Dystrophin

Last updated
DMD
PBB Protein DMD image.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases DMD , BMD, CMD3B, DXS142, DXS164, DXS206, DXS230, DXS239, DXS268, DXS269, DXS270, DXS272, MRX85, dystrophin
External IDs OMIM: 300377 MGI: 94909 HomoloGene: 20856 GeneCards: DMD
Orthologs
SpeciesHumanMouse
Entrez

1756

13405

Ensembl

ENSG00000198947

ENSMUSG00000045103

UniProt

P11532

P11531

RefSeq (mRNA)
RefSeq (protein)
Location (UCSC) Chr X: 31.1 – 33.34 Mb Chr X: 81.99 – 84.25 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
In humans, the DMD gene is located on the short (p) arm of the X chromosome between positions 21.2 and 21.1 DMD gene location.png
In humans, the DMD gene is located on the short (p) arm of the X chromosome between positions 21.2 and 21.1

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 (DAPC). Many muscle proteins, such as α-dystrobrevin, syncoilin, synemin, sarcoglycan, dystroglycan, and sarcospan, colocalize with dystrophin at the costamere. It has a molecular weight of 427 kDa [5] [6]

Dystrophin is coded for by the DMD gene – the largest known human gene, covering 2.4 megabases (0.08% of the human genome) at locus Xp21. The primary transcript in muscle measures about 2,100 kilobases and takes 16 hours to transcribe; [7] the mature mRNA measures 14.0 kilobases. [8] The 79-exon muscle transcript [9] codes for a protein of 3685 amino acid residues. [10]

Spontaneous or inherited mutations in the dystrophin gene can cause different forms of muscular dystrophy, a disease characterized by progressive muscular wasting. The most common of these disorders caused by genetic defects in dystrophin is Duchenne muscular dystrophy.

Function

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 other support proteins that reside on the inside surface of each muscle fiber's plasma membrane (sarcolemma). These support proteins 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 the absence of dystrophin reduces muscle stiffness, increases sarcolemmal deformability, and compromises the mechanical stability of costameres and their connections to nearby myofibrils. This has been shown in recent studies where biomechanical properties of the sarcolemma and its links through costameres to the contractile apparatus were measured, [11] 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. The dystrophin associated protein complex also helps scaffold various signalling and channel proteins, implicating the DAPC in regulation of signalling processes. [12]

Pathology

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 deletions of one or several exons of the dystrophin DMD gene cause Duchenne and Becker muscular dystrophies. [13] The large cytosolic protein was first identified in 1987 by Louis M. Kunkel, [14] after concurrent works by Kunkel and Robert G. Worton to characterize the mutated gene that causes Duchenne muscular dystrophy (DMD). [15] [16] At least nine disease-causing mutations in this gene have been discovered. [17]

Normal skeletal muscle tissue contains only small amounts of dystrophin (about 0.002% of total muscle protein), [14] 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. Variants (mutations) in the DMD gene that lead to the production of too little or a defective, internally shortened but 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 variant will result in a DMD or BMD phenotype, is the reading frame rule. [18]

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. [19]

Research

A number of models are used to facilitate research on DMD gene defects. These include the mdx mouse, GRMD (golden retriever muscular dystrophy) dog, and HFMD (hypertrophic feline muscular dystrophy) cat. [20]

The mdx mouse contains a nonsense mutation in exon 23, leading to a shortened dystrophin protein. [21] Levels of dystrophin in this model is not zero: a variety of mutation alleles exist with measurable levels certain of dystrophin isoforms. [20] Muscle degeneration pathology is most easily visible in the diaphragm. [22] Generally, clinically relevant pathology is observed with older mdx mice. [22]

The GRMD dog is one of several existing dystrophin-deficient dogs identified where substantial characterization has been performed. [23] Clinically relevant pathology can be observed at 8 weeks after birth, with continued gradual deterioration of muscle function. [24] Muscle histology is most analogous to clinical presentation of DMD in humans with necrosis, fibrosis and regeneration. [25]

The HFMD cat has a deletion in the promoter region of the DMD gene. [26] Muscle histology shows necrosis but no fibrosis. [27] Extensive hypertrophy has been observed which is thought to be responsible for shorter lifespans. [28] [27] Due to the hypertrophy, this model may have limited uses for DMD studies.  

Therapeutic microdystrophin

Interactions

Dystrophin has been shown to interact with:

Neanderthal admixture

A variant of the DMD gene, which is on the X chromosome, named B006, appears to be an introgression from a Neanderthal-modern human mating. [37]

Related Research Articles

<span class="mw-page-title-main">Duchenne muscular dystrophy</span> Type of muscular dystrophy

Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy predominantly affecting boys. The onset of muscle weakness typically begins around age four, with rapid progression. Initially, muscle loss occurs in the thighs and pelvis, extending to the arms, which can lead to difficulties in standing up. By the age of 12, most individuals with Duchenne muscular dystrophy are unable to walk. Affected muscles may appear larger due to an increase in fat content, and scoliosis is common. Some individuals may experience intellectual disability, and females carrying a single copy of the mutated gene may show mild symptoms.

