title: Disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding and impaired spermatogenesis.
abstract: 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.
authors.affiliation: Dulbecco Telethon Institute, San Raffaele Scientific Institute, 20132 Milan, Italy. bolino.alessandra@hsr.it
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bolino
authors.forename: Annalisa
authors.initials: A
authors.lastname: Bolis
authors.forename: Stefano Carlo
authors.initials: SC
authors.lastname: Previtali
authors.forename: Giorgia
authors.initials: G
authors.lastname: Dina
authors.forename: Simona
authors.initials: S
authors.lastname: Bussini
authors.forename: Gabriele
authors.initials: G
authors.lastname: Dati
authors.forename: Stefano
authors.initials: S
authors.lastname: Amadio
authors.forename: Ubaldo
authors.initials: U
authors.lastname: Del Carro
authors.forename: Dolores D
authors.initials: DD
authors.lastname: Mruk
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Feltri
authors.forename: C Yan
authors.initials: CY
authors.lastname: Cheng
authors.forename: Angelo
authors.initials: A
authors.lastname: Quattrini
authors.forename: Lawrence
authors.initials: L
authors.lastname: Wrabetz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000074288:Discs Large Homolog 1 Protein; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D051528:Guanylate Kinases; D006706:Homeostasis / Q000235:genetics; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009154:Mutation / Q000235:genetics; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009845:Oligospermia / Q000235:genetics* / Q000378:metabolism; D010525:Peripheral Nerves / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency* / Q000235:genetics; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D011901:Ranvier's Nodes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D012583:Schwann Cells / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D012671:Seminiferous Tubules / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074288:Discs Large Homolog 1 Protein; C000614189:Dlg1 protein, mouse; D029721:Drosophila Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018129:Phosphatidylinositol Phosphates; D025521:Tumor Suppressor Proteins; C106336:phosphatidylinositol 3,5-diphosphate; C070350:dlg1 protein, Drosophila; D051528:Guanylate Kinases; C498717:Mtmr2 protein, mouse; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor