scholarly journals Lack of collagen α6(IV) chain in mice does not cause severe-to-profound hearing loss or cochlear malformation, a distinct phenotype from nonsyndromic hearing loss with COL4A6 missense mutation

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0249909
Author(s):  
Shaoying Tang ◽  
Tomoko Yonezawa ◽  
Yukihide Maeda ◽  
Mitsuaki Ono ◽  
Takahiro Maeba ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hearing Loss ◽  
Missense Mutation ◽  
Response Analysis ◽  
Spiral Ligament ◽  
Nonsyndromic Hearing Loss ◽  
Root Cells ◽  
Hereditary Hearing Loss ◽  
Brainstem Response ◽  
Cochlear Malformation

Congenital hearing loss affects 1 in every 1000 births, with genetic mutations contributing to more than 50% of all cases. X-linked nonsyndromic hereditary hearing loss is associated with six loci (DFNX1-6) and five genes. Recently, the missense mutation (c.1771G>A, p.Gly591Ser) in COL4A6, encoding the basement membrane (BM) collagen α6(IV) chain, was shown to be associated with X-linked congenital nonsyndromic hearing loss with cochlear malformation. However, the mechanism by which the COL4A6 mutation impacts hereditary hearing loss has not yet been elucidated. Herein, we investigated Col4a6 knockout (KO) effects on hearing function and cochlear formation in mice. Immunohistochemistry showed that the collagen α6(IV) chain was distributed throughout the mouse cochlea within subepithelial BMs underlying the interdental cells, inner sulcus cells, basilar membrane, outer sulcus cells, root cells, Reissner’s membrane, and perivascular BMs in the spiral limbus, spiral ligament, and stria vascularis. However, the click-evoked auditory brainstem response analysis did not show significant changes in the hearing threshold of Col4a6 KO mice compared with wild-type (WT) mice with the same genetic background. In addition, the cochlear structures of Col4a6 KO mice did not exhibit morphological alterations, according to the results of high-resolution micro-computed tomography and histology. Hence, loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation, which differs from humans with the COL4A6 missense mutation c.1771G>A, p.Gly591Ser. Therefore, the deleterious effects in the auditory system caused by the missense mutation in COL4A6 are likely due to the dominant-negative effects of the α6(IV) chain and/or α5α6α5(IV) heterotrimer with an aberrant structure that would not occur in cases with loss of gene expression.

Mechanism of a novel missense mutation, p.V174M, of the human connexin31 (GJB3) in causing nonsyndromic hearing loss

2014 ◽  
Vol 92 (4) ◽  
pp. 251-257 ◽  
Author(s):  
Tung-Cheng Li ◽  
Yu-Hsiang Kuan ◽  
Tzu-Yu Ko ◽  
Chuan Li ◽  
Jiann-Jou Yang
Keyword(s):  
Hearing Loss ◽  
Gap Junction ◽  
Missense Mutation ◽  
Functional Change ◽  
Dominant Negative ◽  
Mutant Protein ◽  
Dominant Negative Effect ◽  
Nonsyndromic Hearing Loss ◽  
Dye Transfer ◽  
Gap Junction Channel

Hearing loss is the most common sensory disorder, worldwide. In a recent study, we have identified a missense mutation, p.V174M, in the connexin 31 encoded by the GJB3 gene, in a patient with nonsyndromic hearing loss. However, the functional change in the CX31V174M mutant remains unknown. This study compared the intracellular distribution and assembly of the mutant CX31V174M with that of the wild-type (WT) CX31 in HeLa cells, and it examined the effect that the mutant protein had on those cells. A fluorescent localization assay of WT CX31 showed the typical punctuate pattern of a gap junction channel between the neighboring expression cells. Conversely, the p.V174M missense mutation resulted in the accumulation of the mutant protein in the lysosomes rather than in the cytoplasmic membrane. Moreover, dye transfer experiments have also demonstrated that the CX31V174M mutant did not form functional gap junction channels, probably due to the incorrect assembly or the altered properties of the CX31 channels. In addition, we found that CX31V174M-transfection can cause cell death by MTT assay. CX31V174M co-expressed with either CX31WT or CX26WT studies, suggested the impairment of the ability of CX26WT proteins to intracellular trafficking and targeting to the plasma membrane, but did not influence the trafficking of CX31WT. Based on these findings, we suggest that the CX31V174M mutant may have an effect on the formation and function of the gap junction, and CX31V174M has a trans-dominant negative effect on the function of wild types CX26. These results provide a novel molecular explanation for the role that GJB3 plays in hearing loss.

