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Literature summary extracted from

  • Bolis, A.; Zordan, P.; Coviello, S.; Bolino, A.
    Myotubularin-related (MTMR) phospholipid phosphatase proteins in the peripheral nervous system (2007), Mol. Neurobiol., 35, 308-316.
    View publication on PubMed

Application

EC Number Application Comment Organism
3.1.3.64 medicine Charcot-Marie-Tooth type 4B1 animal model created by Mtmr2 null mice Mus musculus
3.1.3.64 medicine loss of either MTMR2 or MTMR13 specifically causes Charcot-Marie-Tooth type 4B1 and B2 (CMT4B1 and CMT4B2) neuropathies, respectively Homo sapiens
3.1.3.64 medicine MTm1 deficient mice serve as an animal model for X-linked myotubular myopathy Mus musculus

Cloned(Commentary)

EC Number Cloned (Comment) Organism
3.1.3.64 overexpression in COS-7 cells Chlorocebus aethiops

Protein Variants

EC Number Protein Variants Comment Organism
3.1.3.64 E276X another animal model for Charcot-Marie-Tooth type 4B1 is produced by introducing the E276X mutation in exon 9. Phosphatase activity is inactivated toward PtdIns3P and PtdIns(3,5)P2. Nerve morphology in these mice is similar to that observed in Mtmr2-null mice, although a huge variability in the number of myelin outfoldings between different mice is noted. In both mutants, Mtmr2-null and E276X, the dysmyelinating phenotype is less severe than that observed in human Charcot-Marie-Tooth type 4B1 Mus musculus
3.1.3.64 G103E mutations in the PH-GRAM domain affect both binding to the membrane and the phosphatase activity, as demonstrated for the G103E mutation Homo sapiens
3.1.3.64 additional information it is demonstrated that putative loss of function mutations in MTMR2 cause Charcot-Marie-Tooth type 4B1 (CMT4B1). Additional mutations are identified mainly in familial CMT4B1 cases. Most of the MTMR2 identified mutations affect the broad PTP domain, resulting in loss of the enzymatic activity, as has been functionally demonstrated for some of them Homo sapiens
3.1.3.64 additional information MTM-6 and MTM-9 have been identified in a genetic screening as proteins required for endocytosis in coelomocytes: a dramatical alteration in PtdIns3P localization is observed in coelomocyte from mtm-6 and mtm-9 mutants Caenorhabditis elegans
3.1.3.64 additional information Mtm1 deficient mice have, after birth, normal muscle fibers with nuclei located at the periphery. Starting at 4 weeks of age, these mice develop a progressive myopathy characterized by hypotrophy and an increasing number of fibers with centrally located nuclei Mus musculus
3.1.3.64 additional information MTM1 overexpression in COS-7 cells extensively treated with EGF induces large endosomal vacuoles and inhibits EGFR trafficking from late endosome to lysosome, while, in myotubes, MTM1 overexpression leads to the displacement of early endosomal antigen 1 (EEA1) from early endosomes and to a decreased insulin-induced glucose uptake Chlorocebus aethiops
3.1.3.64 additional information Mtmr2-null mouse are created as an animal model for Charcot-Marie-Tooth type 4B1 by removing exon 4, which encodes part of the PH-GRAM domain. Mice are viable. In both motor and sensory nerves of mutant mice, myelin outfoldings are observed starting at 3-4 weeks after birth. Semithin analysis is performed in longitudinal section of nerves. Myelin outfoldings predominantly arise at paranodal regions extending throughout the internode. At 12-15 months of age, myelin outfoldings also arise at Schmidt-Lanterman incisures, other regions enriched in Schwann cell cytoplasm. Axonal loss is observed only in Mtmr2-null mice at later stages (around 15 months) in more distal nerves. Dysmyelinating phenotype is less severe than that observed in human Charcot-Marie-Tooth type 4B1. Mtmr2-null mice have also defects in spermatogenesis, again, starting at 3-4 weeks of age Mus musculus
3.1.3.64 additional information myotubularins all share a PH-GRAM (Pleckstrin Homology-Glucosyltransferase, Rab-like GTPase Activators and Myotubularins) domain at the N-terminus, a protein tyrosine phosphatase domain and a coiled-coil region at the C-terminus. The PHGRAM domain binds to poliphosphoinositides, mainly PtdIns5P and PtdIns(3,5)P2 and in MTMR2, it has been shown to mediate the targeting of the phosphatase to the membrane of vacuoles formed under hypoosmotic stress Homo sapiens
3.1.3.64 additional information putative loss of function mutations in MTMR13, encoding a catalytically inactive phosphatase, cause Charcot-Marie-Tooth type 4B2 (CMT4B2). The first reported mutation is an in frame deletion removing part of the DENN domain at the N-terminus of the protein. DENN/GEF/AEX-3 is a well-conserved motif in signaling molecules. Cytoplasmic proteins lacking part of this domain delocalize to the nucleus where they might activate other proteins Homo sapiens
3.1.3.64 additional information several interactions between active and inactive myotubularins have been demonstrated. The active MTMR2 phosphatase binds to MTMR5 and MTMR13, which are both inactive enzymes Homo sapiens
3.1.3.64 additional information X-linked myotubular myopathy (XLMTM) is a severe skeletal muscle disorder affecting newborn males, characterized by hypotonia and generalized muscle weakness. More than 200 mutations in MTM1 are identified thus far in XLMTM patients leading to loss of MTM1 protein. Lack of endogenous MTM1 in XLMTM patient myoblasts does not significantly affect the pool of PtdIns3P or the localization of early endosomal antigen 1 (EEA1) Chlorocebus aethiops
3.1.3.64 Q426X phosphatase activity is inactivated toward PtdIns3P and PtdIns(3,5)P2 in vitro Mus musculus
3.1.3.64 Q482X phosphatase activity is inactivated toward PtdIns3P and PtdIns(3,5)P2 in vitro Mus musculus

