Alternative titles; symbols
HGNC Approved Gene Symbol: MTMR2
SNOMEDCT: 715803003;
Cytogenetic location: 11q21 Genomic coordinates (GRCh38): 11:95,832,880-95,924,107 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q21 | Charcot-Marie-Tooth disease, type 4B1 | 601382 | Autosomal recessive | 3 |
The MTMR2 gene encodes a protein that belongs to the myotubularin family, which is characterized by the presence of a phosphatase domain (summary by Laporte et al., 1998). See also MTMR1 (300171).
By searching an EST database for sequences related to MTM1 (300415), Laporte et al. (1996) identified partial cDNAs encoding MTMR2 (myotubularin-related protein-2). Laporte et al. (1998) isolated additional cDNAs corresponding to the entire MTMR2 coding region. Sequence comparisons of the conserved protein-tyrosine phosphatase/dual-specificity phosphatase regions of myotubularin family members indicated that MTM1, MTMR1, MTMR2, a zebrafish ortholog of MTMR2, and Drosophila Mtmh1 form a distinct subgroup. Northern blot analysis revealed that the 4-kb MTMR2 mRNA is expressed ubiquitously.
In the course of positional cloning to identify the gene responsible for Charcot-Marie-Tooth disease type 4B (CMT4B1; 601382) on chromosome 11q22, Bolino et al. (2000) identified a gene, called KIAA1073 by Kikuno et al. (1999), with an open reading frame of 1,932 basepairs encoding a protein of 643 amino acids. KIAA1073 shares 100% nucleotide identity with a partial 1,203-bp cDNA corresponding to MTMR2. In both patients and controls, Bolino et al. (2000) identified by RT-PCR 3 additional exons, 1A, 2A, and 2B, of 71, 73, and 124 basepairs, respectively, at the 5-prime end of the cDNA that were not described in the published sequence. They found the same differentially spliced forms in RNA isolated from peripheral nerve, defining a common ORF of 1,716 basepairs with the initiation codon in exon 3, which corresponded to a shorter protein (571 amino acids). Using RT-PCR ELISA, Kikuno et al. (1999) found intermediate expression of KIAA1073 in all adult and fetal tissues and specific brain regions examined except spinal cord and corpus callosum, where expression was higher.
Berger et al. (2002) cloned and characterized the mouse Mtmr2 gene, which encodes a 643-amino acid protein that shares 97% sequence identity with the human protein.
Berger et al. (2002) determined that mouse Mtmr2 dephosphorylates phosphatidylinositol 3-phosphate (PI3P) and phosphatidylinositol 3,5-bisphosphate (PI3,5P2) with high efficiency and peak activity at neutral pH. This is distinct from the activity of myotubularin, which only acts on PI3P. Analysis of CMT4B1-associated MTMR2 mutations showed dramatically reduced phosphatase activity, suggesting that this activity is crucial for the proper functioning of peripheral nerves. Berger et al. (2002) hypothesized that mutations in MTMR2 may lead to malfunction of neural membrane recycling, membrane trafficking, and endo- and exocytic processes, which may be crucial elements underlying the disease mechanism in CMT4B1.
Previtali et al. (2003) detected MTMR2 in all cytoplasmic compartments of myelin-forming Schwann cells, as well as in the cytoplasm of non-myelin-forming Schwann cells and both sensory and motor neurons. In contrast, MTMR2 was detected in the nucleus of Schwann cells and motor neurons, but not in the nucleus of sensory neurons. NFL (162280) interacted with MTMR2 in yeast 2-hybrid screenings using both fetal brain and peripheral nerve libraries and was found to interact with MTMR2 in both Schwann cells and neurons.
Kim et al. (2003) identified a protein that specifically interacts with MTMR2 but not with MTM1; using mass spectrometry, they identified the protein as MTMR5 (603560), a catalytically inactive member of the myotubularin family. MTMR2 interacts with MTMR5 via its coiled-coil domain. Mutations in the coiled-coil domain of either MTMR2 or MTMR5 abrogate this interaction. Through this interaction, MTMR5 increases the enzymatic activity of MTMR2 and dictates its subcellular localization. Thus an active myotubularin family member is regulated by an inactive member.
