Both gain- and loss-of-function variants of <i>KCNA1</i> are associated with paroxysmal kinesigenic dyskinesia

Wan-Bing Sun; Jing-Xin Fu; Yu-Lan Chen; Hong-Fu Li; Zhi-Ying Wu; Dian-Fu Chen

doi:10.1016/j.jgg.2024.03.013

Volume 51 Issue 8

Aug. 2024

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Article Navigation > Journal of Genetics and Genomics > 2024 > 51(8): 801-810

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Both gain- and loss-of-function variants of KCNA1 are associated with paroxysmal kinesigenic dyskinesia

doi: 10.1016/j.jgg.2024.03.013

a. Department of Medical Genetics and Center for Rare Diseases, and Department of Neurology, and Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation in Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China;
b. Nanhu Brain-computer Interface Institute, Hangzhou, Zhejiang 314050, China;
c. MOE Frontier Science Center for Brain Science and Brain-machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang 310012, China

Funds:

This study was supported by grants from the National Natural Science Foundation of China (82101526, 82171238, and 81330025).

Received Date: 2023-12-03
Accepted Date: 2024-03-29
Rev Recd Date: 2024-03-28

Available Online: 2025-06-06

Publish Date: 2024-04-02

Abstract

Abstract

KCNA1 is the coding gene for Kv1.1 voltage-gated potassium-channel α subunit. Three variants of KCNA1 have been reported to manifest as paroxysmal kinesigenic dyskinesia (PKD), but the correlation between them remains unclear due to the phenotypic complexity of KCNA1 variants as well as the rarity of PKD cases. Using the whole exome sequencing followed by Sanger sequencing, we screen for potential pathogenic KCNA1 variants in patients clinically diagnosed with paroxysmal movement disorders and identify three previously unreported missense variants of KCNA1 in three unrelated Chinese families. The proband of one family (c.496G>A, p.A166T) manifests as episodic ataxia type 1, and the other two (c.877G>A, p.V293I and c.1112C>A, p.T371A) manifest as PKD. The pathogenicity of these variants is confirmed by functional studies, suggesting that p.A166T and p.T371A cause a loss-of-function of the channel, while p.V293I leads to a gain-of-function with the property of voltage-dependent gating and activation kinetic affected. By reviewing the locations of PKD-manifested KCNA1 variants in Kv1.1 protein, we find that these variants tend to cluster around the pore domain, which is similar to epilepsy. Thus, our study strengthens the correlation between KCNA1 variants and PKD and provides more information on genotype-phenotype correlations of KCNA1 channelopathy.
- Paroxysmal kinesigenic dyskinesia,
- KCNA1,
- Loss-of-function,
- Gain-of-function,
- Channelopathy,
- Episodic ataxia type 1

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References(31)

References

Begum, R., Bakiri, Y., Volynski, K.E., Kullmann, D.M., 2016. Action potential broadening in a presynaptic channelopathy. Nat. Commun. 7, 12102.

Bhuyan, R., Seal, A., 2015. Conformational dynamics of shaker-type Kv1.1 ion channel in open, closed, and two mutated states. J. Membr. Biol. 248, 241-255.

Browne, D.L., Brunt, E.R., Griggs, R.C., Nutt, J.G., Gancher, S.T., Smith, E.A., Litt, M., 1995. Identification of two new KCNA1 mutations in episodic ataxia/myokymia families. Hum. Mol. Genet. 4, 1671-1672.

Browne, D.L., Gancher, S.T., Nutt, J.G., Brunt, E.R., Smith, E.A., Kramer, P., Litt, M., 1994. Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nat. Genet. 8, 136-140.

Bruno, M.K., Hallett, M., Gwinn-Hardy, K., Sorensen, B., Considine, E., Tucker, S., Lynch, D.R., Mathews, K.D., Swoboda, K.J., Harris, J., et al., 2004. Clinical evaluation of idiopathic paroxysmal kinesigenic dyskinesia: new diagnostic criteria. 63, 2280-2287.

Cai, L., Zheng, L.A., He, L., 2018. The forty years of medical genetics in China. J Genet. Genomics. 45, 569-582.

Chen, G., Gao, W., Reinert, K.C., Popa, L.S., Hendrix, C.M., Ross, M.E., Ebner, T.J., 2005. Involvement of Kv1 potassium channels in spreading acidification and depression in the cerebellar cortex. J. Neurophysiol. 94, 1287-1298.

Chen, W.J., Lin, Y., Xiong, Z.Q., Wei, W., Ni, W., Tan, G.H., Guo, S.L., He, J., Chen, Y.F., Zhang, Q.J. et al., 2011. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat. Genet. 43, 1252-1255.

Chen, Y.L., Chen, D.F., Zhao, S.Y., Liu, G.L., Li, H.F., Wu, Z.Y., 2021. Penetrance estimation of PRRT2 variants in paroxysmal kinesigenic dyskinesia and infantile convulsions. Front. Med. 15, 877-886.

Chen, Y.L., Chen, D.F., Li, H.F., Wu, Z.Y., 2022. Features differ between paroxysmal kinesigenic dyskinesia patients with PRRT2 and TMEM151A variants. Mov. Disord. 37, 608-613.

Eunson, L.H., Rea, R., Zuberi, S.M., Youroukos, S., Panayiotopoulos, C.P., Liguori, R., Avoni, P., McWilliam, R.C., Stephenson, J.B.P., Hanna, M.G. et al., 2000. Clinical, genetic, and expression studies of mutations in the potassium channel gene KCNA1 reveal new phenotypic variability. 48, 647-656.

Hao, M., Pu, W., Li, Y., Wen, S., Sun, C., Ma, Y., Zheng, H., Chen, X., Tan, J., Zhang, G., et al., 2021. The HuaBiao project: whole-exome sequencing of 5000 Han Chinese individuals. J Genet. Genomics 48, 1032-1035.

Herson, P.S., Virk, M., Rustay, N.R., Bond, C.T., Crabbe, J.C., Adelman, J.P., Maylie, J., 2003. A mouse model of episodic ataxia type-1. Nat. Neurosci. 6, 378-383.

Imbrici, P., D'Adamo, M.C., Kullmann, D.M., Pessia, M., 2006. Episodic ataxia type 1 mutations in the KCNA1 gene impair the fast inactivation properties of the human potassium channels Kv1.4-1.1/Kvbeta1.1 and Kv1.4-1.1/Kvbeta1.2. Eur. J. Neurosci. 24, 3073-3083.

Jen, J.C., Graves, T.D., Hess, E.J., Hanna, M.G., Griggs, R.C., Baloh, R.W., 2007. Primary episodic ataxias: diagnosis, pathogenesis and treatment. Brain 130, 2484-2493.

Kegele, J., Kruger, J., Koko, M., Lange, L., Marco Hernandez, A.V., Martinez, F., Munchau, A., Lerche, H., Lauxmann, S., 2021. Genetics of paroxysmal dyskinesia: novel variants corroborate the role of KCNA1 in paroxysmal dyskinesia and highlight the diverse phenotypic spectrum of KCNA1- and SLC2A1-related disorders. Front. Neurol. 12, 701351.

Kertesz, A., 1967. Paroxysmal kinesigenic choreoathetosis. An entity within the paroxysmal choreoathetosis syndrome. Description of 10 cases, including 1 autopsied. 17, 680-690.

Li, H.-F., Chen, Y.-L., Zhuang, L., Chen, D.-F., Ke, H.-Z., Luo, W.-J., Liu, G.-L., Wu, S.-N., Zhou, W.-H., Xiong, Z.-Q., et al., 2021. TMEM151A variants cause paroxysmal kinesigenic dyskinesia. . 7, 83-86.

Li, H.F., Chen, W.J., Ni, W., Wang, K.Y., Liu, G.L., Wang, N., Xiong, Z.Q., Xu, J., Wu, Z.Y., 2013. PRRT2 mutation correlated with phenotype of paroxysmal kinesigenic dyskinesia and drug response. 80, 1534-1535.

Mestre, T.A., Manole, A., MacDonald, H., Riazi, S., Kraeva, N., Hanna, M.G., Lang, A.E., Mannikko, R., Yoon, G., 2016. A novel KCNA1 mutation in a family with episodic ataxia and malignant hyperthermia. Neurogenetics 17, 245-249.

Miceli, F., Guerrini, R., Nappi, M., Soldovieri, M.V., Cellini, E., Gurnett, C.A., Parmeggiani, L., Mei, D., Taglialatela, M., 2022. Distinct epilepsy phenotypes and response to drugs in KCNA1 gain- and loss-of function variants. Epilepsia 63, e7-e14.

Muller, P., Takacs, D.S., Hedrich, U.B.S., Coorg, R., Masters, L., Glinton, K.E., Dai, H., Cokley, J.A., Riviello, J.J., Lerche, H., et al., 2023. KCNA1 gain-of-function epileptic encephalopathy treated with 4-aminopyridine. 10, 656-663.

Ovsepian, S.V., LeBerre, M., Steuber, V., O'Leary, V.B., Leibold, C., Oliver Dolly, J., 2016. Distinctive role of KV1.1 subunit in the biology and functions of low threshold K(+) channels with implications for neurological disease. Pharmacol. Ther. 159, 93-101.

Paulhus, K., Ammerman, L., Glasscock, E., 2020. Clinical spectrum of KCNA1 mutations: new insights into episodic ataxia and epilepsy comorbidity. Int. J. Mol. Sci. 21, 2802-2821.

Paulhus, K., Glasscock, E., 2023. Novel genetic variants expand the functional, molecular, and pathological diversity of KCNA1 channelopathy. Int. J. Mol. Sci. 24, 8826-8843.

Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W.W., Hegde, M., Lyon, E., Spector, E., et al., 2015. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and enomics and the Association for Molecular athology. Genet. Med. 17, 405-424.

Tian, W.T., Huang, X.J., Mao, X., Liu, Q., Liu, X.L., Zeng, S., Guo, X.N., Shen, J.Y., Xu, Y.Q., Tang, H.D., et al., 2018. Proline-rich transmembrane protein 2-negative paroxysmal kinesigenic dyskinesia: clinical and genetic analyses of 163 patients. Mov. Disord. 33, 459-467.

Tristan-Clavijo, E., Scholl, F.G., Macaya, A., Iglesias, G., Rojas, A.M., Lucas, M., Castellano, A., Martinez-Mir, A., 2016. Dominant-negative mutation p.Arg324Thr in KCNA1 impairs Kv1.1 channel function in episodic ataxia. Mov. Disord. 31, 1743-1748.

Verdura, E., Fons, C., Schluter, A., Ruiz, M., Fourcade, S., Casasnovas, C., Castellano, A., Pujol, A., 2020. Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia. J. Med. Genet. 57, 132-137.

Xu, J.J., Li, H.F., Wu, Z.Y., 2023. Paroxysmal kinesigenic dyskinesia: genetics and pathophysiological mechanisms. Neurosci. Bull. https://doi.org/10.1007/s12264-023-01157-z.

Yin, X.M., Lin, J.H., Cao, L., Zhang, T.M., Zeng, S., Zhang, K.L., Tian, W.T., Hu, Z.M., Li, N., Wang, J.L., et al., 2018. Familial paroxysmal kinesigenic dyskinesia is associated with mutations in the KCNA1 gene. Hum. Mol. Genet. 27, 625-637.

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