A novel frameshift mutation in  KCNQ4  in a family with autosomal recessive non-syndromic hearing loss

Wasano, Koichiro; Mutai, Hideki; Obuchi, Chie; Masuda, Sawako; Matsunaga, Tatsuo

doi:10.1016/j.bbrc.2015.05.099

Cited by 13 publications

(18 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These rare diseases are all characterized by cardiac arrhythmias. Another mutation in a gene of the same family, KCNQ4, was recently associated to deafness and hearing loss [50]. These associations suggest that the interaction of zanamivir with KCNQ1 (3HFE_1) and perhaps other members of this family such as KCNQ4 could cause the observed side effects.…”

Section: Resultsmentioning

confidence: 99%

Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects

Chartier

Morency

Zylber

et al. 2017

BMC Pharmacol Toxicol

View full text Add to dashboard Cite

BackgroundPromiscuity in molecular interactions between small-molecules, including drugs, and proteins is widespread. Such unintended interactions can be exploited to suggest drug repurposing possibilities as well as to identify potential molecular mechanisms responsible for observed side-effects.MethodsWe perform a large-scale analysis to detect binding-site molecular interaction field similarities between the binding-sites of the primary target of 400 drugs against a dataset of 14082 cavities within 7895 different proteins representing a non-redundant dataset of all proteins with known structure. Statistically-significant cases with high levels of similarities represent potential cases where the drugs that bind the original target may in principle bind the suggested off-target. Such cases are further analysed with docking simulations to verify if indeed the drug could, in principle, bind the off-target. Diverse sources of data are integrated to associated potential cross-reactivity targets with side-effects.ResultsWe observe that promiscuous binding-sites tend to display higher levels of hydrophobic and aromatic similarities. Focusing on the most statistically significant similarities (Z-score ≥ 3.0) and corroborating docking results (RMSD < 2.0 Å), we find 2923 cases involving 140 unique drugs and 1216 unique potential cross-reactivity protein targets. We highlight a few cases with a potential for drug repurposing (acetazolamide as a chorismate pyruvate lyase inhibitor, raloxifene as a bacterial quorum sensing inhibitor) as well as to explain the side-effects of zanamivir and captopril. A web-interface permits to explore the detected similarities for each of the 400 binding-sites of the primary drug targets and visualise them for the most statistically significant cases.ConclusionsThe detection of molecular interaction field similarities provide the opportunity to suggest drug repurposing opportunities as well as to identify potential molecular mechanisms responsible for side-effects. All methods utilized are freely available and can be readily applied to new query binding-sites. All data is freely available and represents an invaluable source to identify further candidates for repurposing and suggest potential mechanisms responsible for side-effects.Electronic supplementary materialThe online version of this article (doi:10.1186/s40360-017-0128-7) contains supplementary material, which is available to authorized users.

show abstract

Section: Resultsmentioning

confidence: 99%

Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects

Chartier

Morency

Zylber

et al. 2017

BMC Pharmacol Toxicol

View full text Add to dashboard Cite

show abstract

“…To date, 20 mutations in KCNQ4 have been reported to cause hearing loss. All are located in exons 1, 4–8 of KCNQ4 (Table 3) [4, 7, 11–25]. …”

Section: Discussionmentioning

confidence: 99%

“…However, Wasano et al recently identified another novel KCNQ4 mutation, c.1044_1051del8 (p.A349Pfs), in a family with autosomal recessive NSHL [25]. This suggests that mutation in KCNQ4 can cause autosomal recessive hearing loss with a more severe phenotype than autosomal dominant hearing loss.…”

