Title: Functional analysis of missense mutations in Kv8.2 causing cone dystrophy with supernormal rod electroretinogram.

Authors: Katie E Smith, Susan E Wilkie, Joseph T Tebbs-Warner, Bradley J Jarvis, Linn Gallasch, Martin Stocker, David M Hunt

Journal, date & volume: J. Biol. Chem., 2012 Dec 21 , 287, 43972-83

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/23115240

Abstract
Mutations in KCNV2 have been proposed as the molecular basis for cone dystrophy with supernormal rod electroretinogram. KCNV2 codes for the modulatory voltage-gated potassium channel α-subunit, Kv8.2, which is incapable of forming functional channels on its own. Functional heteromeric channels are however formed with Kv2.1 in heterologous expression systems, with both α-subunit genes expressed in rod and cone photoreceptors. Of the 30 mutations identified in the KCNV2 gene, we have selected three missense mutations localized in the potassium channel pore and two missense mutations localized in the tetramerization domain for analysis. We characterized the differences between homomeric Kv2.1 and heteromeric Kv2.1/Kv8.2 channels and investigated the influence of the selected mutations on the function of heteromeric channels. We found that two pore mutations (W467G and G478R) led to the formation of nonconducting heteromeric Kv2.1/Kv8.2 channels, whereas the mutations localized in the tetramerization domain prevented heteromer generation and resulted in the formation of homomeric Kv2.1 channels only. Consequently, our study suggests the existence of two distinct molecular mechanisms involved in the disease pathology.