Myotubular myopathy

Histopathological features are dominated by the large number of centrally-placed muscle nuclei, sometimes affecting more than 90% of muscle fibers. The nuclei form long chains in the middle of the fiber and are surrounded by cytoplasm, which contains mitochondria and membranous vesicles, but no myofibrils. This morphological appearance has prompted comparison with myotubes, and in fact centronuclear myopathies are sometimes referred to as myotubular myopathies. This is a misnomer, however, since although the affected fibers retain some of the structural features of myotubes, and maturational arrest may play a role in their formation, the vast majority of such fibers are fully differentiated histochemically into either type 1 or type 2. 

Blondeau, E Laporte, J. Bodin, S. Superti-Furga, G. Payrastre, B. Man-del, J.-L. Myotubularin, a phosphatase deficient in myotubular myopathy, acts on phosphatidylinositol 3-kinase and phosphatidylinositol 3-phosphate pathway. Hum. Mol. Genet., 9, 2223-2229 (2000)... 

Emery-Dreifuss muscular dystrophy Diabetes insipidus, nephrogenic, X-linked Myotubular myopathy, X-linked Otopalatodigital syndrome, type I... 

In part two, we review the role of Pis in human disease. Although Pis are not abundant in biological systems, they have displayed numerous important functions in multiple signal transduction pathways. A number of human diseases are characterized by dysfunctional PI pathways, including cancer, type 2 diabetes, Lowe syndrome, myotubular myopathy, and Charcot-Marie-Tooth disease. 

Herman, G.E., Kopacz, K., Zhao, W., Mills, P.L., Metzenberg, A., and Das, S., 2002, Characterization of mutations in fifty North American patients with X-linked myotubular myopathy. Hum. Mutat. 19 114-121. 

Laporte, J., Biancalana, V, Tanner, S.M., Kress, W., Schneider, V, Wallgren-Pettersson, C., Herger, F., Buj-Bello, A., Blondeau, F., Liechti-Gallati, S., and Mandel, J.L., 2000, MTM1 mutations in X-linked myotubular myopathy. Hum. Mutat. 15 393 409. 

Nishino, I., Minami, N., Kobayashi, O., Ikezawa, M., Goto, Y., Arahata, K., and Nonaka, I., 1998, MTM1 gene mutations in Japanese patients with the severe infantile form of myotubular myopathy. Neuromuscul. Disord. 8 453-458. 

Sarnat, H.B., 1990, Myotubular myopathy Arrest of morphogenesis of myofibres associated with persistence of fetal vimentin and desmin. Four cases compared with fetal and neonatal muscle. 

Tanner, S.M., Schneider, V, Thomas, N.S., Clarke, A., Lazarou, L., and Liechti-Gallati, S., 1999, Characterization of 34 novel and six known MTM1 gene mutations in 47 unrelated X-linked myotubular myopathy patients. Neuromuscul. Disord. 9 41 49. 

Taylor, G.S., Maehama, T., and Dixon, J.E., 2000, Inaugural article Myotubularin, a protein tyrosine phosphatase mutated in myotubular myopathy, dephosphorylates the lipid second messenger, phosphatidylinositol 3-phosphate. Proc. Natl. Acad. Sci. U. S. A. 97 8910-8915. 

Phosphatidylinositol 3,5-bisphosphate (PI-3,5-P2, 6) is the low abundance, newest member of PIPn family (33). It is involved in mediation of several cellular processes such as vacuolar homeostasis, membrane trafficking, and vesicular protein sorting (36, 38). The recently discovered PI-3,5-P2 effectors include a family of -propeller, epsin, and CHMP protein families (39). The importance of PI-3,5-P2 in human physiology is demonstrated by its role in insulin signaling, myotubular myopathy, and corneal dystrophy (38). 

Begley MJ, Taylor GS, Kim SA et al (2003) Crystal structure of a phosphoinositide phosphatase, MTMR2 insights into myotubular myopathy and Charcot-Marie-Tooth syndrome. Mol Cell 12 1391-1402... 

Laporte J, Hu LJ, Kretz C et al (1996) A gene mutated in X-hnked myotubular myopathy defines a new putative tyrosine phosphatase family conserved in yeast. Nat Genet 13 ... 

Figure 3. Pathways of phosphoinositide synthesis and interconversions. The figure shows the main pathways of phosphoinositide synthesis in mammalian cells. For the sake of clarity only the enzymatic activities (3-, 4- or 5-kinases or phosphatases) are indicated. In some cases the identification of key enzymes is mentioned (class I, II and III PI 3-kinases, PTEN, MTM, MTMR or SHIP). PI3K, phosphoinositide 3-kinase. PTEN, phosphatase and tensin homolog deleted on chromosome ten. MTM, myotubularin. MTMR, myotubular myopathy-related protein. SHIP, Src homology 2-containing inositol 5-phosphatase. PLC, phospholipase C. DAG, diacylglycerol.

The gene mutated in X-linked myotubular myopathy (XLMTM), a severe congenital disorder characterized by generalized muscle weakness and hypotonia, codes for a ubiquitously expressed protein, myotubularin. This protein presents the conserved sequence of the phosphotyrosine phosphatase s active site. However, studies of its substrate specificity have shown that myotubularin s preferred substrates are PtdIns(3)P and Ptdlns(3,5)P2 (Blondeau et al, 2000 Schaletzky et al, 2003). Accordingly, it has been shown that... 

Kim, SA, Taylor, GS, Torgersen, KM and Dixon, JE (2002) Myotubularin and MTMR2, phosphatidylinositol 3-phosphatases mutated in myotubular myopathy and type 4 B Char-cot-Marie-Thooth disease. J Biol Chem, 211, 4526-4531. 

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