Disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding and impaired spermatogenesis.
Disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding and impaired spermatogenesis.
复制标题
MTMR2的破坏会产生CMT4B1样神经病，髓磷脂外折叠和精子发生受损。
DOI：
10.1083/jcb.200407010
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发表时间：
2004-11-22
影响因子：
7.8
通讯作者：
Wrabetz, Lawrence
中科院分区：
文献类型：
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作者：
Bolino, Alessandra;Bolis, Annalisa;Previtali, Stefano Carlo;Dina, Giorgia;Bussini, Simona;Dati, Gabriele;Amadio, Stefano;Del Carro, Ubaldo;Mruk, Dolores D;Feltri, Maria Laura;Cheng, C Yan;Quattrini, Angelo;Wrabetz, Lawrence
MTMR2（肌管蛋白相关 2 基因）的突变会导致常染色体隐性夏科-马里-图思 (CMT) 4B1 型，这是一种伴有髓鞘外折叠和无精症的脱髓鞘神经病。 MTMR2 编码一种普遍表达的磷酸酶，其首选底物是磷脂酰肌醇 (3,5)-二磷酸，它是膜稳态和囊泡运输的调节剂。我们培育了 Mtmr2 缺失小鼠，这些小鼠出现进行性神经病，其特征是髓鞘外折叠和循环循环（主要在节旁髓鞘），以及生精上皮中精细胞和精母细胞的消耗，从而导致无精症。雪旺细胞中 Mtmr2 的破坏会导致髓磷脂异常。我们还在雪旺细胞中发现了 Mtmr2 和椎间盘大 1 (Dlg1)/突触相关蛋白 97（一种在节点/副节点区域富集的支架分子）之间的新型物理相互作用。 Dlg1 同源物已位于多种类型的细胞连接中，并在细胞极性和膜添加中发挥作用。我们提出雪旺细胞自主丧失 Mtmr2-Dlg1 相互作用会失调节旁区域的膜稳态，从而产生髓磷脂的外折叠和循环环。
Mutations in MTMR2, the myotubularin-related 2 gene, cause autosomal recessive Charcot-Marie-Tooth (CMT) type 4B1, a demyelinating neuropathy with myelin outfolding and azoospermia. MTMR2 encodes a ubiquitously expressed phosphatase whose preferred substrate is phosphatidylinositol (3,5)-biphosphate, a regulator of membrane homeostasis and vesicle transport. We generated Mtmr2-null mice, which develop progressive neuropathy characterized by myelin outfolding and recurrent loops, predominantly at paranodal myelin, and depletion of spermatids and spermatocytes from the seminiferous epithelium, which leads to azoospermia. Disruption of Mtmr2 in Schwann cells reproduces the myelin abnormalities. We also identified a novel physical interaction in Schwann cells, between Mtmr2 and discs large 1 (Dlg1)/synapse-associated protein 97, a scaffolding molecule that is enriched at the node/paranode region. Dlg1 homologues have been located in several types of cellular junctions and play roles in cell polarity and membrane addition. We propose that Schwann cell–autonomous loss of Mtmr2–Dlg1 interaction dysregulates membrane homeostasis in the paranodal region, thereby producing outfolding and recurrent loops of myelin.