Abstract
The voltage-gated Kv10.1 potassium channel, also known as ether-a-go-go-related gene 1, encoded by KCNH1 (potassium voltage-gated channel, subfamily H (eag related), member 1) is predominantly expressed in the central nervous system. Recently, de novo missense KCNH1 mutations have been identified in six patients with Zimmermann–Laband syndrome and in four patients with Temple–Baraitser syndrome. These syndromes were historically considered distinct. Here we report three de novo missense KCNH1 mutations in four patients with syndromic developmental delay and epilepsy. Two novel KCNH1 mutations (p.R357Q and p.R357P), found in three patients, were located at the evolutionally highly conserved arginine in the channel voltage-sensor domain (S4). Another mutation (p.G496E) was found in the channel pore domain (S6) helix, which acts as a hinge in activation gating and mainly conducts non-inactivating outward potassium current. A previously reported p.G496R mutation was shown to produce no voltage-dependent outward current in CHO cells, suggesting that p.G496E may also disrupt the proper function of the Kv channel pore. Our report confirms that KCNH1 mutations are associated with syndromic neurodevelopmental disorder, and also support the functional importance of the S4 domain.
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Acknowledgements
We thank the patients and their families for participating in this work. This work was supported in part by a grant for Research on Measures for Intractable Diseases, a grant for Comprehensive Research on Disability Health and Welfare, the Strategic Research Program for Brain Science, and a grant for Initiative on Rare and Undiagnosed Diseases in Pediatrics; a Grant-in-Aid for Scientific Research on Innovative Areas (Transcription Cycle) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; Grants-in-Aid for Scientific Research (A, B and C), and challenging Exploratory Research from the Japan Society for the Promotion of Science; the fund for Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems from the Japan Science and Technology Agency; the Takeda Science Foundation; the Yokohama Foundation for Advancement of Medical Science; and the Hayashi Memorial Foundation for Female Natural Scientists.
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Fukai, R., Saitsu, H., Tsurusaki, Y. et al. De novo KCNH1 mutations in four patients with syndromic developmental delay, hypotonia and seizures. J Hum Genet 61, 381–387 (2016). https://doi.org/10.1038/jhg.2016.1
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DOI: https://doi.org/10.1038/jhg.2016.1
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