Dystrophin is a rod-shaped cytoplasmic protein, and a vital part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane. This complex is variously known as the costamere or the dystrophin-associated protein complex. Many muscle proteins, such as α-dystrobrevin, syncoilin, synemin, sarcoglycan, dystroglycan, and sarcospan, colocalize with dystrophin at the costamere.
The dystrophin gene is one of the longest human genes known, covering 2.2 megabases (0.07% of the human genome) at locus Xp21. The primary transcript measures about 2,400 kilobases and takes 16 hours to transcribe;[1] the mature mRNA measures 14.0 kilobases.[2] The 79 exons[3] code for a protein of over 3500 amino acid residues.[4]
Function [edit]
Dystrophin is a protein located between the sarcolemma and the outermost layer of myofilaments in the muscle fiber (myofiber). It is a cohesive protein, linking actin filaments to another support protein that resides on the inside surface of each muscle fiber’s plasma membrane (sarcolemma). This support protein on the inside surface of the sarcolemma in turn links to two other consecutive proteins for a total of three linking proteins. The final linking protein is attached to the fibrous endomysium of the entire muscle fiber. Dystrophin supports muscle fiber strength and helps to prevent muscle fiber injury. Movement of thin filaments (actin) creates a pulling force on the extracellular connective tissue that eventually becomes the tendon of the muscle.
Pathology [edit]
Dystrophin deficiency has been definitively established as one of the root causes of the general class of myopathies collectively referred to as muscular dystrophy. The large cytosolic protein was first identified in 1987 by Louis M. Kunkel,[5] after the 1986 discovery of the mutated gene that causes Duchenne muscular dystrophy (DMD) .[6]
Normal skeletal muscle tissue contains only small amounts of dystrophin (about 0.002% of total muscle protein), but its absence (or abnormal expression) leads to the development of a severe and currently incurable constellation of symptoms most readily characterized by several aberrant intracellular signaling pathways that ultimately yield pronounced myofiber necrosis as well as progressive muscle weakness and fatigability. Most DMD patients become wheelchair-dependent early in life, and the gradual development of cardiac hypertrophy—a result of severe myocardial fibrosis—typically results in premature death in the first two or three decades of life. Mutations in the dystrophin gene that lead to the production of less defective, but still only partially functional dystrophin protein, result in a display of a much milder dystrophic phenotype in affected patients, resulting in the disease known as Becker's muscular dystrophy (BMD). In some cases the patient's phenotype is such that experts may decide differently on whether a patient should be diagnosed with DMD or BMD. The theory currently most commonly used to predict whether a mutation will result in a DMD or BMD phenotype, is the reading frame rule.[7]
Though its role in airway smooth muscle is not well established, recent research indicates that dystrophin along with other subunits of dystrophin glycoprotein complex is associated with phenotype maturation.[8]
Interactions [edit]
Dystrophin has been shown to interact with SNTB1,[9] Syntrophin, alpha 1[10][11][12] and DTNA.[13]
Neanderthal admixture [edit]
A variant of the dysmorphin gene, which is on the X chromosome, named B2006, appears to be an introgression from a Neanderthal-modern human mating.[14]
References [edit]
- ^ Tennyson CN, Klamut HJ, Worton RG (1995). "The human dystrophin gene requires 16 hours to be transcribed and is cotranscriptionally spliced". Nature Genetics 9 (2): 184–90. doi:10.1038/ng0295-184. PMID 7719347.
- ^ NCBI Sequence Viewer v2.0
- ^ Strachan T and Read AP, 1999. Human molecular genetics, BIOS Scientific, New York, USA
- ^ NCBI Sequence Viewer v2.0
- ^ Hoffman E, Brown R, Kunkel L (1987). "Dystrophin: the protein product of the Duchenne muscular dystrophy locus". Cell 51 (6): 919–28. doi:10.1016/0092-8674(87)90579-4. PMID 3319190.
- ^ Monaco A, Neve R, Colletti-Feener C et al. (1986). "Isolation of candidate cDNAs for portions of the Duchenne muscular dystrophy gene". Nature 323 (6089): 646–50. doi:10.1038/323646a0. PMID 3773991.
- ^ Aartsma-Rus A et al. (2006). "Entries in the Leiden Duchenne muscular dystrophy mutation database: an overview of mutation types and paradoxical cases that confirm the reading-frame rule". Muscle Nerve 34 (2): 135–44. doi:10.1002/mus.20586. PMID 16770791.
- ^ Sharma P, Tran T, Stelmack GL et al. (2008). "Expression of the dystrophin-glycoprotein complex is a marker for human airway smooth muscle phenotype maturation". Am. J. Physiol. Lung Cell Mol. Physiol. 294 (1): L57–68. doi:10.1152/ajplung.00378.2007. PMID 17993586.
