Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011053 (deafness)
 10,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Potassium channels regulate electrical signaling and the ionic composition of biological fluids. Mutations in the three known genes of the KCNQ branch of the K+ channel gene family underlie inherited cardiac arrhythmias (in some cases associated with deafness) and neonatal epilepsy. We have now cloned KCNQ4, a novel member of this branch. It maps to the DFNA2 locus for a form of nonsyndromic dominant deafness. In the cochlea, it is expressed in sensory outer hair cells. A mutation in this gene in a DFNA2 pedigree changes a residue in the KCNQ4 pore region. It abolishes the potassium currents of wild-type KCNQ4 on which it exerts a strong dominant-negative effect. Whereas mutations in KCNQ1 cause deafness by affecting endolymph secretion, the mechanism leading to KCNQ4-related hearing loss is intrinsic to outer hair cells.
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PMID:KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. 1002 9

Mutations in the GJB3 gene encoding connexin31 (Cx31) can cause a dominant non-syndromic form of hearing loss (DFNA2). To determine whether mutations at this locus can also cause recessive non-syndromic deafness, we screened 25 Chinese families with recessive deafness and identified in two families affected individuals who were compound heterozygotes for Cx31 mutations. The three affected individuals in the two families were born to non-consanguineous parents and had an early onset bilateral sensorineural hearing loss. In both families, differing SSCP patterns were observed in affected and unaffected individuals. Sequence analysis in both families demonstrated an in-frame 3 bp deletion (423-425delATT) in one allele, which leads to the loss of an isoleucine residue at codon 141, and a 423A-->G transversion in the other allele, which creates an Ile-->Val substitution at codon 141 (I141V). Neither of these two mutations was detected in DNA from 100 unrelated control subjects. The altered isoleucine residue lies within the third conserved alpha-helical transmembrane domain (M3), which is critical for the formation of the wall of the gap junction pore. Both the deletion of the isoleucine residue 141 and its substitution to valine in the two families could alter the structure of M3, and impair the function of the gap junction. The present data demonstrate that, like mutations in connexin26, mutations in Cx31 can lead to both recessive and dominant forms of non-syndromic deafness.
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PMID:Mutations in connexin31 underlie recessive as well as dominant non-syndromic hearing loss. 1058 79

DFNA2 is a locus for autosomal dominant non-syndromal hearing impairment (ADNSHI) located on chromosome 1p34 and six linked families have been identified. An audiometric study of these families showed that despite small differences in the phenotype all families suffer from progressive hearing impairment starting in the high frequencies. A detailed genetic analysis revealed that this deafness locus contains more than one gene responsible for hearing impairment. Thus far, two genes on chromosome 1p34 have been implicated in ADNSHI. The first, connexin 31 (GJB3), is a member of the connexin gene family. Connexins form gap junctions. These are connections between neighbouring cells that allow transport of small molecules. GJB3 mutations were found in two small Chinese families with ADNSHI. The second is KCNQ4, a voltage-gated K+ channel. Mutations in KCNQ4 were first found in a small French family, later in five of the six linked DFNA2 families. No GJB3 or KCNQ4 mutations were detected in patients of an extended Indonesian DFNA2 family. Two pathways have been proposed for the recycling of K+ from the hair cells back to the endolymph. These pathways involve the use of gap junctions, K+ pumps and K+ channels. The expression of GJB3 and KCNQ4 in the inner ear and their functions suggest that both DFNA2 genes may play a role in K+ homeostasis.
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PMID:The DFNA2 locus for hearing impairment: two genes regulating K+ ion recycling in the inner ear. 1089 Jan 42

DFNA2 is a complex locus. Two hearing loss genes have been identified at this site: GJB3, the gene that encodes the gap junction protein connexin 31, and KCNQ4, a voltage-gated potassium channel gene. A third gene has previously been postulated to explain the hearing loss in an Indonesian family linked to the region but devoid of mutation in either known gene (Van Hauwe et al. [1999: Nat Genet 21:263]). We have identified a large five-generation family with nonsyndromic, autosomal dominant progressive high-frequency hearing loss. The hearing impairment maps to 1p34, the site of the DFNA2 locus. Two-point linkage analysis of microsatellite markers spanning the locus resulted in a lod score of 6.6 at D1S391 at theta = 0. We have investigated both identified deafness genes in affected and unaffected family members and have not found any disease-causing mutations, suggesting that another hearing impairment gene resides at the DFNA2 locus.
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PMID:Further evidence for a third deafness gene within the DFNA2 locus. 1192 Aug 35

