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 Ataxias with Autosomal, X-Chromosomal or Maternal Inheritance

2009 ◽  
Vol 36 (4) ◽  
pp. 409-428 ◽  
Author(s):  
Josef Finsterer
Keyword(s):  
Ataxia Telangiectasia ◽  
Large Scale ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Late Onset ◽  
Fragile X ◽  
Axonal Neuropathy ◽  
Friedreich Ataxia ◽  
Point Mutations ◽  
Spinocerebellar Ataxias

Heredoataxias are a group of genetic disorders with a cerebellar syndrome as the leading clinical manifestation. The current classification distinguishes heredoataxias according to the trait of inheritance into autosomal dominant, autosomal recessive, X-linked, and maternally inherited heredoataxias. The autosomal dominant heredoataxias are separated into spinocerebellar ataxias (SCA1-8, 10-15, 17-23, 25-30, and dentato-rubro-pallido-luysian atrophy), episodic ataxias (EA1-7), and autosomal dominant mitochondrial heredoataxias (Leigh syndrome, MIRAS, ADOAD, and AD-CPEO). The autosomal recessive ataxias are separated into Friedreich ataxia, ataxia due to vitamin E deficiency, ataxia due to Abeta-lipoproteinemia, Refsum disease, late-onset Tay-Sachs disease, cerebrotendineous xanthomatosis, spinocerebellar ataxia with axonal neuropathy, ataxia telangiectasia, ataxia telangiectasia-like disorder, ataxia with oculomotor apraxia 1 and 2, spastic ataxia of Charlevoix-Saguenay, Cayman ataxia, Marinesco-Sjögren syndrome, and autosomal recessive mitochondrial ataxias (AR-CPEO, SANDO, SCAE, AHS, IOSCA, MEMSA, LBSL CoQ-deficiency, PDC-deficiency). Only two of the heredoataxias, fragile X/tremor/ataxia syndrome, and XLSA/A are transmitted via an X-linked trait. Maternally inherited heredoataxias are due to point mutations in genes encoding for tRNAs, rRNAs, respiratory chain subunits or single large scale deletions/duplications of the mitochondrial DNA and include MELAS, MERRF, KSS, PS, MILS, NARP, and non-syndromic mitochondrial disorders. Treatment of heredoataxias is symptomatic and supportive and may have a beneficial effect in single patients.**Please see page 424 for abbreviation list.

scholarly journals Deletion of Tricellulin Causes Progressive Hearing Loss Associated with Degeneration of Cochlear Hair Cells

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Toru Kamitani ◽  
Hirofumi Sakaguchi ◽  
Atsushi Tamura ◽  
Takenori Miyashita ◽  
Yuji Yamazaki ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Progressive Hearing Loss ◽  
Cochlear Hair Cells

scholarly journals Disruption of Hars2 in Cochlear Hair Cells Causes Progressive Mitochondrial Dysfunction and Hearing Loss in Mice

2021 ◽  
Vol 15 ◽  
Author(s):  
Pengcheng Xu ◽  
Longhao Wang ◽  
Hu Peng ◽  
Huihui Liu ◽  
Hongchao Liu ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Mitochondrial Dysfunction ◽  
Hair Cells ◽  
Cell Loss ◽  
Outer Hair Cells ◽  
Hair Cell Loss ◽  
Progressive Hearing Loss ◽  
Cochlear Hair Cells ◽  
Inner Hair Cells

Mutations in a number of genes encoding mitochondrial aminoacyl-tRNA synthetases lead to non-syndromic and/or syndromic sensorineural hearing loss in humans, while their cellular and physiological pathology in cochlea has rarely been investigated in vivo. In this study, we showed that histidyl-tRNA synthetase HARS2, whose deficiency is associated with Perrault syndrome 2 (PRLTS2), is robustly expressed in postnatal mouse cochlea including the outer and inner hair cells. Targeted knockout of Hars2 in mouse hair cells resulted in delayed onset (P30), rapidly progressive hearing loss similar to the PRLTS2 hearing phenotype. Significant hair cell loss was observed starting from P45 following elevated reactive oxygen species (ROS) level and activated mitochondrial apoptotic pathway. Despite of normal ribbon synapse formation, whole-cell patch clamp of the inner hair cells revealed reduced calcium influx and compromised sustained synaptic exocytosis prior to the hair cell loss at P30, consistent with the decreased supra-threshold wave I amplitudes of the auditory brainstem response. Starting from P14, increasing proportion of morphologically abnormal mitochondria was observed by transmission electron microscope, exhibiting swelling, deformation, loss of cristae and emergence of large intrinsic vacuoles that are associated with mitochondrial dysfunction. Though the mitochondrial abnormalities are more prominent in inner hair cells, it is the outer hair cells suffering more severe cell loss. Taken together, our results suggest that conditional knockout of Hars2 in mouse cochlear hair cells leads to accumulating mitochondrial dysfunction and ROS stress, triggers progressive hearing loss highlighted by hair cell synaptopathy and apoptosis, and is differentially perceived by inner and outer hair cells.

