Abstract
BackgroundMutation of the voltage-gated potassium channel KCNQ4 causes DFNA2-type nonsyndromic autosomal dominant sensorineural hearing loss. KCNQ4 is expressed predominantly in the auditory sensory outer hair cells, which are critical for sound amplification.ResultsWe sequenced KCNQ4 from Japanese patients with sensorineural hearing loss, and identified a novel missense mutation encoding a Tyr270His located at the N-terminus of the highly conserved pore helix sequence. As this patient was not accessible to us and information about them was limited, we used molecular modeling to investigate whether this novel mutation is hypothetically pathogenic. A careful examination of an in silico structural model of the KCNQ4 pore region revealed that the Tyr270His mutation caused an alteration in the electrostatic surface potential of the pore helix.ConclusionWe propose two possible means by which the Tyr270His mutation causes hearing loss: a positively charged His270 side chain might enhance the helix dipole moment of the pore helix, thereby destabilizing the helix and/or the pore region, or it might disturb transport of K+ through the channel by electrostatic repulsion.
Highlights
Mutation of the voltage-gated potassium channel Potassium voltage-gated channel (KCNQ4) causes Nonsyndromic autosomal dominant sensorineural deafness type 2 (DFNA2)-type nonsyndromic autosomal dominant sensorineural hearing loss
Prior to this report, 14 missense mutations, a splice-site mutation, and 2 small deletion mutations in KCNQ4 were reported to be associated with hearing loss [7,8,9]
Because 11 of the missense mutations were found in the pore region, it was considered a pathogenic “hot spot”
Summary
Mutation of the voltage-gated potassium channel KCNQ4 causes DFNA2-type nonsyndromic autosomal dominant sensorineural hearing loss. The genetic causes of nonsyndromic hearing loss are autosomal dominant, autosomal recessive, X-chromosome linked, and mitochondrial in nature. 25, 40, 3, and 6 genes have been identified that are responsible for autosomal dominant-, autosomal recessive-, X-chromosome linked-, and mitochondrial hearing loss, respectively http://hereditaryhearingloss.org/. Autosomal dominant nonsyndromic sensorineural deafness type 2 (DFNA2) hearing loss affects the ability of children to hear high frequencies, and results in hearing loss at all frequencies later in life [4]. KCNQ4 is the causative gene [5] and encodes the membrane protein KQT-like, subfamily member 4, KCNQ4 is a member of the five muscarinic receptorregulated and voltage-gated potassium (M-type K+ channel) channels present in ear and epithelia [6]. Because patients with KCNQ4 mutations show progressive hearing loss, development of drugs that improve KCNQ4 function should attenuate hearing loss
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