This web page was produced as an assignment for Genetics 564, an undergraduate capstone course at UW-Madison.
What is XLMTM?
X-Linked Myotubular Myopathy
XLMTM falls under a category of diseases known as centronuclear myopathies (CNM) . In particular, a mutation in the myotubularin gene (MTM1) located on the X chromosome, cause muscle weakness (myopathy) and decreased muscle tone (hypotonia) which is recognized early in development [1]. Due to the nature of this condition, myopathy and hypotonia, developmental defects are severe. Muscular deficiencies affect bone development, impair motor skills, and make breathing difficult without assistance due to increasing muscle weakness. This genetic disease is a result of a mutation in the gene encoding for the protein myotubularin[3]. Myotubularin is key in myocyte development and required for proper cellular function. Disruption in this protein results in the failure of protein trafficking and cellular development [2].
XLMTM falls under a category of diseases known as centronuclear myopathies (CNM) . In particular, a mutation in the myotubularin gene (MTM1) located on the X chromosome, cause muscle weakness (myopathy) and decreased muscle tone (hypotonia) which is recognized early in development [1]. Due to the nature of this condition, myopathy and hypotonia, developmental defects are severe. Muscular deficiencies affect bone development, impair motor skills, and make breathing difficult without assistance due to increasing muscle weakness. This genetic disease is a result of a mutation in the gene encoding for the protein myotubularin[3]. Myotubularin is key in myocyte development and required for proper cellular function. Disruption in this protein results in the failure of protein trafficking and cellular development [2].
Myotubularin:
A Key Player
Myotubularin plays a crucial role in muscle cell differentiation. This protein functions as a protein tyrosine phosphatase. Myotubularin acts as a phosphatase for phosphatidylinositol 3-phosphate (PIP3), a critical protein involved in protein trafficking [4]. Mutations in the myotubularin protein reduce its ability to dephosphorylate PIP3; this causes observable pathology in myocytes during myogenesis [2]. Interactions of a functional Myotubularin protein with related proteins such as Myotubularin Related Protein-12 (MTMR12) during myogenesis are crucial for cell development and cellular morphology. Mutated Myotubularin has impaired interactions, and this loss of protein interaction results in the centronucleated pathology [5].
MTM1 Inheritance:
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Disease Pathology
Due to various mutations occuring the the MTM1 gene encoding a key protein in muscle cell development, disease symptoms are obvious. Severe muscle weakness leads to respiratory failure and typically death within 1-2 years in humans, other animals affected by this disease typically have shorter expectancies [7]. X-Linked Myotubular Myopathy falls under the, usually autosomally inherited, Central Nuclear Myopathies [1]. These diseases, including XLMTM, show myocytes with a centrally located nucleus rather than the typical peripherally positioned nuclei. This mispositioning is of the myonuclei is a common feature in many muscle disorders, and is speculated to not only be a symptom of disease, but also plays a role in disease progression [9]. Myotubularin is localized to the cisternae of the sacroplasmic retculum in normal skeletal muscle where it performs its enzymatic activity-lipid regulation. However, in myotubularin deficient cells, abnormal T-tubule localization is seen [10], often localized in myofibers that are also found to contain abnormally condensed levels of mutated myotubularin [8].
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-Rudolph Virchow
Kyle Krellwitz, [email protected], date page last updated www.genetics564.weebly.com
References:
[1] NORD X-linked MTM. <https://rarediseases.org/rare-diseases/x-linked-myotubular-myopathy/
[2] PNAS: Myotubularin. < Taylor GS, Maehama T, Dixon JE. Myotubularin, a protein tyrosine phosphatase mutated in myotubular myopathy, dephosphorylates the lipid second messenger, phosphatidylinositol 3-phosphate. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(16):8910-8915.
[3] XLMTM: Genetics Home Reference. <https://ghr.nlm.nih.gov/condition/x-linked-myotubular-myopathy#statistics
[4] Science Direct: Myotubularin-1. <https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/myotubularin-1
[5] PLOS.<http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1003583
[6] Elsevier. <Hedberg-Oldorfs, C. (2017). Grand paternal inheritance of X-linked myotubular myopathy due to mosaicism, and identification of necklace fibers in an asymptomatic male[Scholarly project]. In Science Direct. Retrieved February 6, 2018, from https://www.sciencedirect.com/science/article/pii/S0960896617301505?via%3Dihub#bb0010
[7] Gene and Cell Therapy. <Mack, David L. et al. Molecular Therapy , Volume 25 , Issue 4 , 839 - 854www.sciencedirect.com/science/article/pii/S0960896617301505?via%3Dihub#bb0010
[8] PNAS: MTM1 Mut. in Labradors. <Beggs AH, Böhm J, Snead E, et al. MTM1 mutation associated with X-linked myotubular myopathy in Labrador Retrievers. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(33):14697-14702. doi:10.1073/pnas.1003677107.