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
3.1.3.64 membrane when hypoosmotic stress is induced in COS7 cells, a condition that increases PtdIns(3,5)P2 levels, MTMR2 delocalizes to membranes of intracellular vacuoles Homo sapiens 16020
-

Organism

EC Number Organism UniProt Comment Textmining
3.1.3.64 Caenorhabditis elegans
-
-
-
3.1.3.64 Caenorhabditis elegans Q965W9
-
-
3.1.3.64 Chlorocebus aethiops
-
-
-
3.1.3.64 Homo sapiens
-
-
-
3.1.3.64 Mus musculus
-
-
-
3.1.3.64 Mus musculus Q9Z2C4
-
-
3.1.3.64 Rattus norvegicus
-
-
-

Source Tissue

EC Number Source Tissue Comment Organism Textmining
3.1.3.64 COS-7 cell
-
Chlorocebus aethiops
-
3.1.3.64 ganglion satellite cells of dorsal root ganglia Rattus norvegicus
-
3.1.3.64 motoneuron
-
Rattus norvegicus
-
3.1.3.64 myotube
-
Chlorocebus aethiops
-
3.1.3.64 neuron sensory neuron Rattus norvegicus
-
3.1.3.64 peripheral nerve detected in vivo in axons in peripheral nerves Rattus norvegicus
-
3.1.3.64 Schwann cell detected in vivo in the cytoplasm of myelin-forming and nonmyelinforming Schwann cells Rattus norvegicus
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3.1.3.64 spinal cord ventral roots of spinal cord Rattus norvegicus
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Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
3.1.3.64 phosphatidylinositol 3,5-bisphosphate + H2O
-
Mus musculus phosphatidylinositol 5-phosphate + phosphate
-
?
3.1.3.64 phosphatidylinositol 3,5-bisphosphate + H2O
-
Homo sapiens phosphatidylinositol 5-phosphate + phosphate
-
?
3.1.3.64 phosphatidylinositol 3,5-bisphosphate + H2O
-
Rattus norvegicus phosphatidylinositol 5-phosphate + phosphate
-
?
3.1.3.64 phosphatidylinositol 3,5-bisphosphate + H2O
-
Caenorhabditis elegans phosphatidylinositol 5-phosphate + phosphate
-
?
3.1.3.64 phosphatidylinositol 3,5-bisphosphate + H2O
-
Chlorocebus aethiops phosphatidylinositol 5-phosphate + phosphate
-
?
3.1.3.64 phosphatidylinositol 3-phosphate + H2O
-
Mus musculus phosphatidylinositol + phosphate
-
?
3.1.3.64 phosphatidylinositol 3-phosphate + H2O
-
Homo sapiens phosphatidylinositol + phosphate
-
?
3.1.3.64 phosphatidylinositol 3-phosphate + H2O
-
Rattus norvegicus phosphatidylinositol + phosphate
-
?
3.1.3.64 phosphatidylinositol 3-phosphate + H2O
-
Caenorhabditis elegans phosphatidylinositol + phosphate
-
?
3.1.3.64 phosphatidylinositol 3-phosphate + H2O
-
Chlorocebus aethiops phosphatidylinositol + phosphate
-
?

Synonyms

EC Number Synonyms Comment Organism
3.1.3.64 MTM-6
-
Caenorhabditis elegans
3.1.3.64 MTM-9
-
Caenorhabditis elegans
3.1.3.64 MTM1
-
Mus musculus
3.1.3.64 MTM1
-
Chlorocebus aethiops
3.1.3.64 MTMR13
-
Homo sapiens
3.1.3.64 MTMR2
-
Homo sapiens
3.1.3.64 MTMR2
-
Rattus norvegicus
3.1.3.64 MTMR2
-
Mus musculus
3.1.3.64 myotubularin
-
Mus musculus
3.1.3.64 myotubularin
-
Caenorhabditis elegans
3.1.3.64 myotubularin
-
Chlorocebus aethiops
3.1.3.64 myotubularin-related protein
-
Homo sapiens
3.1.3.64 myotubularin-related protein
-
Rattus norvegicus
3.1.3.64 myotubularin-related protein
-
Mus musculus