Novel COCH mutation in a family with autosomal dominant late onset sensorineural hearing impairment and tinnitus

Gallant, Emily; Francey, Lauren J.; Fetting, Heather; Kaur, Maninder; Hákonarson, Hákon; Clark, Dinah; Devoto, Marcella; Krantz, Ian D.

doi:10.1016/j.amjoto.2012.11.002

Cited by 30 publications

(28 citation statements)

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“…We performed a comprehensive review and analysis of previously collected and reported clinical information on individuals and families with all 21 currently known COCH mutations (14 in the LCCL domain and seven in the vWFA domains), in addition to molecular characteristics of mutant cochlins from our new findings in this study and from past reports [Robertson et al., , ; de Kok et al., ; Fransen and Van Camp, ; Fransen et al., ; Kamarinos et al., ; Grabski et al., ; Usami et al., ; Nagy et al., ; Kemperman et al., ; Street et al., ; Collin et al., ; Pauw et al., , ; Yuan et al., ; Hildebrand et al., ; Baek et al., ; Hildebrand et al., ; Yao et al., ; Faletra et al., ; Cho et al.,) ; Dodson et al., ; Chen et al., ; Choi et al., ; Gallant et al., ; Gao et al., ]. These results are summarized in Table .…”

Section: Resultsmentioning

confidence: 99%

“…Since the identification of COCH as the causative gene for DFNA9 in 1998, 21 COCH mutations have been reported, and several mechanisms by which COCH mutations cause hearing defects and vestibular disorder have been proposed [Robertson et al., ; de Kok et al., ; Kamarinos et al., ; Usami et al., ; Nagy et al., ; Street et al., ; Collin et al., ; Pauw et al., ; Yuan et al., ; Hildebrand et al., ; Yao et al., ; Faletra et al., ; Cho et al., ; Dodson et al., ; Chen et al., ; Choi et al., ; Gallant et al., ; Gao et al., ]. However, the exact function of cochlin and the role of cochlin mutations in hearing loss and vestibular dysfunction remain to be elucidated fully.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in COCH are causative of autosomal‐dominant nonsyndromic hearing loss, DFNA9, which has a late onset (ranging from 2 nd to 7 th decade of life) and progressive presentation, with variable degrees of vestibular malfunction such as dizziness, vertigo, and instability in the dark. To date, 21 COCH mutations (19 missense and two in‐frame deletions) have been reported throughout the world [Robertson et al., ; de Kok et al., ; Kamarinos et al., ; Usami et al., ; Nagy et al., ; Street et al., ; Collin et al., ; Pauw et al., , ; Yuan et al., ; Hildebrand et al., ; Faletra et al., ; Cho et al., ; Dodson et al., ; Chen et al., ; Choi et al., ; Gallant et al., ; Gao et al., ]. The true worldwide incidence of COCH mutations is not known, as systematic genetic screening for this and other genes resulting in late‐onset disorders is typically not performed.…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2014

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Mutations in COCH cause autosomal dominant non-syndromic hearing loss with variable degrees of clinical onset and vestibular malfunction. We selected eight uncharacterized mutations and performed immunocytochemical and Western blot analyses to track cochlin through the secretory pathway. We then performed a comprehensive analysis of clinical information from DFNA9 patients with all 21 known COCH mutations in conjunction with cellular and molecular findings to identify genotype-phenotype correlations. Our studies revealed that five mutants were not secreted into the media: two vWFA domain mutants, which were not transported from the ER to Golgi complex and formed high-molecular-weight aggregates in cell lysates; and three LCCL domain mutants, which were detected as intracellular dimeric cochlins. Mutant cochlins that were not secreted and accumulated in cells result in earlier age of onset of hearing defects. In addition, individuals with LCCL domain mutations show accompanying vestibular dysfunction, whereas those with vWFA domain mutations exhibit predominantly hearing loss. This is the first report showing failure of mutant cochlin transport through the secretory pathway, abolishment of cochlin secretion, and formation and retention of dimers and large multimeric intracellular aggregates, and high correlation with earlier onset and progression of hearing loss in individuals with these DFNA9-causing mutations.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

et al. 2014

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“…The COCH protein, cochlin, is abundantly expressed in the cochlea and vestibular system of the inner ear. Mutations in the COCH gene lead to autosomal dominant nonsyndromic sensorineural deafness 9 (DFNA9), which has been clinically characterized by progressive late-onset hearing loss with or without vestibular dysfunction [ 29 ]. Presently, 18 COCH mutations have been identified in DFNA9 families ( http://www.hgmd.org/ , designed by P.D.Stenson HGMD®), most of which are located in the LCCL region.…”