Section: Discussionmentioning

confidence: 99%

“…The age of onset of hearing loss caused by p.Q71fs in the N-terminal, p.G285C in the pore region, and p.A349Pfs in S6trans is in the first decade of life [15, 23, 25]. However, the average age of onset of hearing loss associated with the mutations p.W275R, p.G285S and p.G296S, located in the pore region, ranges from the first to the fourth decade [4, 7, 24].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A novel pore-region mutation, c.887G > A (p.G296D) in KCNQ4, causing hearing loss in a Chinese family with autosomal dominant non-syndromic deafness 2

et al. 2017

View full text Add to dashboard Cite

BackgroundHereditary non-syndromic hearing loss is the most common inherited sensory defect in humans. The KCNQ4 channel belongs to a family of potassium ion channels that play crucial roles in physiology and disease. Mutations in KCNQ4 underlie deafness non-syndromic autosomal dominant 2, a subtype of autosomal dominant, progressive, high-frequency hearing loss.MethodsA six-generation Chinese family from Hebei Province with autosomal dominantly inherited, sensorineural, postlingual, progressive hearing loss was enrolled in this study. Mutation screening of 129 genes associated with hearing loss was performed in five family members by next-generation sequencing (NGS). We also carried out variant analysis on DNA from 531 Chinese individuals with normal hearing as controls.ResultsThis family exhibits postlingual, progressive, symmetrical, bilateral, non-syndromic sensorineural hearing loss. NGS, bioinformatic analysis, and Sanger sequencing confirmed the co-segregation of a novel mutation [c.887G > A (p.G296D)] in KCNQ4 with the disease phenotype in this family. This mutation leads to a glycine-to-aspartic acid substitution at position 296 in the pore region of the KCNQ4 channel. This mutation affects a highly conserved glutamic acid. NGS is a highly efficient tool for identifying gene mutations causing heritable disease.ConclusionsProgressive hearing loss is common in individuals with KCNQ4 mutations. NGS together with Sanger sequencing confirmed that the five affected members of this Chinese family inherited a missense mutation, c.887G > A (p.G296D), in exon 6 of KCNQ4. Our results increase the number of identified KCNQ4 mutations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-017-0396-5) contains supplementary material, which is available to authorized users.

show abstract

“…) (Trune, ). Mutations in ion channels and transporters have been implicated in a number of ear disorders including hearing loss and Meniere's disease in humans (Table ) (Gao et al, ; Wang et al, ; Wasano et al, ; Lopes et al, ). A number of mouse models have been generated to decipher the role of ion channels and transporters in the auditory system (Table ) (Gao et al, ; Chang et al, ; Ito et al, ; Han et al, ; Ingham et al, ; Rainey et al, ; Rehman et al, ; Sexton et al, ).…”

Section: A Summary Of Ion Channels and Transporters Present In The Aumentioning

confidence: 99%

Indispensable Role of Ion Channels and Transporters in the Auditory System

Mittal

Aranke

Debs

et al. 2016

Journal Cellular Physiology

View full text Add to dashboard Cite

Ear is a complex system where appropriate ionic composition is essential for maintaining the tissue homeostasis and hearing function. Ion transporters and channels present in the auditory system plays a crucial role in maintaining proper ionic composition in the ear. The extracellular fluid, called endolymph, found in the cochlea of the mammalian inner ear is particularly unique due to its electrochemical properties. At an endocochlear potential of about +80 mV, signaling initiated by acoustic stimuli at the level of the hair cells is dependent on the unusually high potassium (K ) concentration of endolymph. There are ion channels and transporters that exists in the ear to ensure that K is continually being cycled into the stria media endolymph. This review is focused on the discussion of the molecular and genetic basis of previously and newly recognized ion channels and transporters that support sensory hair cell excitation based on recent knock-in and knock-out studies of these channels. This article also addresses the molecular and genetic defects and the pathophysiology behind Meniere's disease as well as how the dysregulation of these ion transporters can result in severe defects in hearing or even deafness. Understanding the role of ion channels and transporters in the auditory system will facilitate in designing effective treatment modalities against ear disorders including Meniere's disease and hearing loss. J. Cell. Physiol. 232: 743-758, 2017. © 2016 Wiley Periodicals, Inc.

show abstract

A novel frameshift mutation in KCNQ4 in a family with autosomal recessive non-syndromic hearing loss

Cited by 13 publications

References 21 publications

Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects

Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects

A novel pore-region mutation, c.887G > A (p.G296D) in KCNQ4, causing hearing loss in a Chinese family with autosomal dominant non-syndromic deafness 2

Indispensable Role of Ion Channels and Transporters in the Auditory System

Contact Info

Product

Resources

About