scholarly journals Peripheral Vestibular Dysfunction Is a Common Occurrence in Children With Non-syndromic and Syndromic Genetic Hearing Loss

2021 ◽  
Vol 12 ◽  
Author(s):  
Alicia Wang ◽  
A. Eliot Shearer ◽  
Guang Wei Zhou ◽  
Margaret Kenna ◽  
Dennis Poe ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Cochlear Implantation ◽  
Vestibular Evoked Myogenic Potentials ◽  
Common Finding ◽  
Vestibular Loss ◽  
Cochlear Hair Cells ◽  
Vestibular Hair Cells ◽  
Vestibular Testing

Hearing loss (HL) is the most common sensory deficit in humans and is frequently accompanied by peripheral vestibular loss (PVL). While often overlooked, PVL is an important sensory dysfunction that may impair development of motor milestones in children and can have a significant negative impact on quality of life. In addition, many animal and in vitro models of deafness use vestibular hair cells as a proxy to study cochlear hair cells. The extent of vestibular end organ dysfunction associated with genetic pediatric hearing loss is not well-understood. We studied children with a known genetic cause of hearing loss who underwent routine preoperative vestibular testing prior to cochlear implantation between June 2014 and July 2020. Vestibular testing included videonystagmography, rotary chair, video head impulse testing, and/or vestibular evoked myogenic potentials. Etiology of HL was determined through history, physical examination, imaging, laboratory testing, and/or genetic testing. Forty-four children (21 female/23 male) met inclusion criteria; 24 had genetic non-syndromic and 20 had genetic syndromic forms of HL. Mean age at the time of testing was 2.8 ± 3.8 years (range 7 months−17 years). The most common cause of non-syndromic HL was due to mutations in GJB2 (n = 13) followed by MYO15A (3), MYO6 (2), POU3F4 (2), TMPRSS3 (1), CDH23 (1), TMC1 (1), and ESRRB (1). The most common forms of syndromic HL were Usher syndrome (4) and Waardenburg (4), followed by SCID/reticular dysgenesis (3), CHARGE (2), CAPOS (1), Coffin-Siris (1), Jervell and Lange-Nielsen (1), Noonan (1), peroxisome biogenesis disorder (1), Perrault (1), and Trisomy 21 (1). Overall, 23 patients (52%) had PVL. A larger proportion of children with syndromic forms of HL had PVL (12/20, 60%) compared with children with genetic non-syndromic HL (11/24, 46%), though without statistical significant (p = 0.3). The occurrence of PVL varied by affected gene. In conclusion, PVL is a common finding in children with syndromic and non-syndromic genetic HL undergoing vestibular evaluation prior to cochlear implantation. Improved understanding of the molecular physiology of vestibular hair cell dysfunction is important for clinical care as well as research involving vestibular hair cells in model organisms and in vitro models.

Detailed Hearing and Vestibular Profiles in the Patients with COCH Mutations

2015 ◽  
Vol 124 (1_suppl) ◽  
pp. 100S-110S ◽  
Author(s):  
Keita Tsukada ◽  
Aya Ichinose ◽  
Maiko Miyagawa ◽  
Kentaro Mori ◽  
Mitsuru Hattori ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Late Onset ◽  
Mutation Screening ◽  
Pure Tone Audiometry ◽  
Vestibular Dysfunction ◽  
Supporting Evidence ◽  
Novel Mutations ◽  
Progressive Hearing Loss ◽  
Dynamic Posturography ◽  
Short Period

Objectives: To evaluate the clinical features of Japanese DFNA9 families with mutations of the COCH gene. Methods: Mutation screening was performed using targeted next-generation sequencing (NGS) for 63 previously reported deafness genes. The progression of hearing loss and vestibular dysfunction were evaluated by pure-tone audiometry, caloric testing, cVEMP, and computed dynamic posturography. Results: We detected 1 reported mutation of p.G88E and 2 novel mutations of p.I372T and p.C542R. The patients with the novel mutations of p.I372T and p.C542R within the vWFA2 domain showed early onset progressive hearing loss, and the patients with the p.G88E mutation showed late onset hearing loss and acute hearing deterioration over a short period. Vestibular symptoms were reported in the patients with p.G88E and p.C542R. Vestibular testing was performed for the family with the p.G88E mutation. Severe vestibular dysfunction was observed in the proband, and the proband’s son showed unilateral semicircular canal dysfunction with mild hearing loss. Conclusions: Targeted exon resequencing of selected genes using NGS successfully identified mutations in the relatively rare deafness gene, COCH, in the Japanese population. The phenotype is compatible with that described in previous reports. Additional supporting evidence concerning progressive hearing loss and deterioration of vestibular function was obtained from our study.