Section: Discussionmentioning

confidence: 99%

Targeted genomic capture and massively parallel sequencing to identify novel variants causing Chinese hereditary hearing loss

et al. 2014

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BackgroundHereditary hearing loss is genetically heterogeneous, and hundreds of mutations in than 60 genes are involved in this disease. Therefore, it is difficult to identify the causative gene mutations involved. In this study, we combined targeted genomic capture and massively parallel sequencing (MPS) to address this issue.MethodsUsing targeted genomic capture and MPS, 104 genes and three microRNA regions were selected and simultaneously sequenced in 23 unrelated probands of Chinese families with nonsyndromic hearing loss. The results were validated by Sanger sequencing for all available members of the probands’ families. To analyze the possible pathogenic functional effects of the variants, three types of prediction programs (Mutation Taster, PROVEAN and SIFT) were used. A total of 195 healthy Chinese Han individuals were compared as controls to verify the novel causative mutations.ResultsOf the 23 probands, six had mutations in DFNA genes [WFS1 (n = 2), COCH, ACTG1, TMC1, and POU4F3] known to cause autosomal dominant nonsyndromic hearing loss. These included one novel in-frame indel mutation, three novel missense mutations and two reported missense mutations. Furthermore, one proband from a family with recessive DFNB carried two monoallelic mutations in the GJB2 and USH2A genes. All of these mutations co-segregated with the hearing loss phenotype in 36 affected individuals from 7 families and were predicted to be pathogenic.ConclusionsMutations in uncommon deafness genes contribute to a portion of nonsyndromic deafness cases. In the future, critical gene mutations may be accurately and quickly identified in families with hereditary hearing loss by targeted genomic capture and MPS.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-014-0311-1) contains supplementary material, which is available to authorized users.

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“…Esta heterogeneidad fenotípica que se aprecia en los pacientes con acúfenos explicaría, al menos en parte, porque han fracasado los intentos por encontrar marcadores genéticos en los pacientes con acúfeno crónico (10)(11)(12)(13)(14)(15). Precisamente, la dificultad para definir las características psicoacústicas de los acufenos, intensidad y frecuencia principalmente, permite comprender por qué los estudios de agregación familiar no han demostrado ninguna heredabilidad (16), y que no se haya podido establecer diferencias en la prevalencia de los acúfenos de acuerdo al origen étnico de la población (17)(18)(19).…”

Section: Genética De Los Acúfenosunclassified

Role of inheritance in tinnitus: it is time to search the genome

López-Escámez¹,

Cederroth²,

Espinosa-Sánchez³

2017

Actual. Med

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Papel de la herencia en los acúfenos: es hora de buscar en el genoma ResumenLos acúfenos son un síntoma frecuente que puede estar causado por muy diversas enfermedades y que, independientemente de sus características psicoacústicas, tienen una repercusión muy variable en la calidad de vida de cada individuo afecto. Esta heterogeneidad clínica hace que hoy día se considere imprescindible una mejora en la definición del fenotipo y una categorización según distintos subtipos para que la investigación avance en esta área. Los factores hereditarios pueden ser importantes en algunos tipos de acúfenos. Los estudios previos de agregación familiar y de concordancia entre gemelos monocigóticos que habían evaluado el papel de la herencia en los acúfenos no han podido encontrar una contribución significativa de los factores genéticos en la aparición de los acufenos. Sin embargo, estos diseños han incluido un espectro clínico muy amplio de pacientes con acúfenos Un estudio reciente realizado sobre una cohorte de gemelos suecos ha evidenciado que existe una heredabilidad significativa entre los pacientes con acúfenos bilaterales. Esto demuestra la heterogeneidad clínica y la necesidad de establecer una caracterización fenotípica de los pacientes con acúfenos para definir la contribución de los factores genéticos en subgrupos específicos de pacientes. De este modo se podría desarrollar un tratamiento personalizados y más efectivo. AbstractTinnitus is a common symptom that may be caused by a variety of diseases. Its impact on the quality of life differs widely for each patient, regardless of their psychoacoustic characteristics. This clinical heterogeneity makes it essential a precise phenotyping and subtyping for tinnitus research nowadays. Hereditary factors could be important in some tinnitus subtypes. Previous familial aggregation studies and concordance studies in monozygotic twins have assessed the role of inheritance in tinnitus, but they have not evidenced a significant influence of genetic factors to tinnitus. However, these studies have included a wide spectrum of tinnitus patients. A recent Swedish twin study has shown a significant heritability in patients with bilateral tinnitus. This demonstrates the clinical heterogeneity and the need for a deep phenotyping to define the contribution of genetic factors to specific subtypes of tinnitus patients to develop a personalized and more effective treatment. Enviado: 28-07-2017 Revisado: 10-08-2017 Aceptado: 20-08-2017 Jose Antonio Lopez-Escamez, MD, PhD Centro Pfizer -Universidad de Granada -Junta de Andalucía de Genómica e Investigación Oncológica (GENYO Actual. Med. 2017; 102: (801): 88-92 INTRODUCCIÓNLos acúfenos son la percepción de un sonido en ausencia de un estímulo sonoro externo. Afectan al 5-15% de la población adulta, aumentando su frecuencia al incrementarse la edad, y en el 1% ocasionan un problema importante por su impacto en la calidad de vida relacionada con la salud (1).La fisiopatología de los acúfenos es compleja y todavía no es bien comprendid...

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Novel COCH mutation in a family with autosomal dominant late onset sensorineural hearing impairment and tinnitus

Cited by 30 publications

References 14 publications

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

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

Targeted genomic capture and massively parallel sequencing to identify novel variants causing Chinese hereditary hearing loss

Role of inheritance in tinnitus: it is time to search the genome

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