scholarly journals Association of a novel missense mutation in MYO15A with nonsyndromic hearing loss: a case report

2020 ◽  
Author(s):  
Siji Wang ◽  
Ziqi Chen ◽  
Jiaqiu Dai ◽  
Xi Ouyang ◽  
Lin Zhu ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Missense Mutation ◽  
Sanger Sequencing ◽  
Three Dimensional ◽  
Sensorineural Deafness ◽  
Chinese Family ◽  
Common Disease ◽  
Compound Heterozygous ◽  
Nonsyndromic Hearing Loss ◽  
Genetic Sequencing

Abstract Background Hearing loss is a common disease globally, and more than 50% of the cases are genetic. Autosomal recessive nonsyndromic hearing loss (ARNSHL) is one of the most common types of hereditary hearing loss. Here, a novel MYO15A missense mutation was identified in a Chinese family with ARNSHL, using targeted genetic sequencing and Sanger sequencing. Case presentation: A 6-year-old girl with congenital nonsyndromic sensorineural deafness was presented from the First Affiliated hospital of Chongqing Medical University, China. We used targeted region sequencing, Sanger sequencing, functional prediction, and three-dimensional protein structure modeling to identify and verify the genes responsible for deafness in the family. Conclusions We found pathogenic compound heterozygous mutations in MYO15A, including a novel missense mutation, c.6353T > C (p.Leu2118Pro). It could provide help not only for genetic counseling but also for further understanding of the functional role of MYO15A mutations.

scholarly journals Age-Related Hearing Loss and Degeneration of Cochlear Hair Cells in Mice Lacking Thyroid Hormone Receptor β1

Endocrinology ◽  
2015 ◽  
Vol 156 (10) ◽  
pp. 3853-3865 ◽  
Author(s):  
Lily Ng ◽  
Emily Cordas ◽  
Xuefeng Wu ◽  
Kristen R. Vella ◽  
Anthony N. Hollenberg ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Thyroid Hormone ◽  
Hair Cells ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Spiral Ganglion ◽  
Spiral Ligament ◽  
Root Cells ◽  
Cochlear Hair Cells ◽  
Age Related

A key function of the thyroid hormone receptor β (Thrb) gene is in the development of auditory function. However, the roles of the 2 receptor isoforms, TRβ1 and TRβ2, expressed by the Thrb gene are unclear, and it is unknown whether these isoforms promote the maintenance as well as development of hearing. We investigated the function of TRβ1 in mice with a Thrbb1 reporter allele that expresses β-galactosidase instead of TRβ1. In the immature cochlea, β-galactosidase was detected in the greater epithelial ridge, sensory hair cells, spiral ligament, and spiral ganglion and in adulthood, at low levels in the hair cells, support cells and root cells of the outer sulcus. Although deletion of all TRβ isoforms causes severe, early-onset deafness, deletion of TRβ1 or TRβ2 individually caused no obvious hearing loss in juvenile mice. However, over subsequent months, TRβ1 deficiency resulted in progressive loss of hearing and loss of hair cells. TRβ1-deficient mice had minimal changes in serum thyroid hormone and thyrotropin levels, indicating that hormonal imbalances were unlikely to cause hearing loss. The results suggest mutually shared roles for TRβ1 and TRβ2 in cochlear development and an unexpected requirement for TRβ1 in the maintenance of hearing in adulthood.

scholarly journals Four Novel Variants in POU4F3 Cause Autosomal Dominant Nonsyndromic Hearing Loss

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Tian-Yi Cui ◽  
Xue Gao ◽  
Sha-Sha Huang ◽  
Yan-Yan Sun ◽  
Si-Qi Zhang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Autosomal Dominant ◽  
Asian Population ◽  
Nonsyndromic Hearing Loss ◽  
Hereditary Hearing Loss ◽  
Variant Of Uncertain Significance ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants ◽  
Novel Variants ◽  
Uncertain Significance

