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.