Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes

Nature Genetics
Michael F WatersStefan M Pulst

Abstract

Potassium channel mutations have been described in episodic neurological diseases. We report that K+ channel mutations cause disease phenotypes with neurodevelopmental and neurodegenerative features. In a Filipino adult-onset ataxia pedigree, the causative gene maps to 19q13, overlapping the SCA13 disease locus described in a French pedigree with childhood-onset ataxia and cognitive delay. This region contains KCNC3 (also known as Kv3.3), encoding a voltage-gated Shaw channel with enriched cerebellar expression. Sequencing revealed two missense mutations, both of which alter KCNC3 function in Xenopus laevis expression systems. KCNC3(R420H), located in the voltage-sensing domain, had no channel activity when expressed alone and had a dominant-negative effect when co-expressed with the wild-type channel. KCNC3(F448L) shifted the activation curve in the negative direction and slowed channel closing. Thus, KCNC3(R420H) and KCNC3(F448L) are expected to change the output characteristics of fast-spiking cerebellar neurons, in which KCNC channels confer capacity for high-frequency firing. Our results establish a role for KCNC3 in phenotypes ranging from developmental disorders to adult-onset neurodegeneration and suggest voltage-gated ...Continue Reading

References

Aug 14, 1992·Biochemical and Biophysical Research Communications·E Vega-Saenz de Miera, B Rudy
Dec 5, 1995·Proceedings of the National Academy of Sciences of the United States of America·F DupratE Honore
Jun 1, 1997·The Journal of General Physiology·C C ShiehG E Kirsch
Apr 18, 1998·The Journal of General Physiology·C J Smith-MaxwellR W Aldrich
Sep 25, 1998·The Journal of Biological Chemistry·C T SchulteisD M Papazian
Mar 14, 2000·Experimental Eye Research·J L Rae, A R Shepard
Aug 17, 2001·Trends in Neurosciences·B Rudy, C J McBain
Jan 25, 2003·Journal of the American Academy of Child and Adolescent Psychiatry·James S SutcliffePaul J Lombroso
Apr 22, 2004·Lancet Neurology·Ludger SchölsOlaf Riess
Jul 17, 2004·The European Journal of Neuroscience·B E McKay, R W Turner
Oct 16, 2004·Journal of Neurochemistry·Ester AnguloRafael Franco
Dec 31, 2004·Journal of Neurophysiology·Marjorie A ArianoMichael S Levine
Jan 11, 2005·Postgraduate Medical Journal·T D Graves, M G Hanna
Jul 9, 2005·The Journal of Physiology·Bruce E McKay, Ray W Turner
Jul 9, 2005·Science·Stephen B LongRoderick Mackinnon

❮ Previous
Next ❯

Citations

Oct 18, 2007·Journal of Neurology·C ZühlkeK Bürk
Jul 6, 2007·Journal of Human Genetics·Takeshi AminoHidehiro Mizusawa
Sep 22, 2009·Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology·Qian XuBeisha Tang
Oct 7, 2008·Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology·Anastasia V Pischalnikova, Olga S Sokolova
Jul 2, 2008·Current Neurology and Neuroscience Reports·Tanja Schmitz-Hübsch, Thomas Klockgether
Apr 25, 2012·Current Neurology and Neuroscience Reports·Anna Sailer, Henry Houlden
Sep 14, 2011·Journal of Molecular Neuroscience : MN·Enrica BodaFilippo Tempia
Apr 18, 2008·The Cerebellum·Giovanni Stevanin, Alexis Brice
Jul 2, 2008·The Cerebellum·M F Waters, S M Pulst
Feb 28, 2009·The Cerebellum·Rolf H Joho, Edward C Hurlock
Nov 6, 2009·The Cerebellum·Antoni Matilla-DueñasPilar Latorre
Sep 20, 2008·Human Molecular Genetics·Melanie A KnightAndrew B Singleton
Oct 23, 2012·Human Molecular Genetics·Stephen T HansenStefan M Pulst
Sep 4, 2009·Journal of Neuro-ophthalmology : the Official Journal of the North American Neuro-Ophthalmology Society·Henry L Paulson
Jul 29, 2010·Genes, Brain, and Behavior·S MartinE D Bel
Mar 12, 2013·Journal of Neurology, Neurosurgery, and Psychiatry·Sanjeev RajakulendranHelen Stewart
Mar 25, 2010·Annual Review of Neuroscience·Dimitri M Kullmann
Jan 1, 2013·BMC Bioinformatics·Eric C Rouchka, Robert M Flight
May 31, 2011·Orphanet Journal of Rare Diseases·Nathaniel Robb WhaleyZbigniew K Wszolek
Aug 31, 2012·Neurology·Michael F WatersTetsuo Ashizawa
Apr 12, 2011·PloS One·Karla P FigueroaStefan M Pulst
Dec 18, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Edward C HurlockRolf H Joho
Feb 8, 2008·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Edward ZaghaBernardo Rudy
Apr 12, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Elizabeth D ButtermoreManzoor A Bhat
Apr 8, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Emma M PerkinsMandy Jackson
May 6, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Fadi A IssaDiane M Papazian
Jun 23, 2010·Proceedings of the National Academy of Sciences of the United States of America·Xiaowei ChenArthur Konnerth
Sep 14, 2013·Brain : a Journal of Neurology·Andrea H NémethJiannis Ragoussis
Jun 12, 2012·Acta Neuropathologica·Kay SeidelUdo Rüb
Mar 15, 2013·Journal of Cell Science·Joshua BarryChen Gu
Jan 23, 2016·Neurobiology of Disease·C J L M Smeets, D S Verbeek
Jul 24, 2014·Genes·Erin Sandford, Margit Burmeister

❮ Previous
Next ❯

Related Concepts

Related Feeds

Ataxias (MDS)

Ataxia is a neurological condition characterized by lack of voluntary coordination of muscle movements including loss of coordination, balance, and speech. Discover the latest research on ataxia here.

Ataxia

Ataxia is a neurological condition characterized by lack of voluntary coordination of muscle movements including loss of coordination, balance, and speech. Discover the latest research on ataxia here.

Ataxias

Ataxia is a neurological condition characterized by lack of voluntary coordination of muscle movements including loss of coordination, balance, and speech. Discover the latest research on different types of ataxias here.