mechanisms involved in the pathogenesis of progressive sensory function impairment.

scholarly journals Cellular and Molecular Mechanisms of Autosomal Dominant Form of Progressive Hearing Loss, DFNA2

2010 ◽  
Vol 286 (2) ◽  
pp. 1517-1527 ◽  
Author(s):  
Hyo Jeong Kim ◽  
Ping Lv ◽  
Choong-Ryoul Sihn ◽  
Ebenezer N. Yamoah
Keyword(s):  
Hearing Loss ◽  
Molecular Mechanisms ◽  
Autosomal Dominant ◽  
Progressive Hearing Loss ◽  
Dominant Form ◽  
Autosomal Dominant Form

scholarly journals Prevalence and Clinical Features of Autosomal Dominant and Recessive TMC1-Associated Hearing Loss.

2021 ◽  
Author(s):  
Shin-ya Nishio ◽  
Shin-ichi Usami
Keyword(s):  
Hearing Loss ◽  
Clinical Features ◽  
Autosomal Recessive ◽  
Haplotype Analysis ◽  
Autosomal Dominant ◽  
Founder Mutation ◽  
Family Members ◽  
Causative Gene ◽  
Pathogenic Variants ◽  
Syndromic Hearing Loss

Abstract TMC1 is a causative gene for both autosomal dominant non-syndromic hearing loss (DFNA36) and autosomal recessive non-syndromic hearing loss (DFNB7/11). To date, 125 pathogenic variants in TMC1 have been reported. Most of the TMC1 variants are responsible for autosomal recessive hearing loss, with only 7 variants reported as causative for DFNA36. Here we reported the prevalence of TMC1-associated hearing loss in a large non-syndromic hearing loss cohort of about 12,000 subjects. As a result, we identified 26 probands with TMC1-associated hearing loss and the estimated prevalence of TMC1-associated hearing loss in the Japanese hearing loss cohort to be 0.18% among all patients. Among the 26 probands with TMC1-associated hearing loss, 15 cases were identified from autosomal dominant hearing loss families. By using the audiometric data from the probands, family members and previously reported cases, we evaluated the hearing deterioration speed for DFNA36 patients. In addition, we performed haplotype analysis for 11 unrelated autosomal dominant hearing loss families carrying the same variant TMC1: NM_138691:c.1627G > A:p.D543N. The results clearly indicated that the same haplotype was present despite of families being unrelated, supporting the contention that this variant occurred by founder mutation.

Novel TECTA Mutations Identified in Stable Sensorineural Hearing Loss and Their Clinical Implications

2014 ◽  
Vol 20 (1) ◽  
pp. 17-25 ◽  
Author(s):  
Ah Reum Kim ◽  
Mun Young Chang ◽  
Ja-Won Koo ◽  
Seung Ha Oh ◽  
Byung Yoon Choi
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
High Frequency ◽  
Autosomal Dominant ◽  
Sensorineural Hearing ◽  
Clinical Feature ◽  
Phenotype Correlation ◽  
Causative Gene ◽  
Bioinformatics Analyses ◽  
Genotype Phenotype Correlation

TECTA is a causative gene of autosomal dominant (DFNA8/A12) and autosomal recessive (DFNB 21) nonsyndromic sensorineural hearing loss (NSHL). Mutations in TECTA account for 4% of all autosomal dominant NSHL cases in some populations and are thus thought to be one of the major causes of autosomal dominant NSHL. A genotype-phenotype correlation for autosomal dominant mutations in the TECTA gene has been proposed. Two families (SB146 and SB149), which segregated moderate NSHL in an autosomal dominant fashion, were included in this study. We performed targeted resequencing of 134 known deafness genes (TRS-134) and bioinformatics analyses to find causative mutations for NSHL in these 2 families. Through TRS-134, we detected 2 novel mutations, i.e. c.3995G>T (p.C1332F) and c.5618C>T (p.T1873I), in the TECTA gene. These mutations cosegregated with NSHL in the studied families and were not detected in normal controls. The mutations c.3995G>T and c.5618C>T reside in the von Willebrand factor type D3-D4 (vWFD3-D4) interdomain of the zonadhesin (ZA) domain and the zona pellucida (ZP) domain, respectively. p.C1332F is the first mutation detected in the vWFD3-D4 interdomain of the ZA domain. The mutations p.C1332F and p.T1873I were associated with stable high-frequency and mid-frequency hearing loss, respectively. Notably, the cysteine residue mutated to phenylalanine in SB146 was not related to progression of sensorineural hearing loss, which argues against the previous hypothesis. Here we confirm a known genotype-phenotype correlation for the ZP domain and propose a hypothetical genotype-phenotype correlation which relates mutations in vWFD3-D4 to stable high-frequency NSHL in Koreans. This clinical feature makes subjects with the missense mutation in the vWFD3-D4 interdomain of TECTA potentially good candidates for middle ear implantation. i 2014 S. Karger AG, Basel

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

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 273
Author(s):  
Shin-ichiro Oka ◽  
Timothy F. Day ◽  
Shin-ya Nishio ◽  
Hideaki Moteki ◽  
Maiko Miyagawa ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Clinical Characteristics ◽  
Large Scale ◽  
Autosomal Dominant ◽  
Late Onset ◽  
Site Directed Mutagenesis ◽  
Molecular Characteristics ◽  
Progressive Hearing Loss ◽  
Cochlear Hair Cells

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 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.

scholarly journals Corrigendum to: NCOA3 identified as a new candidate to explain autosomal dominant progressive hearing loss

2021 ◽  
Author(s):  
R Salazar-Silva ◽  
Vitor Lima Goes Dantas ◽  
Leandro Ucela Alves ◽  
Ana Carla Batissoco ◽  
Jeanne Oiticica ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Autosomal Dominant ◽  
Progressive Hearing Loss

scholarly journals Prevalence and clinical features of autosomal dominant and recessive TMC1-associated hearing loss

2021 ◽  
Author(s):  
Shin-ya Nishio ◽  
Shin-ichi Usami
Keyword(s):  
Hearing Loss ◽  
Clinical Features ◽  
Autosomal Recessive ◽  
Haplotype Analysis ◽  
Autosomal Dominant ◽  
Founder Mutation ◽  
Family Members ◽  
Causative Gene ◽  
Pathogenic Variants ◽  
Syndromic Hearing Loss

AbstractTMC1 is a causative gene for both autosomal dominant non-syndromic hearing loss (DFNA36) and autosomal recessive non-syndromic hearing loss (DFNB7/11). To date, 125 pathogenic variants in TMC1 have been reported. Most of the TMC1 variants are responsible for autosomal recessive hearing loss, with only 8 variants reported as causative for DFNA36. Here, we reported the prevalence of TMC1-associated hearing loss in a large non-syndromic hearing loss cohort of about 12,000 subjects. As a result, we identified 26 probands with TMC1-associated hearing loss, with the estimated prevalence of TMC1-associated hearing loss in the Japanese hearing loss cohort being 0.17% among all patients. Among the 26 probands with TMC1-associated hearing loss, 15 cases were identified from autosomal dominant hearing loss families. Based on the audiometric data from the probands, family members and previously reported cases, we evaluated hearing deterioration for DFNA36 patients. In addition, we performed haplotype analysis for 11 unrelated autosomal dominant hearing loss families carrying the same variant TMC1: NM_138691:c.1627G > A:p.Asp543Asn. The results clearly indicated that the same haplotype was present despite the families being unrelated, supporting the contention that this variant occurred by founder mutation.

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