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

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Published 22 November 2004 © The Rockefeller University Press,

0021-9525/2004/11/711

The Journal of Cell Biology, Volume 167, Number 4, 711-721

http://www.jcb.org/cgi/content/abstract/167/4/711

Disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin

outfolding and impaired spermatogenesis

Alessandra Bolino1, lisa Bolis1, Stefano Carlo Previtali2, Giorgia

Dina2, Simona Bussini1, e Dati3, Stefano Amadio2, Ubaldo Del

Carro2, Dolores D. Mruk4, 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

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.

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, phosphotyrosine

phosphatase/dual specificity phosphatase.