Riho Horie1, Tomoya Kubota1, Jinsoo Koh2, Rieko Tanaka3, Yuichiro Nakamura1, Ryogen Sasaki4, Hidefumi Ito2, Masanori P Takahashi1. 1. Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka, Japan. 2. Department of Neurology, Wakayama Medical University, Kimiidera, Wakayama, Wakayama, Japan. 3. Nanairo Kodomo Clinic, Fukiage, Wakayama, Wakayama, Japan. 4. Department of Neurology, Kuwana City Medical Center, Kotobukicho, Kuwana, Mie, Japan.
Abstract
INTRODUCTION: Mutations of the voltage-gated sodium channel gene (SCN4A), which encodes Nav1.4, cause nondystrophic myotonia that occasionally is associated with severe apnea and laryngospasm. There are case reports of nondystrophic myotonia due to mutations in the C-terminal tail (CTerm) of Nav1.4, but the functional analysis is scarce. METHODS: We present two families with nondystrophic myotonia harboring a novel heterozygous mutation (E1702del) and a known heterozygous mutation (E1702K). RESULTS: The proband with E1702K exhibited repeated rhabdomyolysis, and the daughter showed laryngospasm and cyanosis. Functional analysis of the two mutations as well as another known heterozygous mutation (T1700_E1703del), all located on EF hand-like motif in CTerm, was conducted with whole-cell recording of heterologously expressed channel. All mutations displayed impaired fast inactivation. DISCUSSION: The CTerm of Nav1.4 is vital for regulating fast inactivation. The study highlights the importance of accumulating pathological mutations of Nav1.4 and their functional analysis data.
INTRODUCTION: Mutations of the voltage-gated sodium channel gene (SCN4A), which encodes Nav1.4, cause nondystrophic myotonia that occasionally is associated with severe apnea and laryngospasm. There are case reports of nondystrophic myotonia due to mutations in the C-terminal tail (CTerm) of Nav1.4, but the functional analysis is scarce. METHODS: We present two families with nondystrophic myotonia harboring a novel heterozygous mutation (E1702del) and a known heterozygous mutation (E1702K). RESULTS: The proband with E1702K exhibited repeated rhabdomyolysis, and the daughter showed laryngospasm and cyanosis. Functional analysis of the two mutations as well as another known heterozygous mutation (T1700_E1703del), all located on EF hand-like motif in CTerm, was conducted with whole-cell recording of heterologously expressed channel. All mutations displayed impaired fast inactivation. DISCUSSION: The CTerm of Nav1.4 is vital for regulating fast inactivation. The study highlights the importance of accumulating pathological mutations of Nav1.4 and their functional analysis data.
Authors: Po Wei Kang; Nourdine Chakouri; Johanna Diaz; Gordon F Tomaselli; David T Yue; Manu Ben-Johny Journal: Proc Natl Acad Sci U S A Date: 2021-05-25 Impact factor: 11.205