Because the substrates for MTMR2 are localized in the membrane bilayer, membrane targeting of MTMR2 is an important regulatory mechanism. In resting COS cells, Berger et al. (2003) found that transfected mouse Mtmr2 localized mainly in the cytosol, with strong perinuclear staining and partial colocalization with endoplasmic reticulum and Golgi markers. In hypoosmotically stressed COS cells, Mtmr2 bound to membranes of PI(3,5)P2-containing vacuoles formed under these conditions. Using mutant forms of mouse Mtmr2, Berger et al. (2003) determined that the pleckstrin homology (PH)-GRAM domain and the C-terminal coiled-coil domain were required for membrane association. The PH-GRAM domain bound the PI(3,5)P2 substrate and the PI(5)P product, and the coiled-coil domain also mediated Mtmr2 homodimerization. Berger et al. (2003) concluded that phosphoinositide-protein interactions, as well as protein-protein interactions, are necessary for regulation of MTMR2 localization.
Bolino et al. (2000) determined that MTMR2 contains 18 exons, including the 3 additional exons found in the alternatively spliced forms.
By analysis of radiation and somatic cell hybrids and by fluorescence in situ hybridization, Laporte et al. (1998) mapped the MTMR2 gene to 11q22.
In unrelated patients with (CMT4B1; 601382), Bolino et al. (2000) identified 5 different mutations in the MTMR2 gene. Using RT-PCR to screen RNA from lymphoblastoid cell lines of 2 unrelated CMT4B1 patients, Bolino et al. (2000) identified a gln426-to-ter mutation (Q426X; 603557.0001) in homozygosity in an Italian patient and an in-frame deletion (603557.0002) in a Saudi Arabian patient. In the Saudi Arabian patient, an additional glu276-to-ter mutation (E276Q; 603557.0003) was found in homozygosity. Therefore this individual was homozygous for 2 different mutations in the same allele.
To investigate whether mutations in the MTMR2 gene may cause other forms of CMT, Bolino et al. (2001) screened 183 unrelated patients with a broad spectrum of CMT and related neuropathies, using denaturing high-performance liquid chromatography. They identified 4 frequent and 3 rare exonic variants; 2 of the rare variants were identified in 2 unrelated patients with congenital hypomyelinating neuropathy and not in the normal controls. The results indicated that loss-of-function mutations in MTMR2 are preferentially associated with the CMT4B phenotype.
By integrating crystallographic and deuterium exchange/mass spectrometry studies of human MTMR2 in complex with phosphoinositides, Begley et al. (2006) identified the molecular basis for the specificity of MTMR2 for membrane-bound phosphoinositides. Phosphoinositide substrates bound in a pocket located on a positively charged face of the protein, and a flexible, hydrophobic helix made extensive interaction with the diacylglycerol moieties of substrates. An extensive hydrogen-bonding network and charge-charge interaction within the active site pocket determined phosphoinositide headgroup specificity.
Bolino et al. (2004) found that Mtmr2-null mice developed a progressive neuropathy characterized by myelin outfolding and recurrent loops, predominantly at paranodal myelin, similar to patients with CMT4B1. The mutant mice also developed azoospermia, with increased numbers of spermatids and spermatocytes in the lumens of most seminiferous tubules at age 4 months, as well as decreased testicular size and weight. Bolino et al. (2004) noted that 1 patient with CMT4B1 reportedly developed azoospermia (Laporte et al., 2003). In vitro coimmunoprecipitation studies in normal cells showed that Mtmr2 interacted with Dlg1 (601014), a scaffolding molecule, in Schwann cells. Bolino et al. (2004) suggested that Schwann cell-autonomous loss of Mtmr2-Dlg1 interaction dysregulated membrane homeostasis in the paranodal region, resulting in myelin outfolding.
Bonneick et al. (2005) generated a mouse model of CMT4B1 by introducing a E276X mutation in exon 9 of the Mtmr2 gene and deleting the chromosomal region immediately downstream of the stop codon up to within exon 13. The resulting allele closely mimicked the mutation (603557.0002) found in a Saudi Arabian CMT4B1 patient. Animals homozygous for the mutation showed various degrees of complex myelin infoldings and outfoldings exclusively in peripheral nerves. This pathology was progressive with age, and axonal damage was occasionally observed. Distal nerve regions were more affected than proximal parts; however, there were no significant electrophysiologic changes, even in aged (16-month-old) mice, suggesting that myelin infoldings and outfoldings per se may not be invariably associated with detectable electrophysiologic abnormalities.
