title: In silico modeling of the pore region of a KCNQ4 missense mutant from a patient with hearing loss.
abstract: BACKGROUND
  Mutation 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  We 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.
authors.affiliation: Laboratory of Auditory Disorders, National Institute of Sensory Organs, National Tokyo Medical Center, Tokyo, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Namba
authors.forename: Hideki
authors.initials: H
authors.lastname: Mutai
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kaneko
authors.forename: Sho
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Matsunaga
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001299:Audiometry; D001483:Base Sequence; D004252:DNA Mutational Analysis; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D051656:KCNQ Potassium Channels / Q000737:chemistry* / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity
chemical_list: D051656:KCNQ Potassium Channels; C117367:KCNQ4 protein, human