<span class="mw-page-title-main">Becker muscular dystrophy</span> Genetic muscle disorder

Becker muscular dystrophy (BMD) is an X-linked recessive inherited disorder characterized by slowly progressing muscle weakness of the legs and pelvis. It is a type of dystrophinopathy. The cause is mutations and deletions in any of the 79 exons encoding the large dystrophin protein, essential for maintaining the muscle fiber's cell membrane integrity. Becker muscular dystrophy is related to Duchenne muscular dystrophy in that both result from a mutation in the dystrophin gene, however the hallmark of Becker is milder in-frame deletions. and hence has a milder course, with patients maintaining ambulation till 50–60 years if detected early.

The dystrophin-associated protein complex, also known as the dystrophin-associated glycoprotein complex is a multiprotein complex that includes dystrophin and the dystrophin-associated proteins. It is one of the two protein complexes that make up the costamere in striated muscle cells. The other complex is the integrin-vinculin-talin complex.

<span class="mw-page-title-main">Utrophin</span> Mammalian protein found in Homo sapiens

Utrophin is a protein that in humans is encoded by the UTRN gene. The name is a short form for ubiquitous dystrophin.

<span class="mw-page-title-main">Costamere</span> Component of striated muscle cells

The costamere is a structural-functional component of striated muscle cells which connects the sarcomere of the muscle to the cell membrane.

<span class="mw-page-title-main">Sarcospan</span>

Sarcospan is a protein that in humans is encoded by the SSPN gene.

Dystrobrevin is a protein that binds to dystrophin in the costamere of skeletal muscle cells. In humans, there are at least two isoforms of dystrobrevin, dystrobrevin alpha and dystrobrevin beta.

<span class="mw-page-title-main">Syntrophin, alpha 1</span> Protein-coding gene in the species Homo sapiens

Alpha-1-syntrophin is a protein that in humans is encoded by the SNTA1 gene. Alpha-1 syntrophin is a signal transducing adaptor protein and serves as a scaffold for various signaling molecules. Alpha-1 syntrophin contains a PDZ domain, two Pleckstrin homology domain and a 'syntrophin unique' domain.

<span class="mw-page-title-main">SGCB</span> Protein-coding gene in the species Homo sapiens

Beta-sarcoglycan is a protein that in humans is encoded by the SGCB gene.

<span class="mw-page-title-main">SNTB2</span> Protein-coding gene in the species Homo sapiens

Beta-2-syntrophin is a protein that in humans is encoded by the SNTB2 gene.

<span class="mw-page-title-main">SGCA</span> Protein-coding gene in the species Homo sapiens

Alpha-sarcoglycan is a protein that in humans is encoded by the SGCA gene.

<span class="mw-page-title-main">SGCG</span> Protein-coding gene in the species Homo sapiens

Gamma-sarcoglycan is a protein that in humans is encoded by the SGCG gene. The α to δ-sarcoglycans are expressed predominantly (β) or exclusively in striated muscle. A mutation in any of the sarcoglycan genes may lead to a secondary deficiency of the other sarcoglycan proteins, presumably due to destabilisation of the sarcoglycan complex. The disease-causing mutations in the α to δ genes cause disruptions within the dystrophin-associated protein (DAP) complex in the muscle cell membrane. The transmembrane components of the DAP complex link the cytoskeleton to the extracellular matrix in adult muscle fibres, and are essential for the preservation of the integrity of the muscle cell membrane.

<span class="mw-page-title-main">SNTB1</span> Protein-coding gene in the species Homo sapiens

Beta-1-syntrophin is a protein that in humans is encoded by the SNTB1 gene.

<span class="mw-page-title-main">Dystrobrevin alpha</span> Protein found in humans

Dystrobrevin alpha is a protein that in humans is encoded by the DTNA gene.

In molecular biology, exon skipping is a form of RNA splicing used to cause cells to “skip” over faulty or misaligned sections (exons) of genetic code, leading to a truncated but still functional protein despite the genetic mutation.

<span class="mw-page-title-main">Eteplirsen</span> Medication

Eteplirsen is a medication to treat, but not cure, some types of Duchenne muscular dystrophy (DMD), caused by a specific mutation. Eteplirsen only targets specific mutations and can be used to treat about 14% of DMD cases. Eteplirsen is a form of antisense therapy.

