PAR3/INSC/LGN form an evolutionarily conserved complex required for asymmetric cell division in the developing brain, but its post-developmental function and disease relevance in the peripheral nervous system (PNS) remains unknown. We mapped a new locus for axonal Charcot-Marie-Tooth disease (CMT2) and identified a missense mutation c.209 T > G (p.Met70Arg) in the INSC gene. Modeling the INSCM70R variant in Drosophila, we showed that it caused proprioceptive defects in adult flies, leading to gait defects resembling those in CMT2 patients. Cellularly, PAR3/INSC/LGN dysfunction caused tubulin aggregation and necrotic neurodegeneration, with microtubule-stabilizing agents rescuing both morphological and functional defects of the INSCM70R mutation in the PNS. Our findings underscore the critical role of the PAR3/INSC/LGN machinery in the adult PNS and highlight a potential therapeutic target for INSC-associated CMT2.

中文翻译：

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人类 INSC 的错义突变会导致周围神经病变。


PAR3/INSC/LGN 形成了发育中大脑中不对称细胞分裂所需的进化保守复合体，但其在周围神经系统 (PNS) 中的发育后功能和疾病相关性仍然未知。我们绘制了轴突腓骨肌萎缩症 (CMT2) 的新基因座，并在 INSC 基因中发现了一个错义突变 c.209 T > G (p.Met70Arg)。通过对果蝇中的 INSCM70R 变异进行建模，我们发现它会导致成年果蝇的本体感觉缺陷，从而导致与 CMT2 患者类似的步态缺陷。在细胞方面，PAR3/INSC/LGN 功能障碍导致微管蛋白聚集和坏死性神经变性，微管稳定剂可挽救 PNS 中 INSCM70R 突变的形态和功能缺陷。我们的研究结果强调了 PAR3/INSC/LGN 机制在成人 PNS 中的关键作用，并强调了 INSC 相关 CMT2 的潜在治疗靶点。