Novel mutations in the vWFA2 domain of COCH in two Chinese DFNA9 families

Hj, Yuan; Dy, Han; Sun, Qing‐Yuan; Yan, Da; Hj, Sun; Tao, Ran; Cheng, Jing; Qin, Wenxin; Angeli, Simón I.; Xm, Ouyang; Sz, Yang; Feng, Liqun; Jy, Cao; Gy, Feng; Wang, Yafang; Dai, Peng; Sq, Zhai; Wy, Yang; He, Lin; Xz, Liu

doi:10.1111/j.1399-0004.2008.00972.x

Cited by 25 publications

(18 citation statements)

References 12 publications

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“…In addition, a heterozygous missense mutation (p.M512T) at an evolutionarily conserved methionine residue was also identified in the vWFA2 domain in a small family. 101 More importantly, none of the C542F, C542Y and M512T mutation carriers had vestibular complaints (dizziness, vertigo, head movement-dependent oscillopsia and instability in the dark) in their lifetime. 100,101 A genotype–phenotype correlation could thus be established when comparing the vestibular involvement between the DFNA9 families harboring mutations in the LCCL domain and in the vWFA2 domain.…”

Section: Introductionmentioning

confidence: 99%

The genetic bases for non-syndromic hearing loss among Chinese

et al. 2009

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Deafness is an etiologically heterogeneous trait with many known genetic, environmental causes or a combination thereof. The identification of more than 120 independent genes for deafness has provided profound new insights into the pathophysiology of hearing. However, recent findings indicate that a large proportion of both syndromic and non-syndromic forms of deafness in the Chinese population are caused by defects in a small number of genes. Studies of the genetic epidemiology and molecular genetic features revealed that there is a clear relevance of genes causing deafness in Chinese deaf patients as well as a unique spectrum of common and rare deafness gene mutations in the Chinese population. This review is focused on the genetic aspects of non-syndromic and mitochondrial deafness, in which unique molecular genetic features of hearing impairment have been identified in the Chinese population. The current China population is approximately 1.3 billion. It is estimated that 30 000 infants are born with congenital sensorineural hearing loss each year. Better understanding of the genetic causes of deafness in the Chinese population is important for accurate genetics counseling and early diagnosis for timely intervention and treatment options.

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Section: Introductionmentioning

confidence: 99%

The genetic bases for non-syndromic hearing loss among Chinese

et al. 2009

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“…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%

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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“…The mutant cochlin accumulated in these sites may influence saccular function, consistent with the test results for the proband in family #208. Interestingly, VEMP tests were abnormal in all DFNA9 patients tested to date [14, 15], which may suggest that VEMP tests are sensitive indicators for DFNA9. In addition, our recuperative caloric testing and head impulse testing results indicate that semicircular canal functions may be normal in the intervals of the attacks.…”

Section: Discussionmentioning

confidence: 99%

“…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]. Vestibular symptoms including instability, vertigo, dizziness, tinnitus, and fall tendency are reported in those carrying mutations in the LCCL domain.…”

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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Novel mutations in the vWFA2 domain of COCH in two Chinese DFNA9 families

Cited by 25 publications

References 12 publications

The genetic bases for non-syndromic hearing loss among Chinese

The genetic bases for non-syndromic hearing loss among Chinese

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

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

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