A novel KCNQ4 pore-region mutation (p.G296S) causes deafness by impairing cell-surface channel expression |
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Authors: | Ángeles Mencía Daniel González-Nieto Silvia Modamio-Høybjør Ainhoa Etxeberría Gracia Aránguez Nieves Salvador Ignacio del Castillo Álvaro Villarroel Felipe Moreno Luis Barrio Miguel Ángel Moreno-Pelayo |
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Institution: | Unidad de Genética Molecular, Hospital Ramón y Cajal, Carretera de Colmenar Km 9, 28034, Madrid, Spain. |
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Abstract: | Mutations in the potassium channel gene KCNQ4 underlie DFNA2, a subtype of autosomal dominant progressive, high-frequency hearing loss. Based on a phenotype-guided mutational
screening we have identified a novel mutation c.886G>A, leading to the p.G296S substitution in the pore region of KCNQ4 channel.
The possible impact of this mutation on total KCNQ4 protein expression, relative surface expression and channel function was
investigated. When the G296S mutant was expressed in Xenopus oocytes, electrophysiological recordings did not show voltage-activated K+ currents. The p.G296S mutation impaired KCNQ4 channel activity in two manners. It greatly reduced surface expression and,
secondarily, abolished channel function. The deficient expression at the cell surface membrane was further confirmed in non-permeabilized
NIH-3T3 cells transfected with the mutant KCNQ4 tagged with the hemagglutinin epitope in the extracellular S1–S2 linker. Co-expression
of mutant and wild type KCNQ4 in oocytes was performed to mimic the heterozygous condition of the p.G296S mutation in the
patients. 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. This is the first study to identify a trafficking-dependent dominant
mechanism for the loss of KCNQ4 channel function in DFNA2. |
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