Higuchi Y, Yoshizaki K, Nakanishi K, Yuan J, Hobara T, Kojima F, Hiramatsu Y, Ando M, Yoshimura A, Nozuma S, Sakiyama Y, Hashiguchi A, Okamoto Y, Matsuura E, Yamasaki R, Hashida H, Hisano T, Okada J,2026 · 担当区分： 筆頭著者 記述言語： 英語 出版者・発行元： Genetics in Medicine Purpose Despite advances in diagnostics, many inherited peripheral neuropathies remain genetically unexplained. We investigated whether biallelic variants in FAT3 ( FAT Atypical Cadherin 3 ) are implicated in inherited axonal neuropathies. Methods We identified biallelic FAT3 variants in three unrelated individuals among 3315 Japanese patients with inherited peripheral neuropathies. Variants were evaluated by segregation analysis, in silico modeling, and functional studies in Drosophila and mouse models. Results All patients exhibited progressive distal muscle weakness and cranial nerve involvement, including tongue atrophy, dysarthria, and facial weakness. Two required ventilatory support because of respiratory muscle paralysis. One patient additionally showed central hypomyelination, autonomic dysfunction, and developmental anomalies, such as congenital scoliosis and intestinal pseudo-obstruction. Identified variants were ultrarare, affected conserved residues, segregated with disease, and were predicted to impair domain stability. FAT3 knockdown in Drosophila resulted in rough eye phenotype, shortened lifespan, impaired motor function, and defective motor neuron branching. Fat3 knockout and knockin mice displayed perinatal lethality, sciatic nerve axonal degeneration, and central nervous system abnormalities despite preserved motor performance. Conclusion Our findings establish FAT3 as a novel gene for autosomal-recessive axonal neuropathies and support the concept of a FAT3 -related multisystem neurodevelopmental disorder characterized by motor neuron degeneration and systemic abnormalities. DOI： 10.1016/j.gim.2026.102570 Scopus PubMed
Ando M, Okamoto Y, Higuchi Y, Yuan JH, Yoshimura A, Yano C, Nagatomo R, Hobara T, Kojima F, Hiramatsu Y, Nozuma S, Sakiyama Y, Takashima H . Arginine ameliorates motor and survival deficits in2026 · 担当区分： 筆頭著者 記述言語： 英語 出版者・発行元： Neurotherapeutics Charcot-Marie-Tooth disease type 2 A (CMT2A) is an inherited axonal neuropathy linked to mutations in MFN2, a key regulator of mitochondrial dynamics. Currently, no effective drug therapies exist. l-arginine has shown promise in treating mitochondrial disorders, though its effect on MFN2-associated neuropathy remains uncertain. To investigate this, we used Drosophila models with the neuron-specific knockdown of Marf, the fly ortholog of MFN2, employing a temporally controlled GAL4/UAS system. Flies were administered different doses of l-arginine to examine its influence on motor ability and lifespan. To evaluate responses under mitochondrial stress, flies were also treated with rotenone, a mitochondrial complex I inhibitor. l-arginine markedly improved climbing performance under baseline conditions and extended lifespan under both baseline and stress conditions. However under rotenone-induced mitochondrial stress, high-dose l-arginine improved survival without a corresponding improvement in locomotor performance. These results support a neuroprotective role for l-arginine in MFN2-deficient Drosophila, possibly through effects on mitochondrial dynamics involving complex I. l-arginine may hold therapeutic promise for CMT2A, meriting further investigation in vertebrate models. DOI： 10.1016/j.neurot.2026.e00900 Scopus PubMed
