Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder (original) (raw)

• Letter
• Published: 05 June 2005
• Jocelyn F Bautista4,5 na1,
• Huanghe Yang6,
• Ana Diez-Sampedro7,
• Sun-Ah You1,2,
• Lejin Wang1,2,
• Prakash Kotagal4,
• Hans O Lüders4,
• Jingyi Shi6,
• Jianmin Cui6,
• George B Richerson7,8 &
• …
• Qing K Wang1,2,3,9

Nature Genetics volume 37, pages 733–738 (2005)Cite this article

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Abstract

The large conductance calcium-sensitive potassium (BK) channel is widely expressed in many organs and tissues, but its in vivo physiological functions have not been fully defined. Here we report a genetic locus associated with a human syndrome of coexistent generalized epilepsy and paroxysmal dyskinesia on chromosome 10q22 and show that a mutation of the α subunit of the BK channel causes this syndrome. The mutant BK channel had a markedly greater macroscopic current. Single-channel recordings showed an increase in open-channel probability due to a three- to fivefold increase in Ca2+ sensitivity. We propose that enhancement of BK channels in vivo leads to increased excitability by inducing rapid repolarization of action potentials, resulting in generalized epilepsy and paroxysmal dyskinesia by allowing neurons to fire at a faster rate. These results identify a gene that is mutated in generalized epilepsy and paroxysmal dyskinesia and have implications for the pathogenesis of human epilepsy, the neurophysiology of paroxysmal movement disorders and the role of BK channels in neurological disease.

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Acknowledgements

We thank I.B. Levitan, Y. Zhou, L. Salkoff and A. Butler for the expression constructs for KCNMA1; the study participants for their enthusiasm for and support of this study; L. Li for lod score calculation; S. Yong, G. Kirsch, C.J. Lingle, T. Zhang, A. Alexopoulos and I. Najm for help and discussion; and R. Guerrini for providing DNA from two individuals with epilepsy and paroxysmal dyskinesia3 (no KCNMA1 mutation was identified in these two DNA samples). This work was supported by grants from the US National Institutes of Health (Q.K.W., J.F.B., G.B.R. & A.D.-S. and J.C.), an American Heart Association Established Investigator award (Q.K.W.), the VAMC (G.B.R.) and a Clinical Research Training Fellowship from the American Academy of Neurology Foundation (J.F.B.). This work was supported in part by the Chinese Ministry of Science and Technology National High Technology 863 Project grant (Q.K.W.) and a Public Health Service National Center for Research Resources grant at the Cleveland Clinic Foundation (Q.K.W.).

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Author notes

1. Wei Du and Jocelyn F Bautista: These authors contributed equally to this work.

Authors and Affiliations

1. Department of Molecular Cardiology, Department of Cardiovascular Medicine, The Cleveland Clinic Foundation; and Department of Molecular Medicine, Center for Molecular Genetics, Lerner Research Institute; Center for Cardiovascular Genetics, Cleveland Clinic Lerner College of Medicine; Case Western Reserve University,
   Wei Du, Sun-Ah You, Lejin Wang & Qing K Wang
2. Department of Cardiovascular Medicine, Center for Cardiovascular Genetics, The Cleveland Clinic Foundation, Cleveland, 44195, Ohio, USA
   Wei Du, Sun-Ah You, Lejin Wang & Qing K Wang
3. Department of Biological, Geological, and Environmental Science, Cleveland State University, Cleveland, 44115, Ohio, USA
   Wei Du & Qing K Wang
4. Department of Neurology, The Cleveland Clinic Foundation, Cleveland, 44195, Ohio, USA
   Jocelyn F Bautista, Prakash Kotagal & Hans O Lüders
5. Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, 44106, Ohio, USA
   Jocelyn F Bautista
6. Department of Biomedical Engineering, Washington University, St. Louis, 63130, Missouri, USA
   Huanghe Yang, Jingyi Shi & Jianmin Cui
7. Departments of Neurology and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA
   Ana Diez-Sampedro & George B Richerson
8. VAMC, West Haven, 06516, Connecticut, USA
   George B Richerson
9. Huazhong University of Science and Technology Human Genome Research Center, Wuhan, China
   Qing K Wang

Authors

1. Wei Du
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2. Jocelyn F Bautista
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3. Huanghe Yang
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4. Ana Diez-Sampedro
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5. Sun-Ah You
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6. Lejin Wang
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7. Prakash Kotagal
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8. Hans O Lüders
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9. Jingyi Shi
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10. Jianmin Cui
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11. George B Richerson
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12. Qing K Wang
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Corresponding author

Correspondence toQing K Wang.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

KCNMA1 mutation D434G co-segregates with GEPD patients in the family. (PDF 106 kb)

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Du, W., Bautista, J., Yang, H. et al. Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder.Nat Genet 37, 733–738 (2005). https://doi.org/10.1038/ng1585

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• Received: 04 February 2005
• Accepted: 05 May 2005
• Published: 05 June 2005
• Issue Date: 01 July 2005
• DOI: https://doi.org/10.1038/ng1585

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