scholarly journals A Novel Nonsense Mutation ofPOU4F3Gene Causes Autosomal Dominant Hearing Loss

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Chi Zhang ◽  
Mingming Wang ◽  
Yun Xiao ◽  
Fengguo Zhang ◽  
Yicui Zhou ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Nonsense Mutation ◽  
Autosomal Dominant ◽  
Late Onset ◽  
Stop Codon ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Chinese Family ◽  
Nonsyndromic Hearing Loss ◽  
Truncated Protein

POU4F3gene encodes a transcription factor which plays an essential role in the maturation and maintenance of hair cells in cochlea and vestibular system. Several mutations ofPOU4F3have been reported to cause autosomal dominant nonsyndromic hearing loss in recent years. In this study, we describe a pathogenic nonsense mutation located inPOU4F3in a four-generation Chinese family. Target region capture sequencing was performed to search for the candidate mutations from 81 genes related to nonsyndromic hearing loss in this family. A novel nonsense mutation ofPOU4F3, c.337C>T (p.Gln113⁎), was identified in a Chinese family characterized by late-onset progressive nonsyndromic hearing loss. The novel mutation cosegregated with hearing loss in this family and was absent in 200 ethnicity-matched controls. The mutation led to a stop codon and thus a truncated protein with no functional domains remained. Transient transfection and immunofluorescence assay revealed that the subcellular localization of the truncated protein differed markedly from normal protein, which could be the underlying reason for complete loss of its normal function. Here, we report the first nonsense mutation ofPOU4F3associated with progressive hearing loss and explored the possible underlying mechanism. Routine examination ofPOU4F3is necessary for the genetic diagnosis of hereditary hearing loss in the future.

scholarly journals Novel EYA4 variant in Slovak family with late onset autosomal dominant hearing loss: a case report

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Lukas Varga ◽  
Daniel Danis ◽  
Martina Skopkova ◽  
Ivica Masindova ◽  
Zuzana Slobodova ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Case Report ◽  
Autosomal Dominant ◽  
Late Onset

scholarly journals Deep sequencing of mitochondrial DNA and characterization of a novel POLG mutation in a patient with arPEO

2020 ◽  
Vol 6 (1) ◽  
pp. e391
Author(s):  
Carola Hedberg-Oldfors ◽  
Bertil Macao ◽  
Swaraj Basu ◽  
Christopher Lindberg ◽  
Bradley Peter ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Muscle Biopsy ◽  
Deep Sequencing ◽  
Large Scale ◽  
Biochemical Characterization ◽  
Late Onset ◽  
Novel Mutation ◽  
Progressive External Ophthalmoplegia ◽  
Oxidase Deficiency

ObjectiveTo determine the pathogenicity of a novel POLG mutation in a man with late-onset autosomal recessive progressive external ophthalmoplegia using clinical, molecular, and biochemical analyses.MethodsA multipronged approach with detailed neurologic examinations, muscle biopsy analyses, molecular genetic studies, and in vitro biochemical characterization.ResultsThe patient had slowly progressive bilateral ptosis and severely reduced horizontal and vertical gaze. Muscle biopsy showed slight variability in muscle fiber size, scattered ragged red fibers, and partial cytochrome c oxidase deficiency. Biallelic mutations were identified in the POLG gene encoding the catalytic A subunit of POLγ. One allele carried a novel mutation in the exonuclease domain (c.590T>C; p.F197S), and the other had a previously characterized null mutation in the polymerase domain (c.2740A>C; p.T914P). Biochemical characterization revealed that the novel F197S mutant protein had reduced exonuclease and DNA polymerase activities and confirmed that T914P was inactive. By deep sequencing of mitochondrial DNA (mtDNA) extracted from muscle, multiple large-scale rearrangements were mapped and quantified.ConclusionsThe patient's phenotype was caused by biallelic POLG mutations, resulting in one inactive POLγA protein (T914P) and one with decreased polymerase and exonuclease activity (F197S). The reduction in polymerase activity explains the presence of multiple pathogenic large-scale deletions in the patient's mtDNA.

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