A large American family has been mapped to the DFNA2 locus. However, mutation screening of CX31 and KCNQ4, the two genes associated with deafness at this locus, did not identify any mutations. The purpose of this report was to characterize the otologic and audiometric phenotype of this large American family with non-syndromic, autosomal-dominant sensorineural hereditary hearing impairment (HHI). Anamnestic data were obtained, pure-tone audiometry was performed and transient-evoked otoacoustic emissions were recorded. The findings in affected family members were compared to those in unaffected family members and to the respective p50 thresholds of the normal age-matched population. Mutational analysis of the CX26 gene was also performed. The affected members of this family demonstrated progressive symmetric sensorineural hearing impairment. The hearing loss was downward sloping, with mild-to-moderate loss in the low and mid frequencies and severe-to-profound loss in frequencies > 4,000 Hz. The onset of disease was predominantly in the first or early in the second decade. Hearing impairment progressed at approximately 1 dB per year across all frequencies. Transient-evoked otoacoustic emissions revealed a minimal response over all frequencies in affected members but robust responses in all unaffected members. Mutation in the CX26 gene was not present. The affected frequencies observed in this family were similar to those in the original family mapped to DFNA2; however, the age of onset of disease was different and the hearing loss progressed at a slower rate. Therefore, this family provides clinical evidence of genetic heterogeneity at the DFNA2 locus and can serve as a model for age-related hearing loss.
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PMID:Audiologic evidence for further genetic heterogeneity at DFNA2. 1248 50

Mutations in GJB3, the gene encoding the gap junction protein Connexin 31 (CX31), have been pathogenically linked to erythrokeratodermia and non-syndromic autosomal dominant (DFNA2) or recessive hereditary hearing impairment (HHI). To determine the contribution of CX31 to sporadic deafness, we assessed 63 individuals with non-syndromic hearing impairment for CX31 mutations. Single coding exon of CX31 was amplified from genomic DNA and then sequenced. Single nucleotide sequence alteration was present in 15 out of 63 patients (24%), all of the positives being heterozygous for the four different single base pair changes that were detected: C94T, C201T, C357T and C798T. Of these, only C94T transition, identified in two patients, results in amino acid change, R32W, while the other three changes are single nucleotide polymorphisms (SNPs). The R32W substitution in CX31 has been previously documented and is speculated to manifest variable penetrance, similar to the polymorphic allele encoding CX26M34T. Over one-third of all samples were also screened with denaturing high-performance liquid chromatography (dHPLC). Seven out of 25 individuals screened were determined to be positive for CX31 sequence variation. Sequence analysis of the 25 individuals screened identified nucleotide alterations in all of the 7 'positives' and in none of the 16 'negatives' yielding a specificity and sensitivity of 100%. Thus, dHPLC represents a highly efficient CX31 screening technique. This study suggests that while sequence alterations are common, pathogenic mutations of CX31 are infrequent in sporadic non-syndromic hearing impairment.
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PMID:Mutation analysis of Connexin 31 (GJB3) in sporadic non-syndromic hearing impairment. 1263 Sep 65

In the inner ear, hair cell function is inextricably linked with intracellular potassium homeostasis. KCNQ potassium channels may play an important role by preventing accumulation of potassium in the hair cells. Linopirdine, a tool useful in targeting native or heterologous KCNQ channels, was used to study the role of KCNQ channels in the guinea pig cochlea. When perfused into intact cochlea, linopirdine transiently increases the summating potential and endocochlear potential, suggesting that it alters K+ homeostasis. The concomitant decrease in cochlear microphonic potential and distortion product otoacoustic emission amplitude indicates that linopirdine has an effect on the outer hair cells (OHCs). To determine the pathological consequences of the inhibition of cochlear KCNQ channels, we developed a hearing loss model based on a chronic intracochlear perfusion of linopirdine via an osmotic minipump. Ultrastructural analysis reveals that KCNQ channel blockade leads to OHC degeneration. Together, these results demonstrate that KCNQ channels, most probably of the KCNQ4 subtype, are crucial for the function and survival of sensory OHCs. Clinically, KCNQ4 channel dysfunction is known to be associated with the DFNA2 form of nonsyndromic dominant deafness. Our study shows that OHC KCNQ4 dysfunction could contribute to the early (40dB) hearing loss, but not for the profound deafness observed at the final stage of this disease.
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PMID:Degeneration of sensory outer hair cells following pharmacological blockade of cochlear KCNQ channels in the adult guinea pig. 1282 62

