Pathological analysis of limb girdle congenital myasthenia and development of new therapy

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K06925
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 46030:Function of nervous system-related
• Research Institution: Nagoya University
• Principal Investigator: Ito Mikako 名古屋大学, 医学系研究科, 講師 (60444402)
• Co-Investigator(Kenkyū-buntansha): 大河原 美静 名古屋大学, 医学系研究科, 特任准教授 (80589606)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 先天性筋無力症候群 / GFPT1 / 神経筋接合部 / DOK7

Outline of Final Research Achievements

Congenital myasthenia syndrome (CMS) is caused by a mutation in GFPT1 (Glutamine fructose-6-phosphate aminotransferase 1), a protein and lipid glycosylase, characterized by limb-girdle type muscle weakness. To investigate the role of the GFPT1-L variant in skeletal muscle, Gfpt1-L-/- mice, which do not express GFPT1-L, were created, and these mice showed muscle weakness in old age. Gfpt1 knock-in (KI) mice were also created by introducing the c.722r3insG mutation into mice as in CMS patients. They showed a phenotype similar to that of patients, including reduced motor function, reduced amounts of glycosylated proteins, fragmentation of AChR clusters, muscle atrophy and increased inter-myofibrillar space, and observed reduced motor performance and abnormal neuromuscular junction structures with ageing.

Free Research Field

神経筋接合部疾患

Academic Significance and Societal Importance of the Research Achievements

先天性筋無力症候群は指定難病の対象となっており、全身の筋力低下， 易疲労性を呈し，生後 1 年以内に発症することが多い稀な疾患である。神経筋接合部を構成する遺伝子検査を実施し、変異が発見された場合は、CMSの原因となりうる変異かどうかを精査する必要がある。本研究では先天性筋無力症候群患者において、GFPT1内に複合ヘテロ変異を同定し、同じ変異を有するマウスを作成して病態の詳細な解析を行い、骨格筋において不適応な小胞体ストレス応答によりタンパク質凝集体が除去されずアポトーシスを引き起こしていることが明らかになった。今後、治療薬のスクリーニング、治療法の開発へ応用できると期待している。