Disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding and impaired spermatogenesis

doi:10.1083/jcb.200407010

Published 22 November 2004. doi:10.1083/jcb.200407010
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 4, 711-721

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Article

Disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding and impaired spermatogenesis

Alessandra Bolino¹, Annalisa Bolis¹, Stefano Carlo Previtali², Giorgia Dina², Simona Bussini¹, Gabriele Dati³, Stefano Amadio², Ubaldo Del Carro², Dolores D. Mruk⁴, Maria Laura Feltri³, C. Yan Cheng⁴, Angelo Quattrini², and Lawrence Wrabetz³

¹ Dulbecco Telethon Institute, San Raffaele Scientific Institute, 20132 Milan, Italy
² Department of Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy
³ Department of Biological and Technological Research, San Raffaele Scientific Institute, 20132 Milan, Italy
⁴ Population Council, Center for Biomedical Research, The Rockefeller University, New York, NY 10021

Correspondence to Alessandra Bolino: bolino.alessandra{at}hsr.it

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.

Abbreviations used in this paper: CMT, Charcot-Marie-Tooth;CMV, cytomegalovirus; MAG, myelin-associated glycoprotein; MAGUK,membrane-associated guanylate kinase-like; MTM, myotubularin;MTMR, myotubularin-related protein; PDZ, PSD-95/Dlg/ZO-1; PtdIns3,5P2,phosphatidylinositol (3,5)-biphosphate; PTP/DSP, phosphotyrosinephosphatase/dual specificity phosphatase.

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