- ^ Ahn, A H; Kunkel L M (February 1995). "Syntrophin binds to an alternatively spliced exon of dystrophin". J. Cell Biol. (UNITED STATES) 128 (3): 363–71. doi:10.1083/jcb.128.3.363. ISSN 0021-9525. PMC 2120343. PMID 7844150.
- ^ Ahn, A H; Freener C A, Gussoni E, Yoshida M, Ozawa E, Kunkel L M (February 1996). "The three human syntrophin genes are expressed in diverse tissues, have distinct chromosomal locations, and each bind to dystrophin and its relatives". J. Biol. Chem. (UNITED STATES) 271 (5): 2724–30. doi:10.1074/jbc.271.5.2724. ISSN 0021-9258. PMID 8576247.
- ^ Yang, B; Jung D, Rafael J A, Chamberlain J S, Campbell K P (March 1995). "Identification of alpha-syntrophin binding to syntrophin triplet, dystrophin, nNOS NOS1 ,and utrophin". J. Biol. Chem. (UNITED STATES) 270 (10): 4975–8. doi:10.1074/jbc.270.10.4975. ISSN 0021-9258. PMID 7890602.
- ^ Gee, S H; Madhavan R, Levinson S R, Caldwell J H, Sealock R, Froehner S C (January 1998). "Interaction of muscle and brain sodium channels with multiple members of the syntrophin family of dystrophin-associated proteins". J. Neurosci. (UNITED STATES) 18 (1): 128–37. ISSN 0270-6474. PMID 9412493.
- ^ Sadoulet-Puccio, H M; Rajala M, Kunkel L M (November 1997). "Dystrobrevin and dystrophin: an interaction through coiled-coil motifs". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 94 (23): 12413–8. doi:10.1073/pnas.94.23.12413. ISSN 0027-8424. PMC 24974. PMID 9356463.
- ^ Khan, Razib (January 25, 2011). "Neandertal admixture, revisiting results after shaken priors". Discover Magazine.
Other sources [edit]
- Saladin, Kenneth. Anatomy and Physiology: The Unity of Form and Function, 6th ed. McGraw-Hill. New York, 2012.
- "DMD." Genetics Home Reference. U.S. National Library of Medicine, 2 Dec. 2012. Web. 09 Dec. 2012.
Further reading [edit]
- Roberts RG, Gardner RJ, Bobrow M (1994). "Searching for the 1 in 2,400,000: a review of dystrophin gene point mutations". Hum. Mutat. 4 (1): 1–11. doi:10.1002/humu.1380040102. PMID 7951253.
- Tinsley JM, Blake DJ, Zuellig RA, Davies KE (1994). "Increasing complexity of the dystrophin-associated protein complex". Proc. Natl. Acad. Sci. U.S.A. 91 (18): 8307–13. doi:10.1073/pnas.91.18.8307. PMC 44595. PMID 8078878.
- Blake DJ, Weir A, Newey SE, Davies KE (2002). "Function and genetics of dystrophin and dystrophin-related proteins in muscle". Physiol. Rev. 82 (2): 291–329. doi:10.1152/physrev.00028.2001 (inactive 2008-06-22). PMID 11917091.
- Röper K, Gregory SL, Brown NH (2003). "The 'spectraplakins': cytoskeletal giants with characteristics of both spectrin and plakin families". J. Cell. Sci. 115 (Pt 22): 4215–25. doi:10.1242/jcs.00157. PMID 12376554.
- Muntoni F, Torelli S, Ferlini A (2003). "Dystrophin and mutations: one gene, several proteins, multiple phenotypes". Lancet neurology 2 (12): 731–40. doi:10.1016/S1474-4422(03)00585-4. PMID 14636778.
- Haenggi T, Fritschy JM (2006). "Role of dystrophin and utrophin for assembly and function of the dystrophin glycoprotein complex in non-muscle tissue". Cell. Mol. Life Sci. 63 (14): 1614–31. doi:10.1007/s00018-005-5461-0. PMID 16710609.
External links [edit]
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PDB gallery
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1dxx: N-TERMINAL ACTIN-BINDING DOMAIN OF HUMAN DYSTROPHIN
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1eg3: STRUCTURE OF A DYSTROPHIN WW DOMAIN FRAGMENT IN COMPLEX WITH A BETA-DYSTROGLYCAN PEPTIDE
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1eg4: STRUCTURE OF A DYSTROPHIN WW DOMAIN FRAGMENT IN COMPLEX WITH A BETA-DYSTROGLYCAN PEPTIDE
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