Phenotype Analysis of an Australian DFNA9 Family with the I109N <i>COCH</i> Mutation

Pauw, Robert Jan; Huygen, P.L.M.; Colditz, Graham A.; Cremers, C.W.R.J.

doi:10.1177/000348941112000612

Cited by 8 publications

(11 citation statements)

References 27 publications

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“…Mutant cochlins may have either abnormal formation of an intramolecular disulfide bond or impaired post-translational cleavage to produce two shorter fragments [21–26]. We tested the functional changes of the p.C162Y mutant cochlin.…”

Section: Resultsmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

“…Only the c.889G>A (p.C162Y) variant was located in exon 7 encoding the ivd1 domain [17]. These missense mutations and in-frame deletions in COCH gene are etiologically linked to autosomal dominant nonsyndromic deafness 9 (DFNA9), a disorder characterized by late onset and progressive hearing loss and vestibular dysfunction [18–21]. …”

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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“…In addition, there is aggregation of cochlin in the areas that normally express the protein . These deficits can begin to appear at any time in adulthood: early or late …”

Section: Discussionmentioning

confidence: 99%

Genetic Variants Associated With Vincristine‐Induced Peripheral Neuropathy in Two Populations of Children With Acute Lymphoblastic Leukemia

Sajdyk

Smith

et al. 2019

Clin Pharma and Therapeutics

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Vincristine is one of the core chemotherapy agents used in the treatment of pediatric acute lymphoblastic leukemia (ALL). However, one of the major toxicities resulting from vincristine exposure is vincristine‐induced peripheral neuropathy (VIPN). When VIPN results in significant morbidity, the vincristine dose may need to be reduced, thus potentially decreasing the effectiveness of treatment. To date, there are no robust biomarkers used clinically to determine which patients will be at risk for worse neuropathy. The current study included genomewide association study (GWAS) in two independent cohorts: Pediatric Oncology Group (POG) ALL trials and a multicenter study based at Indiana University in children with ALL. A meta‐analysis of the cohorts identified two single‐nucleotide polymorphisms (SNPs), rs1045644 and rs7963521, as being significantly (P value threshold 0.05/4749 = 1.05E‐05) associated with neuropathy. Subsequently these SNPs may be effective biomarkers of VIPN in children with ALL.

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“…The autosomal dominant nonsyndromic hearing disorder DFNA9 is characterized by late onset bilateral progressive high-frequency sensorineural hearing impairment with associated variable vestibular dysfunction and starts to manifest between 20 and 50 years of age [ 24 ]. Its features are similar to those of ARHI but hearing deterioration with DFNA9 occurs at a younger age.…”

Section: Genes Causing Monogenic Hearing Impairment With Phenotypimentioning

confidence: 99%

Progress and Prospects in Human Genetic Research into Age-Related Hearing Impairment

Uchida

Sugiura

Nakashima

2014

BioMed Research International

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Age-related hearing impairment (ARHI) is a complex, multifactorial disorder that is attributable to confounding intrinsic and extrinsic factors. The degree of impairment shows substantial variation between individuals, as is also observed in the senescence of other functions. This individual variation would seem to refute the stereotypical view that hearing deterioration with age is inevitable and may indicate that there is ample scope for preventive intervention. Genetic predisposition could account for a sizable proportion of interindividual variation. Over the past decade or so, tremendous progress has been made through research into the genetics of various forms of hearing impairment, including ARHI and our knowledge of the complex mechanisms of auditory function has increased substantially. Here, we give an overview of recent investigations aimed at identifying the genetic risk factors involved in ARHI and of what we currently know about its pathophysiology. This review is divided into the following sections: (i) genes causing monogenic hearing impairment with phenotypic similarities to ARHI; (ii) genes involved in oxidative stress, biologic stress responses, and mitochondrial dysfunction; and (iii) candidate genes for senescence, other geriatric diseases, and neurodegeneration. Progress and prospects in genetic research are discussed.

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Phenotype Analysis of an Australian DFNA9 Family with the I109N COCH Mutation

Abstract: The phenotype associated with the I109N COCH mutation is largely similar to that associated with the I109T, P51S, G87W, and G88E mutation carriers. However, subtle differences seem to exist in terms of age of onset and rate of progression.

Cited by 8 publications

References 27 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

Genetic Variants Associated With Vincristine‐Induced Peripheral Neuropathy in Two Populations of Children With Acute Lymphoblastic Leukemia

Progress and Prospects in Human Genetic Research into Age-Related Hearing Impairment

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