[9] PMC: Frontiers in Physiology. <Folker ES, Baylies MK. Nuclear positioning in muscle development and disease. Frontiers in Physiology. 2013;4:363. doi:10.3389/fphys.2013.00363.
[10] Skeletal Muscle. <Shelton GD, Rider BE, Child G, et al. X-linked myotubular myopathy in Rottweiler dogs is caused by a missense mutation in Exon 11 of the MTM1gene. Skeletal Muscle. 2015;5(1):1. doi:10.1186/s13395-014-0025-3.
Image and Video citation:
header photo- https://synapse.koreamed.org/search.php?where=aview&id=10.3346/jkms.2007.22.6.1098&code=0063JKMS&vmode=PUBREADER#!po=10.0000
MTM protein model- Ayuka F, Barnett R (2015) Place Effects on Alcohol Consumption: A Literature Review. J Addict Res Ther 6:207. doi: 10.4172/2155-6105.1000207
MTM gene- Ayuka F, Barnett R (2015) Place Effects on Alcohol Consumption: A Literature Review. J Addict Res Ther 6:207. doi: 10.4172/2155-6105.1000207
[1] NORD X-linked MTM. <https://rarediseases.org/rare-diseases/x-linked-myotubular-myopathy/
[2] PNAS: Myotubularin. < Taylor GS, Maehama T, Dixon JE. Myotubularin, a protein tyrosine phosphatase mutated in myotubular myopathy, dephosphorylates the lipid second messenger, phosphatidylinositol 3-phosphate. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(16):8910-8915.
[3] XLMTM: Genetics Home Reference. <https://ghr.nlm.nih.gov/condition/x-linked-myotubular-myopathy#statistics
[4] Science Direct: Myotubularin-1. <https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/myotubularin-1
[5] PLOS.<http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1003583
[6] Elsevier. <Hedberg-Oldorfs, C. (2017). Grand paternal inheritance of X-linked myotubular myopathy due to mosaicism, and identification of necklace fibers in an asymptomatic male[Scholarly project]. In Science Direct. Retrieved February 6, 2018, from https://www.sciencedirect.com/science/article/pii/S0960896617301505?via%3Dihub#bb0010
[7] Gene and Cell Therapy. <Mack, David L. et al. Molecular Therapy , Volume 25 , Issue 4 , 839 - 854www.sciencedirect.com/science/article/pii/S0960896617301505?via%3Dihub#bb0010
[8] PNAS: MTM1 Mut. in Labradors. <Beggs AH, Böhm J, Snead E, et al. MTM1 mutation associated with X-linked myotubular myopathy in Labrador Retrievers. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(33):14697-14702. doi:10.1073/pnas.1003677107.
[9] PMC: Frontiers in Physiology. <Folker ES, Baylies MK. Nuclear positioning in muscle development and disease. Frontiers in Physiology. 2013;4:363. doi:10.3389/fphys.2013.00363.
[10] Skeletal Muscle. <Shelton GD, Rider BE, Child G, et al. X-linked myotubular myopathy in Rottweiler dogs is caused by a missense mutation in Exon 11 of the MTM1gene. Skeletal Muscle. 2015;5(1):1. doi:10.1186/s13395-014-0025-3.
Image and Video citation:
header photo- https://synapse.koreamed.org/search.php?where=aview&id=10.3346/jkms.2007.22.6.1098&code=0063JKMS&vmode=PUBREADER#!po=10.0000
MTM protein model- Ayuka F, Barnett R (2015) Place Effects on Alcohol Consumption: A Literature Review. J Addict Res Ther 6:207. doi: 10.4172/2155-6105.1000207
MTM gene- Ayuka F, Barnett R (2015) Place Effects on Alcohol Consumption: A Literature Review. J Addict Res Ther 6:207. doi: 10.4172/2155-6105.1000207