Targeting and downregulating specific genes with antisense and decoy oligonucleotides, ribozymes or RNA interference (RNAi) offer the theoretical potential of altering a disease phenotype. Here we review the molecular mechanism behind the in vivo application of RNAi-mediated gene silencing, focusing on its application to the inner ear. RNAi is a physiological phenomenon in which small, double-stranded RNA molecules (small interfering RNA, siRNA) reduce expression of homologous genes. Notable for its exquisite sequence specificity, it is ideally applied to diseases caused by a gain-of-function mechanism of action. Types of deafness in which gain-of-function mutations are observed include DFNA2 (KCNQ4), DFNA3 (GJB2) and DFNA5 (DFNA5). Several strategies can be used to deliver siRNA into the inner ear, including cationic liposomes, adeno-associated and lentiviral vectors, and adenoviral vectors. Transduction efficiency with cationic liposomes is low and the effect is transient; with adeno-associated and lentiviral vectors, long-term transfection is possible using a small hairpin RNA expression cassette.
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PMID:Therapeutic regulation of gene expression in the inner ear using RNA interference. 1949 70

Despite advances in identifying deafness genes, determination of the underlying cellular and functional mechanisms for auditory diseases remains a challenge. Mutations of the human K(+) channel hKv7.4 lead to post-lingual progressive hearing loss (DFNA2), which affects world-wide population with diverse racial backgrounds. Here, we have generated the spectrum of point mutations in the hKv7.4 that have been identified as diseased mutants. We report that expression of five point mutations in the pore region, namely L274H, W276S, L281S, G285C, and G296S, as well as the C-terminal mutant G321S in the heterologous expression system, yielded non-functional channels because of endoplasmic reticulum retention of the mutant channels. We mimicked the dominant diseased conditions by co-expressing the wild-type and mutant channels. As compared with expression of wild-type channel alone, the blend of wild-type and mutant channel subunits resulted in reduced currents. Moreover, the combinatorial ratios of wild type:mutant and the ensuing current magnitude could not be explained by the predictions of a tetrameric channel and a dominant negative effect of the mutant subunits. The results can be explained by the dependence of cell surface expression of the mutant on the wild-type subunit. Surprisingly, a transmembrane mutation F182L, which has been identified in a pre-lingual progressive hearing loss patient in Taiwan, yielded cell surface expression and functional features that were similar to that of the wild type, suggesting that this mutation may represent redundant polymorphism. Collectively, these findings provide traces of the cellular mechanisms for DFNA2.
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PMID:Cellular and molecular mechanisms of autosomal dominant form of progressive hearing loss, DFNA2. 2096 80

Mutations inactivating the potassium channel KCNQ4 (K(v)7.4) lead to deafness in humans and mice. In addition to its expression in mechanosensitive hair cells of the inner ear, KCNQ4 is found in the auditory pathway and in trigeminal nuclei that convey somatosensory information. We have now detected KCNQ4 in the peripheral nerve endings of cutaneous rapidly adapting hair follicle and Meissner corpuscle mechanoreceptors from mice and humans. Electrophysiological recordings from single afferents from Kcnq4(-/-) mice and mice carrying a KCNQ4 mutation found in DFNA2-type monogenic dominant human hearing loss showed elevated mechanosensitivity and altered frequency response of rapidly adapting, but not of slowly adapting nor of D-hair, mechanoreceptor neurons. Human subjects from independent DFNA2 pedigrees outperformed age-matched control subjects when tested for vibrotactile acuity at low frequencies. This work describes a gene mutation that modulates touch sensitivity in mice and humans and establishes KCNQ4 as a specific molecular marker for rapidly adapting Meissner and a subset of hair follicle afferents.
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PMID:KCNQ4 K(+) channels tune mechanoreceptors for normal touch sensation in mouse and man. 2219 51


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