In silico modeling of the pore region of a KCNQ4 missense mutant from a patient with hearing loss

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.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.Deafness is a frequently inherited sensory disorder. For every 1000 newborns, more than 1% have bilateral sensorineural hearing loss (SNHL), and 50-70% of the cases are monogenic disorders [1,2]. Hereditary hearing loss is classified as syndromic and nonsyndromic [3]. The genetic causes of nonsyndromic hearing loss are autosomal dominant, autosomal recessive, X-chromosome linked, and mitochondrial in nature. To date, 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/ webcite. In particular, 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, which contains 695 amino acid residues in its longest isoform.KCNQ4 is a member of the five muscarinic receptor-regulated and voltage-gate