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2023 Fiscal Year Final Research Report

Reserch to dicover disease pathogenesis of distal hereditary motor neuropathy

Research Project

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Project/Area Number 22K19506
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 52:General internal medicine and related fields
Research InstitutionNagoya University

Principal Investigator

Iguchi Yohei  名古屋大学, 医学部附属病院, 講師 (80790659)

Co-Investigator(Kenkyū-buntansha) 勝野 雅央  名古屋大学, 医学系研究科, 教授 (50402566)
佐橋 健太郎  名古屋大学, 医学系研究科, 准教授 (90710103)
横井 聡  名古屋大学, 医学系研究科, 特任助教 (30815460)
Project Period (FY) 2022-06-30 – 2024-03-31
Keywords遠位型遺伝性運動ニューロパチー / SLC5A7 / ノックインマウス
Outline of Final Research Achievements

Distal hereditary motor neuropathy (dHMN) is an inherited disorder with progressive distal-dominant lower motor neuron deficits. We identified a novel truncation mutation at the C-terminus of SLC5A7 by genetic analysis of a family history of progressive muscle weakness in the distal muscles of the extremities. Cultured cell experiments confirmed that a specific region at the SLC5A7 C-terminus is essential for intracellular trafficking. We also analyzed Slc5a7 mutation knock-in (Slc5a7KI) mice. We confirmed that they develop progressive motor deficits: axonal degeneration was observed in the anterior root of the lumbar spinal cord in Slc5a7KI/KI mice. In contrast, Slc5a7KI/+ mice showed denervation at the neuromuscular junction of the distal leg muscle. Slc5a7KI mice may serve as a animal model for the pathogenesis of dHMN-VII.

Free Research Field

神経内科学

Academic Significance and Societal Importance of the Research Achievements

遠位型遺伝性運動ニューロパチー (dHMN) は四肢遠位優位の下位運動ニューロン障害による筋萎縮を進行性に認める遺伝性疾患である。SLC5A7のC末端欠失ヘテロ接合変異がdHMN-Ⅶの原因遺伝子として同定されている。SLC5A7は神経筋接合部のシナプス前終末でコリンの再取り込みを担う分子であり、SLC5A7の膜貫通ドメインのホモ接合点変異は常染色体劣性の先天性筋無力症候群を生じる。SLC5A7のC末端欠失変異が運動ニューロパチーを生じる機序は解明されていない。本研究の結果はdHMN-Ⅶの病態解明につながる成果であり治療法開発への応用も期待される。

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Published: 2025-01-30  

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