Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes.
Nat Genet. 2006-02-26; 38(4): 447-451
DOI: 10.1038/ng1758
Lire sur PubMed
1. Nat Genet. 2006 Apr;38(4):447-51. Epub 2006 Feb 26.
Mutations in voltage-gated potassium channel KCNC3 cause degenerative and
developmental central nervous system phenotypes.
Waters MF(1), Minassian NA, Stevanin G, Figueroa KP, Bannister JP, Nolte D, Mock
AF, Evidente VG, Fee DB, Müller U, Dürr A, Brice A, Papazian DM, Pulst SM.
Author information:
(1)Division of Neurology and Rose Moss Laboratory for Parkinson’s and
Neurodegenerative Diseases, Burns and Allen Research Institute, Cedars-Sinai
Medical Center, Los Angeles, California, 90048 USA.
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 K+ channels as candidates for additional neurodegenerative
diseases.
DOI: 10.1038/ng1758
PMID: 16501573 [Indexed for MEDLINE]