Hyperkalemic periodic paralysis associated with a novel missense variant located in the inner pore of Nav1.4.

BACKGROUND: Hyperkalemic periodic paralysis (HyperPP) is an autosomal dominantly inherited disease characterized by episodic paralytic attacks with hyperkalemia, and is caused by mutations of the SCN4A gene encoding the skeletal muscle type voltage-gated sodium channel Nav1.4. The pathological mechanism of HyperPP was suggested to be associated with gain-of-function changes for Nav1.4 gating, some of which are defects of slow inactivation. CASE PRESENTATION & METHODS: We identified a HyperPP family consisting of the proband and his mother, who showed a novel heterozygous SCN4A variant, p.V792G, in an inner pore lesion of segment 6 in Domain II of Nav1.4. Clinical and neurophysiological evaluations were conducted for the proband and his mother. We explored the pathogenesis of the variant by whole-cell patch clamp technique using HEK293T cells expressing the mutant Nav1.4 channel. RESULTS: Functional analysis of Nav1.4 with the V792G mutation revealed a hyperpolarized shift of voltage-dependent activation and fast inactivation. Moreover, steady-state slow inactivation in V792G was impaired with larger residual currents in comparison with wild-type Nav1.4. CONCLUSION: V792G in SCN4A is a pathogenic variant associated with the HyperPP phenotype and the inner pore lesion of Nav1.4 plays a crucial role in slow inactivation.

The myotonic dystrophy health index: Japanese adaption and validity testing.

INTRODUCTION: The Myotonic Dystrophy Health Index (MDHI) is a disease-specific, patient-reported outcome measure. The objective of this study was to translate, evaluate, and validate a Japanese version of the MDHI (MDHI-J). METHODS: We utilized forward and backward translations and qualitative interviews with 11 myotonic dystrophy type 1 (DM1) participants. We subsequently tested the internal consistency, test-retest reliability, concurrent validity against muscle strength, and 3 quality-of-life measures, and the known-groups validity of the MDHI-J with 60 adult patients. RESULTS: The MDHI-J was found to be culturally appropriate, comprehensive, and clinically relevant. The MDHI-J and its subscales had high internal consistency (mean Cronbach's α = 0.91), test-retest reliability (intraclass coefficient 0.678-0.915), and concurrent validity (Spearman's ρ - 0.869 to 0.904). MDHI-J scores were strongly associated with employment, duration of symptoms, and modified Rankin Scale. DISCUSSION: The MDHI-J is suitable and valid to measure patient-reported disease burden in adult Japanese patients with DM1. Muscle Nerve 59:577-577, 2019.

Tip-cell behavior is regulated by transcription factor FoxO1 under hypoxic conditions in developing mouse retinas.

Forkhead box protein O1 (FoxO1) is a transcription factor and a critical regulator of angiogenesis. Various environmental stimuli, including growth factors, nutrients, shear stress, oxidative stress and hypoxia, affect FoxO1 subcellular localization and strongly influence its transcriptional activity; however, FoxO1-localization patterns in endothelial cells (ECs) during development have not been clarified in vivo. Here, we reported that FoxO1 expression was observed in three layers of angiogenic vessels in developing mouse retinas and that among these layers, the front layer showed high levels of FoxO1 expression in the nuclei of most tip ECs. Because tip ECs migrate toward the avascular hypoxic area, we focused on hypoxia as a major stimulus regulating FoxO1 subcellular localization in tip cells. In cultured ECs, FoxO1 accumulated into the nucleus under hypoxic conditions, with hypoxia also inducing expression of tip-cell-specific genes, including endothelial-specific molecule 1 (ESM1), which was suppressed by FoxO1 knockdown. Additionally, in murine models, EC-specific FoxO1 deletion resulted in reduced ESM1 expression and suppressed tip-cell migration during angiogenesis. These findings indicated roles for FoxO1 in tip-cell migration and that its transcriptional activity is regulated by hypoxia.