De novo KCNH1 mutations in four patients with syndromic developmental delay, hypotonia and seizures

Journal of Human Genetics
Ryoko FukaiNaomichi Matsumoto

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 ...Continue Reading

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Citations

Mar 16, 2018·The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry·Zachary Niday, Anastasios V Tzingounis
Jan 24, 2018·American Journal of Medical Genetics. Part a·Takuji EnyaTsukasa Takemura
Mar 14, 2018·Annals of Neurology·Mitsuko NakashimaNaomichi Matsumoto
Jan 19, 2019·Journal of Human Genetics·Mitsuko NakashimaNaomichi Matsumoto
Apr 5, 2019·Annals of Neurology·Shinya IwasawaShigeo Kure
Sep 13, 2019·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Justyna Jędrychowska, Vladimir Korzh
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Sep 1, 2019·Bioelectricity·Ileana Hernandez-ResendizLuis A Pardo

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