Restoration of ion channel function in deafness‐causing KCNQ4 mutants by synthetic channel openers

@article{Leitner2012RestorationOI,
 title={Restoration of ion channel function in deafness‐causing KCNQ4 mutants by synthetic channel openers},
 author={Michael G. Leitner and Anja Feuer and Olga Ebers and Daniela N. Schreiber and Christian Halaszovich and Dominik Oliver},
 journal={British Journal of Pharmacology},
 year={2012},
 volume={165},
 url={https://api.semanticscholar.org/CorpusID:205645502}
}
The possible recovery of channel activity of mutant KCNQ4 induced by syntheticKCNQ channel openers is explored.

38 Citations

Impaired surface expression and conductance of the KCNQ4 channel lead to sensorineural hearing loss
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The c.140T>C (p.Leu47Pro) mutation in KCNQ4 causes progressive NSHL; however, the defective channel activity of the mutant protein can be rescued using channel activators, and NSHL is potentially treatable, or its progression may be delayed byKCNQ activators.

Novel KCNQ4 variants in different functional domains confer genotype- and mechanism-based therapeutics in patients with nonsyndromic hearing loss
Two of the variants were prevented by drug treatment; the third variant proved resistant to the same therapeutic approach; the research contributes to the establishment of a genotype/mechanism-based therapeutic portfolio for DFNA2.

Rare KCNQ4 variants found in public databases underlie impaired channel activity that may contribute to hearing impairment
It is indicated that KCNQ4 variants may contribute more to late-onset NSHL than expected, and therefore, genetic screening for this gene is important for the prevention and treatment of NSHL.

Whole-exome sequencing identifies two novel mutations in KCNQ4 in individuals with nonsyndromic hearing loss
Two novel mutations in KCNQ4 are characterized: a missense mutation and an in-frame deletion mutation that caused complete loss-of-function with a strong dominant-negative effect on functional WT channels.

Kv7 Channels and Excitability Disorders.
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A potassium channel agonist protects hearing function and promotes outer hair cell survival in a mouse model for age-related hearing loss
For the first time in vivo, pharmacological activation of Kv7.4 activation can significantly reduce age-related threshold shifts of auditory brainstem responses as well as OHC loss in the SAMP8 model.

50 References

Mice with altered KCNQ4 K+ channels implicate sensory outer hair cells in human progressive deafness
It is concluded that the hearing loss in DFNA2 is predominantly caused by a slow degeneration of OHCs resulting from chronic depolarization.

Neuronal KCNQ potassium channels:physislogy and role in disease
Humans have over 70 potassium channel genes, but only some of these have been linked to disease. In this respect, the KCNQ family of potassium channels is exceptional: mutations in four out of five...

KCNQ4, a K+ channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway.
The expression pattern of KCNQ4 in the mouse auditory system raises the possibility of a central component in the DFNA2 hearing loss, the first ion channel shown to be specifically expressed in a sensory pathway.

A novel KCNQ4 pore-region mutation (p.G296S) causes deafness by impairing cell-surface channel expression
The results showed that the G296S mutant exerts a strong dominant-negative effect on potassium currents by reducing the wild type KCNQ4 channel expression at the cell surface.

Kv7-type Channel Currents in Spiral Ganglion Neurons
Evidence is provided of the cellular etiology and mechanisms of SGN degeneration in DFNA2 by demonstrating that a sustained increase in intracellular Ca2+ mediated by inhibition of Kv7 current results in significant SGN apoptotic death.

Cellular and Molecular Mechanisms of Autosomal Dominant Form of Progressive Hearing Loss, DFNA2*
Interestingly, 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.

Zinc pyrithione-mediated activation of voltage-gated KCNQ potassium channels rescues epileptogenic mutants.
KCNQ potassium channels are activated by changes in transmembrane voltage and play an important role in controlling electrical excitability. Human mutations of KCNQ2 and KCNQ3 potassium channel genes...

Identification of Novel Mutations in the KCNQ4 Gene of Patients with Nonsyndromic Deafness from Taiwan
The analysis revealed three novel KCNQ4 mutations and many polymorphisms, and the neural network prediction system revealed that it can potentially create a novel splice donor site during transcription.

Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy
It is predicted that a 25% loss of heteromeric KCNQ2/KCNQ3-channel function is sufficient to cause the electrical hyperexcitability in BFNC, and drugs raising intracellular cAMP may prove beneficial in this form of epilepsy.