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

Alessandra Bolino, Annalisa Bolis, Stefano Carlo Previtali, Giorgia Dina, Simona Bussini, Gabriele Dati, Stefano Amadio, Ubaldo Del Carro, Dolores D. Mruk, Maria Laura Feltri, C. Yan Cheng, Angelo Quattrini, Lawrence Wrabetz

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)711-721
Number of pages11
JournalJournal of Cell Biology
Issue number4
Publication statusPublished - Nov 22 2004

ASJC Scopus subject areas

  • Cell Biology


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