Ng et al. (2013) found that sciatic nerves from adult Mtmr13 (607697)- and Mtmr2-null mice showed normal downstream Akt (164730) activation. Immunofluorescence studies showed that both Mtmr13 and Mtmr2 localized to punctate endomembrane structures within the Schwann cell cytoplasm of normal mouse sciatic nerve, but were not present in compact myelin or in the nucleus. However, the endosome-lysosome compartment appeared morphologically normal in both mutant mouse nerves, indicating that loss of these proteins does not cause dysregulation of the endolysosomal system. The protein levels of Mtmr2 were decreased by about 50% in Mtmr13-null nerves, and protein levels of Mtmr13 were decreased by about 70% in Mtmr2-null nerves, suggesting that the proteins depend upon each other to achieve wildtype levels of protein expression in peripheral nerves.
In an inbred Italian family with type 4B1 Charcot-Marie-Tooth disease (CMT4B1; 601382), Bolino et al. (2000) identified a 1276C-T transition in exon 11 of the MTMR2 gene, resulting in a gln426-to-ter (Q426X) substitution in the PTP domain.
In an inbred Saudi Arabian family with type 4B1 Charcot-Marie-Tooth disease (CMT4B1; 601382), Bolino et al. (2000) found homozygosity for 2 mutations on the same allele. One mutation was a G-to-A substitution at intron 13 at the +1 site (IVS13+1G-A), resulting in in-frame exon skipping with deletion of codons 494 to 531 (1480-1593del, phe494-glu531del). The other mutation, a G-to-T transversion at nucleotide 826, resulted in a glu276-to-ter (E276X) substitution.
See 603557.0002 and Bolino et al. (2000).
In 2 Italian sibs with Charcot-Marie-Tooth disease type 4B1 (CMT4B1; 601382), Bolino et al. (2000) identified a homozygous 1444C-T transition in exon 12 of the MTMR2 gene, resulting in a gln482-to-ter (Q482X) substitution.
In an inbred Saudi Arabian family (KAY.690) with Charcot-Marie-Tooth disease type 4B1 (CMT4B1; 601382), Bolino et al. (2000) identified homozygosity for a complex mutation in exon 14 of the MTMR2 gene, a deletion of nucleotides 1736 to 1745 and insertion of 2 bp (CC), referred to as 1736-1745delinsCC, leading to a frameshift at Tyr579 (Tyr579fs) and premature translation termination. The mutation was found in homozygosity in all affected members of the pedigree.
Begley, M. J., Taylor, G. S., Brock, M. A., Ghosh, P., Woods, V. L., Dixon, J. E. Molecular basis for substrate recognition by MTMR2, a myotubularin family phosphoinositide phosphatase. Proc. Nat. Acad. Sci. 103: 927-932, 2006. [PubMed: 16410353] [Full Text: https://doi.org/10.1073/pnas.0510006103]
Berger, P., Bonneick, S., Willi, S., Wymann, M., Suter, U. Loss of phosphatase activity in myotubularin-related protein 2 is associated with Charcot-Marie-Tooth disease type 4B1. Hum. Molec. Genet. 11: 1569-1579, 2002. [PubMed: 12045210] [Full Text: https://doi.org/10.1093/hmg/11.13.1569]
Berger, P., Schaffitzel, C., Berger, I., Ban, N., Suter, U. Membrane association of myotubularin-related protein 2 is mediated by a pleckstrin homology-GRAM domain and a coiled-coil dimerization module. Proc. Nat. Acad. Sci. 100: 12177-12182, 2003. [PubMed: 14530412] [Full Text: https://doi.org/10.1073/pnas.2132732100]
Bolino, A., Bolis, A., Previtali, S. C., Dina, G., Bussini, S., Dati, G., Amadio, S., Del Carro, U., Mruk, D. D., Feltri, M. L., Cheng, C. Y., Quattrini, A., Wrabetz, L. Disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding and impaired spermatogenesis. J. Cell Biol. 167: 711-721, 2004. [PubMed: 15557122] [Full Text: https://doi.org/10.1083/jcb.200407010]
