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: Jun Su, Xu Cao, KeWei Wang
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 286 Issue 50 Pg. 42949-58 (Dec 16 2011) ISSN: 1083-351X [Electronic] United States
• PMID: 21937445 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• KCNQ2 Potassium Channel

Topics

• Blotting, Western
• Cell Line
• Electrophysiology
• Epilepsy (genetics, metabolism)
• Frameshift Mutation (genetics)
• Humans
• KCNQ2 Potassium Channel (genetics, metabolism)
• Microscopy, Confocal
• Microscopy, Fluorescence
• Real-Time Polymerase Chain Reaction