Referenced in: none

Automatically associated channels: Kv7.2

Title: A novel degradation signal derived from distal C-terminal frameshift mutations of KCNQ2 protein which cause neonatal epilepsy.

Authors: Jun Su, Xu Cao, Kewei Wang

Journal, date & volume: J. Biol. Chem., 2011 Dec 16 , 286, 42949-58

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/21937445

Abstract
Benign familial neonatal convulsions is an autosomal-dominant idiopathic form of epilepsy primarily caused by gene mutations of the voltage-gated Kv7.2/KCNQ2/M-channel that exert only partial dominant-negative effects. However, the mechanism underlying the incomplete dominance of channel mutations, which cause epilepsy in infancy, remains unknown. Using mutagenesis and biochemistry combined with electrophysiology, we identified a novel degradation signal derived from distal C-terminal frameshift mutations, which impairs channel function. This degradation signal, transferable to non-channel CD4, can lead to accelerated degradation of mutant proteins through ubiquitin-independent proteasome machinery but does not affect mRNA quantity and protein trafficking. Functional dissection of this signal has revealed a key five-amino acid (RCXRG) motif critical for degradation. Taken together, our findings reveal a mechanism by which proteins that carry this signal are subject to degradation, leading to M-current dysfunction, which causes epilepsy.