Bolino, A., Lonie, L. J., Zimmer, M., Boerkoel, C. F., Takashima, H., Monaco, A. P., Lupski, J. R. Denaturing high-performance liquid chromatography of the myotubularin-related 2 gene (MTMR2) in unrelated patients with Charcot-Marie-Tooth disease suggests a low frequency of mutation in inherited neuropathy. Neurogenetics 3: 107-109, 2001. [PubMed: 11354824] [Full Text: https://doi.org/10.1007/s100480000101]
Bolino, A., Muglia, M., Conforti, F. L., LeGuern, E., Salih, M. A. M., Georgiou, D.-M., Christodoulou, K., Hausmanowa-Petrusewicz, I., Mandich, P., Schenone, A., Gambardella, A., Bono, F., Quattrone, A., Devoto, M., Monaco, A. P. Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nature Genet. 25: 17-19, 2000. [PubMed: 10802647] [Full Text: https://doi.org/10.1038/75542]
Bonneick, S., Boentert, M., Berger, P., Atanasoski, S., Mantei, N., Wessig, C., Toyka, K. V., Young, P., Suter, U. An animal model for Charcot-Marie-Tooth disease type 4B1. Hum. Molec. Genet. 14: 3685-3695, 2005. [PubMed: 16249189] [Full Text: https://doi.org/10.1093/hmg/ddi400]
Kikuno, R., Nagase, T., Ishikawa, K., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 197-205, 1999. [PubMed: 10470851] [Full Text: https://doi.org/10.1093/dnares/6.3.197]
Kim, S.-A., Vacratsis, P. O., Firestein, R., Cleary, M. L., Dixon, J. E. Regulation of myotubularin-related (MTMR)2 phosphatidylinositol phosphatase by MTMR5, a catalytically inactive phosphatase. Proc. Nat. Acad. Sci. 100: 4492-4497, 2003. [PubMed: 12668758] [Full Text: https://doi.org/10.1073/pnas.0431052100]
Laporte, J., Bedez, F., Bolino, A., Mandel, J.-L. Myotubularins, a large disease-associated family of cooperating catalytically active and inactive phosphoinositides phosphatases. Hum. Molec. Genet. 12: R285-R292, 2003. [PubMed: 12925573] [Full Text: https://doi.org/10.1093/hmg/ddg273]
Laporte, J., Blondeau, F., Buj-Bello, A., Tentler, D., Kretz, C., Dahl, N., Mandel, J.-L. Characterization of the myotubularin dual specificity phosphatase gene family from yeast to human. Hum. Molec. Genet. 7: 1703-1712, 1998. [PubMed: 9736772] [Full Text: https://doi.org/10.1093/hmg/7.11.1703]
Laporte, J., Hu, L. J., Kretz, C., Mandel, J.-L., Kioschis, P., Coy, J. F., Klauck, S. M., Poustka, A., Dahl, N. A gene mutated in X-linked myotubular myopathy defines a new putative tyrosine phosphatase family conserved in yeast. Nature Genet. 13: 175-182, 1996. [PubMed: 8640223] [Full Text: https://doi.org/10.1038/ng0696-175]
Ng, A. A., Logan, A. M., Schmidt, E. J., Robinson, F. L. The CMT4B disease-causing phosphatases Mtmr2 and Mtmr13 localize to the Schwann cell cytoplasm and endomembrane compartments, where they depend upon each other to achieve wild-type levels of protein expression. Hum. Molec. Genet. 22: 1493-1506, 2013. [PubMed: 23297362] [Full Text: https://doi.org/10.1093/hmg/dds562]
Previtali, S. C., Zerega, B., Sherman, D. L., Brophy, P. J., Dina, G., King, R. H. M., Salih, M. M., Feltri, L., Quattrini, A., Ravazzolo, R., Wrabetz, L., Monaco, A. P., Bolino, A. Myotubularin-related 2 protein phosphatase and neurofilament light chain protein, both mutated in CMT neuropathies, interact in peripheral nerve. Hum. Molec. Genet. 12: 1713-1723, 2003. [PubMed: 12837694] [Full Text: https://doi.org/10.1093/hmg/ddg179]