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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Adaptor Proteins, Signal Transducing
-
Animals
-
Charcot-Marie-Tooth Disease / genetics*
-
Charcot-Marie-Tooth Disease / metabolism
-
Charcot-Marie-Tooth Disease / pathology
-
Discs Large Homolog 1 Protein
-
Drosophila Proteins / genetics
-
Drosophila Proteins / metabolism
-
Female
-
Guanylate Kinases
-
Homeostasis / genetics
-
Male
-
Membrane Proteins
-
Mice
-
Mice, Knockout
-
Microscopy, Electron, Transmission
-
Mutation / genetics
-
Myelin Sheath / metabolism
-
Myelin Sheath / pathology*
-
Myelin Sheath / ultrastructure
-
Nerve Tissue Proteins / genetics
-
Nerve Tissue Proteins / metabolism
-
Oligospermia / genetics*
-
Oligospermia / metabolism
-
Peripheral Nerves / metabolism
-
Peripheral Nerves / pathology*
-
Peripheral Nerves / physiopathology
-
Phosphatidylinositol Phosphates / metabolism
-
Protein Tyrosine Phosphatases / deficiency*
-
Protein Tyrosine Phosphatases / genetics
-
Protein Tyrosine Phosphatases, Non-Receptor
-
Ranvier's Nodes / metabolism
-
Ranvier's Nodes / pathology
-
Ranvier's Nodes / ultrastructure
-
Schwann Cells / metabolism
-
Schwann Cells / pathology
-
Schwann Cells / ultrastructure
-
Seminiferous Tubules / metabolism
-
Seminiferous Tubules / pathology
-
Seminiferous Tubules / physiopathology
-
Tumor Suppressor Proteins / genetics
-
Tumor Suppressor Proteins / metabolism
Substances
-
Adaptor Proteins, Signal Transducing
-
Discs Large Homolog 1 Protein
-
Dlg1 protein, mouse
-
Drosophila Proteins
-
Membrane Proteins
-
Nerve Tissue Proteins
-
Phosphatidylinositol Phosphates
-
Tumor Suppressor Proteins
-
phosphatidylinositol 3,5-diphosphate
-
dlg1 protein, Drosophila
-
Guanylate Kinases
-
Mtmr2 protein, mouse
-
Protein Tyrosine Phosphatases
-
Protein Tyrosine Phosphatases, Non-Receptor