Identification of Pathogenic Mechanisms of<i>COCH</i>Mutations, Abolished Cochlin Secretion, and Intracellular Aggregate Formation: Genotype-Phenotype Correlations in DFNA9 Deafness and Vestibular Disorder

Bae, Sanghyuk; Robertson, Nahid G.; Cho, Hyun-Ju; Morton, Cynthia C.; Jung, Da Jung; Baek, Jeong‐In; Choi, Soo‐Young; Lee, Jaetae; Lee, Kyu-Yup; Kim, Un-Kyung

doi:10.1002/humu.22701

Cited by 55 publications

(93 citation statements)

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“…Families carrying mutations in the LCCL domain are more likely to have hearing loss and self-reported vestibular dysfunction, whereas those carrying mutations in the vWFA domain present with severe hearing loss without complaints of vestibular symptoms [20]. Up to the present time, all affected DFNA9 family members eventually endure bilateral moderate-severe to profound hearing loss starting from the high frequencies and slowly progressing to all frequencies with the onset age ranging from the 2nd decade to the 6th decade [15, 24].…”

Section: Introductionmentioning

confidence: 99%

Different Phenotypes of the Two Chinese Probands with the Same c.889G>A (p.C162Y) Mutation in COCH Gene Verify Different Mechanisms Underlying Autosomal Dominant Nonsyndromic Deafness 9

Wang

Fei

et al. 2017

PLoS ONE

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ObjectivesBy analyzing the different phenotypes of two Chinese DFNA9 families with the same mutation located in the intervening region between the LCCL and vWFA domains of cochlin and testing the functional changes in the mutant cochlin, we investigated the different pathogeneses for mutations in LCCL and vWFA domains.MethodsTargeted next-generation sequencing for deafness-related genes was used to identify the mutation in the proband in family #208. The probands of family #208 and family #32 with the same p.C162Y mutation were followed for more than 3 years to evaluate the progression of hearing loss and vestibular dysfunction using pure-tone audiometry, caloric testing, electrocochleogram, vestibular-evoked myogenic potential, and video head-impulse test. The disruption of normal cleavage to produce secreted LCCL domain fragments and the tendency to form aggregations of mutant cochlins were tested by in vitro cell experiments.ResultsThe two families showed different clinical symptoms. Family #32 was identified as having early-onset, progressive sensorineural hearing loss, similar to the symptoms in DFNA9 patients with cochlin mutations in the vWFA domain. The proband of family #208 endured late-onset recurrent paroxysmal vertigo attacks and progressively deteriorating hearing, similar to symptoms in those with cochlin mutations in the LCCL domain. We therefore suggest that the disrupted cleavage of the LCCL domain fragment is likely to cause vestibular dysfunction, and aggregation of mutant cochlin caused by mutations in the vWFA domain is responsible for early-onset hearing loss. The p.C162Y mutation causes either disruption of LCCL domain fragment cleavage or aggregation of mutant cochlin, resulting in the different phenotypes in the two families.ConclusionThis study demonstrates that DFNA9 families with the same genotype may have significantly different phenotypes. The mutation site in cochlin is related to the pathological mechanism underlying the different phenotypes.

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Section: Introductionmentioning

confidence: 99%

Different Phenotypes of the Two Chinese Probands with the Same c.889G>A (p.C162Y) Mutation in COCH Gene Verify Different Mechanisms Underlying Autosomal Dominant Nonsyndromic Deafness 9

Wang

Fei

et al. 2017

PLoS ONE

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“…This gene encodes for the Cochlin protein, which is normally secreted into the extracellular matrix of the inner ear (Fransen et al, 1999;Robertson et al, 2006;Robertson et al, 1998). Immunofluorescence and western blotting techniques have been used to assay cochlin secretion, localization, and post-translational modifications subsequent to expression in bacterial cells such as E. coli or mammalian cell lines (Bae et al, 2014;Cho et al, 2012;Grabski et al, 2003;Jung, Kim, Lee, Yang, & Choi, 2015). Compared to wild-type protein, abnormal patterns include absence of extracellular deposition (i.e.…”

Section: Functional Studies (Ps3 Ps3_supporting Bs4_supporting)mentioning

confidence: 99%

Expert Specification of the ACMG/AMP Variant Interpretation Guidelines for Genetic Hearing Loss

Oza

DiStefano

Hemphill

et al. 2018

Preprint

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(200 WORD LIMIT)Due to the high genetic heterogeneity of hearing loss, current clinical testing includes sequencing large numbers of genes, which often yields a significant number of novel variants.Therefore, the standardization of variant interpretation is crucial to provide consistent and accurate diagnoses. The Hearing Loss Variant Curation Expert Panel was created within the Clinical Genome Resource to provide expert guidance for standardized genomic interpretation in the context of hearing loss. As one of its major tasks, our Expert Panel has adapted the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards and guidelines for the interpretation of sequence variants in hearing loss genes. Here, we provide a comprehensive illustration of the newly specified ACMG/AMP . CC-BY-ND 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/313734 doi: bioRxiv preprint first posted online May. 8, 2018; hearing loss rules. Three rules remained unchanged, four rules were removed, and the remaining twenty-one rules were specified. Of the specified rules, four had general recommendations, seven were gene/disease considerations, seven had strength-level specifications, and three rules had both gene/disease and strength-level specifications. These rules were further validated and refined using a pilot set of 51 variants assessed by curators.These hearing loss-specific ACMG/AMP rules will help standardize variant interpretation, ultimately leading to better care for individuals with hearing loss.

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“…The gene encodes for the cochlin protein, which is highly expressed in the cochlea and in the vestibular system [Robertson et al, 1998;Li et al, 2005;Robertson et al, 2006]. The function of cochlin has yet to be fully understood; it is believed to assist the local immunological response and to provide structural support in the inner ear [Bhattacharya, 2006;Py et al, 2013;Bae et al, 2014]. Although interest is increasing in the genomics and pathophysiology underlying COCH-related disease and DFNA9, information about the morphological appearance at imaging are limited.…”

Section: Introductionmentioning

confidence: 99%

Audiovestibular Phenotypes and Advanced Magnetic Resonance Imaging Features of Cochlin Gene Mutation Carriers

et al. 2019

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Objective: to describe clinical and imaging findings in a group of patients affected by non-syndromic deafness A9 (DFNA9), using advanced Magnetic Resonance (MR) imaging with three-dimensional (3D) Fluid-Attenuated Inversion Recovery (FLAIR) sequence.Method: a retrospective case review was conducted in a tertiary referral center in Italy. Four sequential adult DFNA9-affected patients, who had undergone MR imaging at our Department between January 2017 and June 2018, were enrolled (Male = 2, Female = 2; median age: 65,6yr; 8 diseased ears analyzed). Three patients were relatives; the fourth was unrelated. The main outcome measures -age, sex, records of audiological and vestibular testing, genetic assessment, MR imaging findings -were analyzed.Results: All subjects suffered from bilateral progressive sensorineural hearing loss, more severe on the high frequencies and typical clinical pattern of bilateral chronic degenerative cochleo-vestibular deficit. Aural fullness was reported at the onset of the disease. All patient revealed a pathogenic heterozygous mutation in the Limulus factor C, Coch-5b2 and Lgl1 domain (LCCL) of cochlin. None of the patients showed a significant vestibular and cochlear endolymphatic hydrops at MR imaging, while high bilateral contrast enhancement on 4hs-delayed postcontrast 3D-FLAIR sequence was observed in all ears.Conclusions: increased perilymph enhancement on 4hs-delayed postcontrast 3D-FLAIR sequence is the common imaging feature of DFNA9 ears, suggesting that blood-labyrinthine barrier (BLB) breakdown may play the main role in the pathophysiology of this disease. Significant hydrops has been excluded by MR imaging. This finding might be clinically useful in differentiating DFNA9 disease from other pathologies with similar clinical findings like Ménière's disease.

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Identification of Pathogenic Mechanisms ofCOCHMutations, Abolished Cochlin Secretion, and Intracellular Aggregate Formation: Genotype-Phenotype Correlations in DFNA9 Deafness and Vestibular Disorder

Cited by 55 publications

References 42 publications

Different Phenotypes of the Two Chinese Probands with the Same c.889G>A (p.C162Y) Mutation in COCH Gene Verify Different Mechanisms Underlying Autosomal Dominant Nonsyndromic Deafness 9

Different Phenotypes of the Two Chinese Probands with the Same c.889G>A (p.C162Y) Mutation in COCH Gene Verify Different Mechanisms Underlying Autosomal Dominant Nonsyndromic Deafness 9

Expert Specification of the ACMG/AMP Variant Interpretation Guidelines for Genetic Hearing Loss

Audiovestibular Phenotypes and Advanced Magnetic Resonance Imaging Features of Cochlin Gene Mutation Carriers

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