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

Nature Genetics volume 38, pages 447–451 (2006)Cite this article

Abstract

Potassium channel mutations have been described in episodic neurological diseases1. 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 delay2. This region contains KCNC3 (also known as Kv3.3), encoding a voltage-gated Shaw channel with enriched cerebellar expression3. Sequencing revealed two missense mutations, both of which alter KCNC3 function in Xenopus laevis expression systems. KCNC3R420H, located in the voltage-sensing domain4, had no channel activity when expressed alone and had a dominant-negative effect when co-expressed with the wild-type channel. KCNC3F448L shifted the activation curve in the negative direction and slowed channel closing. Thus, KCNC3R420H and KCNC3F448L 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.

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Figure 1: Mid-sagittal T1 sequence MR images.
Figure 2: KCNC3 DNA mutations lead to amino acid substitutions in highly conserved domains.
Figure 3: Subfamily-specific dominant-negative effect of R420H.
Figure 4: Altered gating in F448L.

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Acknowledgements

We thank J.L. Rae for providing the Kv3.3 cDNA clone and T. Otis, L. Timpe and F. Schweizer for manuscript critique. Technical assistance was provided by V. Garibyan, A. Camuzat and N. Benammar. This work was supported in part by US National Institutes of Health grants to S.P. (R01N533123) and D.P. (R01GM43459, R01GM66686), a National Ataxia Foundation Grant to S.P., funding from the Programme Hospitalier de Recherche Clinique (AOMO3059) to A.D., the Verum Foundation to A.B., and the EuroSCA Integrated Project (LSHM-CT-2004-503304) to A.D., A.B. and G.S. M.F.W. is supported by the American Academy of Neurology Raymond D. Adams Fellowship in Neurogenetics. N.A.M. was supported by T32GM065823.

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Authors and Affiliations

  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, 90048, California, USA

    Michael F Waters, Karla P Figueroa & Stefan M Pulst

  2. Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles (UCLA), Los Angeles, 90024, California, USA

    Michael F Waters & Stefan M Pulst

  3. Department of Physiology, David Geffen School of Medicine at the University of California, Los Angeles (UCLA), Los Angeles, 90024, California, USA

    Natali A Minassian, John P A Bannister, Allan F Mock & Diane M Papazian

  4. INSERM U679 and Department of Genetics, Cytogenetics, and Embryology of Assistance Publique - Hopitaux de Paris, Hôpital de la Salpêtrière, Paris, 75013, France

    Giovanni Stevanin, Alexandra Dürr & Alexis Brice

  5. Institut für Humangenetik, Justus-Liebig-Universität, Giessen, 35392, Germany

    Dagmar Nolte & Ulrich Müller

  6. Department of Neurology, Mayo Clinic, Scottsdale, 85259, Arizona, USA

    Virgilio Gerald H Evidente

  7. Department of Neurology, University of Kentucky College of Medicine, Lexington, 40536, Kentucky, USA

    Dominic B Fee

  8. Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, 90095, California, USA

    Stefan M Pulst

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Correspondence to Stefan M Pulst.

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Supplementary information

Supplementary Fig. 1

Filipino pedigree with autosomal dominant spinocerebellar ataxia. (PDF 134 kb)

Supplementary Table 1

Primer sequences for amplification of marker MF1. (PDF 32 kb)

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Waters, M., Minassian, N., Stevanin, G. et al. Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes. Nat Genet 38, 447–451 (2006). https://doi.org/10.1038/ng1758

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