Disease relevance of MTMR2

• Mutations in the gene encoding myotubularin-related protein 2 (MTMR2) are responsible for autosomal recessive Charcot-Marie-Tooth disease type 4B1 (CMT4B1), a severe hereditary motor and sensory neuropathy characterized by focally folded myelin sheaths and demyelination [1].
• Charcot-Marie-Tooth disease type 4B (CMT4B) is a severe, demyelinating peripheral neuropathy characterized by distinctive, focally folded myelin sheaths [2].
• Crystal structure of a phosphoinositide phosphatase, MTMR2: insights into myotubular myopathy and Charcot-Marie-Tooth syndrome [3].
• Hereditary motor and sensory neuropathy (HMSN) with focally folded myelin sheaths, or Charcot-Marie-Tooth type 4B (CMT4B), is a distinct clinical entity belonging to the heterogeneous group of autosomal recessive demyelinating neuropathies [4].

High impact information on MTMR2

• A gene mutated in Charcot-Marie-Tooth disease type 4B (CMT4B), an autosomal recessive demyelinating neuropathy with myelin outfoldings, has been mapped on chromosome 11q22 [5].
• Finally, the MTMR2 structure will serve as a model for other members of the myotubularin family and provide a framework for understanding the mechanism whereby mutations in these proteins lead to disease [3].
• Through this interaction, MTMR5 increases the enzymatic activity of MTMR2 and dictates its subcellular localization [6].
• Mutations in the myotubularin (MTM)-related protein 2 (MTMR2) gene are responsible for the severe autosomal recessive neuropathy Charcot-Marie-Tooth disease type 4B1 [7].
• Our data indicate that phosphoinositide-protein interactions, as well as protein-protein interactions, are necessary for the correct regulation of MTMR2 [7].

Chemical compound and disease context of MTMR2

• Myotubularins are a family of Phosphatidylinositol 3-phosphate (PtdIns3P) phosphatases identified by the positional cloning of the MTM1 gene in patients suffering from X-linked myotubular myopathy and the MTMR2 gene in patients suffering from the demyelinating neuropathy Charcot-Marie-Tooth disease type 4B [8].

Biological context of MTMR2

• Such a mechanism would explain the strikingly similar phenotypes of patients with recessive mutations in either MTMR2 or MTMR13 [2].
• Thus, the demyelinating neuropathy CMT4B1 might be triggered by the malfunction of neural membrane recycling, membrane trafficking, and/or endocytic or exocytotic processes, combined with altered axon-Schwann cell interactions [1].
• Molecular study of the SBF2 gene in the CMT4B family demonstrated the presence of a homozygous inframe deletion of SBF2 exons 11 and 12 in all four affected individuals [9].
• Charcot-Marie-Tooth type 4B (CMT4B) is caused by mutations in the myotubularin-related 2 gene, MTMR2, on chromosome 11q22 [10].
• Point mutations were found in the myotubularin-related protein-2 (MTM2) gene for CMT1 AR B1 [11].

Anatomical context of MTMR2

• We demonstrate that the known disease-associated MTMR2 mutations lead to dramatically reduced phosphatase activity, suggesting that the MTMR2 phosphatase activity is crucial for the proper function of peripheral nerves in CMT4B1 [1].
• The neurofilament light chain protein, NF-L, was identified repeatedly in both screenings, and found to interact with MTMR2 in both Schwann cells and neurons [12].

Associations of MTMR2 with chemical compounds

• MTMR2 encodes a member of the myotubularin family of phosphoinositide-3-phosphatases, which dephosphorylate phosphatidylinositol 3-phosphate (PI(3)P) and bisphosphate PI(3,5)P2 [2].
• Molecular basis for substrate recognition by MTMR2, a myotubularin family phosphoinositide phosphatase [13].
• A homozygous cytosine to thymine missense mutation at nucleotide position 847, resulting in an amino acid substitution of arginine to tryptophan at codon 283, was detected in exon 9 of the MTMR2 gene [14].

Other interactions of MTMR2

• MTM1 is a phosphatidylinositol phosphatase with reported specificity toward PtdIns3P, while the related proteins MTMR2 and MTMR3 hydrolyze both PtdIns3P and PtdIns(3,5)P2 [8].
• All active MTMs we have tested (MTM1, MTMR2-MTMR4) reduce endosomal PtdIns3P levels upon overexpression [15].
• One patient was heterozygous for a novel MTMR2 mutation and still another was homozygous for the founder mutation, R148X, in NDRG1 [16].
• Exclusion of the SCN2B gene as candidate for CMT4B [17].

Analytical, diagnostic and therapeutic context of MTMR2

• To investigate whether mutations in MTMR2 may also cause different forms of CMT, we screened 183 unrelated patients with a broad spectrum of CMT and related neuropathies using denaturing high-performance liquid chromatography [18].
• An animal model for CMT4B would provide insights into the pathogenesis of this disorder [10].

References