title: A novel degradation signal derived from distal C-terminal frameshift mutations of KCNQ2 protein which cause neonatal epilepsy.
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.
authors.affiliation: Department of Neurobiology, Neuroscience Research Institute, Peking University Health Science Center, Peking University School of Pharmaceutical Sciences, Beijing 100191, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Su
authors.forename: Xu
authors.initials: X
authors.lastname: Cao
authors.forename: KeWei
authors.initials: K
authors.lastname: Wang
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D004594:Electrophysiology; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism*; D016368:Frameshift Mutation / Q000235:genetics*; D006801:Humans; D051658:KCNQ2 Potassium Channel / Q000235:genetics* / Q000378:metabolism*; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D051658:KCNQ2 Potassium Channel