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Abstract

Disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding and impaired spermatogenesis (PDF) (HTML) 
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,Chuen-yan; Quattrini,Angelo; Wrabetz,Lawrence
Journal of Cell Biology 167(4): 711-721
Publication date: 2004

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Mutations in MTMR2, the myotubularin-related 2 gene, cause autosomalrecessive Charcot-Marie-Tooth (CMT) type 4B1, a demyelinatingneuropathy with myelin outfolding and azoospermia. MTMR2 encodesa ubiquitously expressed phosphatase whose preferred substrateis phosphatidylinositol (3,5)-biphosphate, a regulator of membranehomeostasis and vesicle transport. We generated Mtmr2-null mice,which develop progressive neuropathy characterized by myelinoutfolding and recurrent loops, predominantly at paranodal myelin,and depletion of spermatids and spermatocytes from the seminiferousepithelium, which leads to azoospermia. Disruption of Mtmr2in Schwann cells reproduces the myelin abnormalities. We alsoidentified a novel physical interaction in Schwann cells, betweenMtmr2 and discs large 1 (Dlg1)/synapse-associated protein 97,a scaffolding molecule that is enriched at the node/paranoderegion. Dlg1 homologues have been located in several types ofcellular junctions and play roles in cell polarity and membraneaddition. We propose that Schwann cell-autonomous lossof Mtmr2-Dlg1 interaction dysregulates membrane homeostasisin the paranodal region, thereby producing outfolding and recurrentloops of myelin.

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