Hereditary hearing loss is one of the most common sensory disabilities worldwide. Mutation of POU domain class 4 transcription factor 3 (POU4F3) is considered the pathogenic cause of autosomal dominant nonsyndromic hearing loss (ADNSHL), designated as autosomal dominant nonsyndromic deafness 15. In this study, four novel variants in POU4F3, c.696G>T (p.Glu232Asp), c.325C>T (p.His109Tyr), c.635T>C (p.Leu212Pro), and c.183delG (p.Ala62Argfs∗22), were identified in four different Chinese families with ADNSHL by targeted next-generation sequencing and Sanger sequencing. Based on the American College of Medical Genetics and Genomics guidelines, c.183delG (p.Ala62Argfs∗22) is classified as a pathogenic variant, c.696G>T (p.Glu232Asp) and c.635T>C (p.Leu212Pro) are classified as likely pathogenic variants, and c.325C>T (p.His109Tyr) is classified as a variant of uncertain significance. Based on previous reports and the results of this study, we speculated that POU4F3 pathogenic variants are significant contributors to ADNSHL in the East Asian population. Therefore, screening of POU4F3 should be a routine examination for the diagnosis of hereditary hearing loss.

scholarly journals Gene Expression Profiles of the Cochlea and Vestibular Endorgans

2015 ◽  
Vol 124 (1_suppl) ◽  
pp. 6S-48S ◽  
Author(s):  
Shin-ya Nishio ◽  
Mitsuru Hattori ◽  
Hideaki Moteki ◽  
Keita Tsukada ◽  
Maiko Miyagawa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hearing Loss ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Profiles ◽  
Vestibular Function ◽  
Specific Expression ◽  
Hereditary Hearing Loss ◽  
Vestibular Endorgans ◽  
Gene Symbols

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.

scholarly journals A Novel Missense Mutation in the Connexin30 Causes Nonsyndromic Hearing Loss

PLoS ONE ◽  
2011 ◽  
Vol 6 (6) ◽  
pp. e21473 ◽  
Author(s):  
Wen-Hung Wang ◽  
Yu-Fan Liu ◽  
Ching-Chyuan Su ◽  
Mao-Chang Su ◽  
Shuan-Yow Li ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Missense Mutation ◽  
Nonsyndromic Hearing Loss

scholarly journals Novel form of X-linked nonsyndromic hearing loss with cochlear malformation caused by a mutation in the type IV collagen gene COL4A6

2013 ◽  
Vol 22 (2) ◽  
pp. 208-215 ◽  
Author(s):  
Simone Rost ◽  
Elisa Bach ◽  
Cordula Neuner ◽  
Indrajit Nanda ◽  
Sandra Dysek ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Type Iv Collagen ◽  
Collagen Gene ◽  
Nonsyndromic Hearing Loss ◽  
Type Iv ◽  
Cochlear Malformation

scholarly journals A Missense Mutation in POU4F3 Causes Midfrequency Hearing Loss in a Chinese ADNSHL Family

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Xue Gao ◽  
Jin-Cao Xu ◽  
Wei-Qian Wang ◽  
Yong-Yi Yuan ◽  
Dan Bai ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Missense Mutation ◽  
Autosomal Dominant ◽  
Genetic Diagnosis ◽  
Bioinformatic Analysis ◽  
Chinese Family ◽  
Nonsyndromic Hearing Loss ◽  
Family Routine ◽  
Targeted Capture ◽  
Normal Controls

Hereditary nonsyndromic hearing loss is extremely heterogeneous. Mutations in the POU class 4 transcription factor 3 (POU4F3) are known to cause autosomal dominant nonsyndromic hearing loss linked to the loci of DFNA15. In this study, we describe a pathogenic missense mutation in POU4F3 in a four-generation Chinese family (6126) with midfrequency, progressive, and postlingual autosomal dominant nonsyndromic hearing loss (ADNSHL). By combining targeted capture of 129 known deafness genes, next-generation sequencing, and bioinformatic analysis, we identified POU4F3 c.602T>C (p.Leu201Pro) as the disease-causing variant. This variant cosegregated with hearing loss in other family members but was not detected in 580 normal controls or the ExAC database and could be classified as a “pathogenic variant” according to the American College of Medical Genetics and Genomics guidelines. We conclude that POU4F3 c.602T>C (p.Leu201Pro) is related to midfrequency hearing loss in this family. Routine examination of POU4F3 is necessary for the genetic diagnosis of midfrequency hearing loss.

Cochlear malformation and sensorineural hearing loss in the Silver-Russell Syndrome

2018 ◽  
Vol 70 (6) ◽  
Author(s):  
Stefania Bigoni ◽  
Antonio Mauro ◽  
Alessandra Ferlini ◽  
Virginia Corazzi ◽  
Andrea Ciorba ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Sensorineural Hearing ◽  
Cochlear Malformation ◽  
Silver Russell Syndrome
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