Vestibular Functions of Hereditary Hearing Loss Patients with &lt;b&gt;&lt;i&gt;GJB2&lt;/i&gt;&lt;/b&gt; Mutations

Tsukada, Keita; Fukuoka, Hisakuni; Usami, Shin‐ichi

doi:10.1159/000368292

Cited by 11 publications

(9 citation statements)

References 33 publications

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“…Dominant GJB2 mutations related to syndromic hearing loss and skin manifestations were excluded in Family 304. Compared with the results of previous studies in which subjects with bilateral GJB2 mutations showed normal caloric responses and significantly lower cVEMP amplitudes, the vestibular function assessed by caloric tests and cVEMP were normal in this study 7 . Notably, hearing loss is an etiologically heterogeneous trait that is related to many genetic and environmental causes 8 .…”

Section: Discussioncontrasting

confidence: 91%

A novel dominant GJB2 (DFNA3) mutation in a Chinese family

Wang

2017

The Journal of the Acoustical Society of America

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To decipher the phenotype and genotype of a Chinese family with autosomal dominant non-syndromic hearing loss (ADNSHL) and a novel dominant missense mutation in the GJB2 gene (DFNA3), mutation screening of GJB2 was performed on the propositus from a five-generation ADNSHL family through polymerase chain reaction amplification and Sanger sequencing. The candidate variation and the cosegregation of the phenotype were verified in all ascertained family members. Targeted genes capture and next-generation sequencing (NGS) were performed to explore additional genetic variations. We identified the novel GJB2 mutation c.524C > A (p.P175H), which segregated with high frequency and was involved in progressive sensorineural hearing loss. One subject with an additional c.235delC mutation showed a more severe phenotype than did the other members with single GJB2 dominant variations. Four patients diagnosed with noise-induced hearing loss did not carry this mutation. No other pathogenic variations or modifier genes were identified by NGS. In conclusion, a novel missense mutation in GJB2 (DFNA3), affecting the second extracellular domain of the protein, was identified in a family with ADNSHL.Mutations in the gene GJB2, which encodes the gap junction protein connexin 26, play a key role in hereditary hearing loss and represent the most common cause of non-syndromic hearing loss 1 . Variations in GJB2 may cause either autosomal dominant or recessive non-syndromic hearing loss (NSHL) as well as syndromic hearing loss (SHL). The inheritance pattern is ultimately determined by how the variation affects the expression and function of the connexin 26 protein. More than two hundred mutations in GJB2 (DFNB1, MIM220290) have been found to be related to autosomal recessive non-syndromic hearing loss 2 , whereas only nineteen GJB2 mutations have been associated with hereditary autosomal dominant non-syndromic deafness (DFNA3, MIM601544). Previous studies of dominant GJB2 mutations are rare and have been limited to cases or simplex families. In this study, via traditional PCR and Sanger sequencing, a novel GJB2 heterozygous mutation was identified in a Chinese family with autosomal dominant non-syndromic hearing loss (ADNSHL). Results Clinical description. From Family 304, a total of 32 family members, including 16 clinically affected and 16unaffected individuals, were included in this study (Fig. 1). Among the 16 affected cases, 4 subjects had explicit noise exposure history. In this family, the 12 affected members without noise exposure history showed symmetrical and bilateral non-syndromic sensorineural hearing loss, but no clear onset age was described (although the ages of identification were generally within childhood). The propositus (IV:2) was a 26-year-old male with bilateral progressive hearing loss when he first visited our outpatient clinic in 2004. The hearing impairment initially presented at high frequencies. He showed moderate or mild hearing loss at 0.5 kHz and 1 kHz and severe or profound hearing loss at 2 kHz, 4 kHz and ...

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Section: Discussioncontrasting

confidence: 91%

A novel dominant GJB2 (DFNA3) mutation in a Chinese family

Wang

2017

The Journal of the Acoustical Society of America

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“…In another study on seven subjects with DFNB1 HI, vestibular dysfunction was bilateral in one subject and unilateral in four subjects, as revealed by either VEMP recording or the caloric test (Kasai et al, 2010 ). In a series of 23 subjects with two mutant DFNB1 alleles, only 2 had unilaterally abnormal caloric responses, but 17 showed decreased VEMP amplitudes (Tsukada et al, 2015 ), which again would suggest a saccular dysfunction. No patient in this series complained of vertigo or dizziness (Tsukada et al, 2015 ).…”

Section: Clinical Features Of Dfnb1 Himentioning

confidence: 98%

“…In a series of 23 subjects with two mutant DFNB1 alleles, only 2 had unilaterally abnormal caloric responses, but 17 showed decreased VEMP amplitudes (Tsukada et al, 2015 ), which again would suggest a saccular dysfunction. No patient in this series complained of vertigo or dizziness (Tsukada et al, 2015 ). In another study, a survey was used to assess symptoms of vestibular dysfunction in subjects with two GJB2 mutant alleles, and 127 out of 235 participants (54%) reported dizziness and vertigo (Dodson et al, 2011 ).…”

Section: Clinical Features Of Dfnb1 Himentioning

confidence: 98%

DFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated Phenotypes

Castillo

2017

Front. Mol. Neurosci.

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The inner ear is a very complex sensory organ whose development and function depend on finely balanced interactions among diverse cell types. The many different kinds of inner ear supporting cells play the essential roles of providing physical and physiological support to sensory hair cells and of maintaining cochlear homeostasis. Appropriately enough, the gene most commonly mutated among subjects with hereditary hearing impairment (HI), GJB2, encodes the connexin-26 (Cx26) gap-junction channel protein that underlies both intercellular communication among supporting cells and homeostasis of the cochlear fluids, endolymph and perilymph. GJB2 lies at the DFNB1 locus on 13q12. The specific kind of HI associated with this locus is caused by recessively-inherited mutations that inactivate the two alleles of the GJB2 gene, either in homozygous or compound heterozygous states. We describe the many diverse classes of genetic alterations that result in DFNB1 HI, such as large deletions that either destroy the GJB2 gene or remove a regulatory element essential for GJB2 expression, point mutations that interfere with promoter function or splicing, and small insertions or deletions and nucleotide substitutions that target the GJB2 coding sequence. We focus on how these alterations disrupt GJB2 and Cx26 functions and on their different effects on cochlear development and physiology. We finally discuss the diversity of clinical features of DFNB1 HI as regards severity, age of onset, inner ear malformations and vestibular dysfunction, highlighting the areas where future research should be concentrated.

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“…Concerning vestibular function, the patients showed normal vestibular function, as evaluated by caloric test and cVEMP ( Figure 5), and none of the patients showed vestibular symptoms. 33 Vestibular compensation may be related to these complications, and this possibility should be further examined in future studies. Weegerink et al 8 reported that 5 out of 9 patients showed mild hyperreflexia/hyporeflexia on rotatory and caloric tests.…”

Section: Discussionmentioning

confidence: 96%

“…32 A similar discrepancy between gene expression, vestibular testing, and vestibular symptoms has also been reported for GJB2 -associated deafness. 33 Vestibular compensation may be related to these complications, and this possibility should be further examined in future studies.…”

Section: Discussionmentioning

confidence: 96%