2026-07-01 カリフォルニア大学サンディエゴ校（UCSD）
◆研究では、患者由来細胞や分子解析技術を用いて、変異が筋細胞の機能に及ぼす影響を詳細に解析し、それぞれの変異に応じた治療候補を評価した。その結果、特定の遺伝子変異による異常なタンパク質機能や細胞内シグナルを標的とすることで、筋細胞の機能改善が期待できることを示した。
◆本成果は、一律の治療法ではなく、患者ごとの遺伝学的特徴に基づいて最適な治療法を選択する個別化医療の実現に向けた重要な一歩であり、希少疾患だけでなく他の遺伝性疾患への応用も期待される。また、遺伝子解析と創薬を組み合わせた新たな治療開発モデルとして、今後の臨床応用が期待されている。
Credit: Huanhuan Li, Hibbs Lab, UC San Diego.
＜関連情報＞
- https://today.ucsd.edu/story/uc-san-diego-researchers-uncover-precision-medicine-strategy-for-rare-inherited-muscle-disorders
- https://www.nature.com/articles/s41586-026-10706-1
先天性重症筋無力症に伴うアセチルコリン受容体欠損の矯正 Correcting congenital myasthenia-associated acetylcholine receptor defects
Huanhuan Li,Nuriya Mukhtasimova,Jinfeng Teng,Elfie S. Cavalli,Xilin Gu,Jason K. Sello,Steven M. Sine & Ryan E. Hibbs
Nature Published:01 July 2026
DOI:https://doi.org/10.1038/s41586-026-10706-1
Abstract
Voluntary muscle contraction is triggered by the neurotransmitter acetylcholine binding its receptors on the postsynaptic membrane of the neuromuscular junction, opening ion channels that allow cation influx and initiate depolarization1,2,3. Mutations in muscle acetylcholine receptors disrupt this process by either impairing (fast-channel) or prolonging (slow-channel) channel openings1,4. These defects cause congenital myasthenic syndromes (CMS), characterized by severe muscle weakness that is often present at birth and, in some cases, progresses to paralysis and death5,6. The structural mechanisms underlying these pathogenic defects and their pharmacological correction remain unknown. Here, using cryogenic electron microscopy, chemical biology and electrophysiology, we determined the structures and functional consequences of representative CMS mutant receptors with and without drugs. In fast-channel disease-associated mutants, we discovered a cryptic allosteric site targeted by positive modulators that restore gating in a mutation-specific manner. In receptor mutants associated with slow-channel disease, quinidine, fluoxetine and reboxetine act as pore blockers; notably, the antidepressant reboxetine selectively blocks desensitized receptors in a mutation-independent fashion, suggesting repurposing potential. Mechanistically, fast-channel mutations uncouple agonist binding from gating, whereas slow-channel mutations stabilize an abnormally widened, desensitized-like pore. These findings reveal unifying principles of CMS pathogenesis and provide a framework for precision therapies.