The mdx mouse is a popular model for studying Duchenne muscular dystrophy (DMD). The mdx mouse has a point mutation in its DMD gene, changing the amino acid coding for a glutamine to STOP codon. This causes the muscle cells to produce a small, nonfunctional dystrophin protein. As a result, the mouse has a mild form of DMD where there is increased muscle damage and weakness.

<span class="mw-page-title-main">Ezutromid</span> Chemical compound

Ezutromid is an orally administered small molecule utrophin modulator involved in a Phase 2 clinical trial produced by Summit Therapeutics for the treatment of Duchenne muscular dystrophy (DMD). DMD is a fatal x-linked recessive disease affecting approximately 1 in 5000 males and is a designated orphan disease by the FDA and European Medicines Agency. Approximately 1/3 of the children obtain DMD as a result of spontaneous mutation in the dystrophin gene and have no family history of the disease. Dystrophin is a vital component of mature muscle function, and therefore DMD patients have multifarious forms of defunct or deficient dystrophin proteins that all manifest symptomatically as muscle necrosis and eventually organ failure. Ezutromid is theorized to maintain utrophin, a protein functionally and structurally similar to dystrophin that precedes and is replaced by dystrophin during development. Utrophin and dystrophin are reciprocally expressed, and are found in different locations in a mature muscle cell. However, in dystrophin-deficient patients, utrophin was found to be upregulated and is theorized to replace dystrophin in order to maintain muscle fibers. Ezutromid is projected to have the potential to treat all patients suffering with DMD as it maintains the production of utrophin to counteract the lack of dystrophin to retard muscle degeneration. Both the FDA and European Medicines Agency has given ezutromid an orphan drug designation. The FDA Office of Orphan Products and Development offers an Orphan Drug Designation program (ODD) that allows drugs aimed to treat diseases that affect less than 200,000 people in the U.S. monetary incentives such as a period of market exclusivity, tax incentives, and expedited approval processes.

Viltolarsen, sold under the brand name Viltepso, is a medication used for the treatment of Duchenne muscular dystrophy (DMD). Viltolarsen is a Morpholino antisense oligonucleotide.

Casimersen, sold under the brand name Amondys 45, is an antisense oligonucleotide medication used for the treatment of Duchenne muscular dystrophy (DMD) in people who have a confirmed mutation of the dystrophin gene that is amenable to exon 45 skipping. It is an antisense oligonucleotide of phosphorodiamidate morpholino oligomer (PMO). Duchenne muscular dystrophy is a rare disease that primarily affects boys. It is caused by low levels of a muscle protein called dystrophin. The lack of dystrophin causes progressive muscle weakness and premature death.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000198947 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000045103 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Lederfein D, Levy Z, Augier N, Mornet D, Morris G, Fuchs O, et al. (June 1992). "A 71-kilodalton protein is a major product of the Duchenne muscular dystrophy gene in brain and other nonmuscle tissues". Proceedings of the National Academy of Sciences of the United States of America. 89 (12): 5346–50. Bibcode:1992PNAS...89.5346L. doi: 10.1073/pnas.89.12.5346 . PMC   49288 . PMID   1319059.
  6. ↑ "DMD - Dystrophin - Homo sapiens (Human) - DMD gene & protein". www.uniprot.org. Retrieved 1 December 2021.
  7. ↑ Tennyson CN, Klamut HJ, Worton RG (February 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. S2CID   7858296.
  8. ↑ NCBI Sequence Viewer v2.0
  9. ↑ Strachan T and Read AP, 1999. Human molecular genetics, BIOS Scientific, New York, USA
  10. ↑ "dystrophin isoform Dp427c [Homo sapiens] - Protein - NCBI". www.ncbi.nlm.nih.gov.
  11. ↑ García-Pelagio KP, Bloch RJ, Ortega A, González-Serratos H (March 2011). "Biomechanics of the sarcolemma and costameres in single skeletal muscle fibers from normal and dystrophin-null mice". Journal of Muscle Research and Cell Motility. 31 (5–6): 323–36. doi:10.1007/s10974-011-9238-9. PMC   4326082 . PMID   21312057.
  12. ↑ Constantin B (February 2014). "Dystrophin complex functions as a scaffold for signalling proteins". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1838 (2): 635–42. doi: 10.1016/j.bbamem.2013.08.023 . PMID   24021238.
  13. ↑ Le Rumeur E (July 2015). "Dystrophin and the two related genetic diseases, Duchenne and Becker muscular dystrophies". Bosnian Journal of Basic Medical Sciences. 15 (3): 14–20. doi:10.17305/bjbms.2015.636. PMC   4594321 . PMID   26295289.
  14. 1 2 Hoffman EP, Brown RH, Kunkel LM (December 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. S2CID   33548364.
  15. ↑ Monaco AP, Neve RL, Colletti-Feener C, Bertelson CJ, Kurnit DM, Kunkel LM (1986). "Isolation of candidate cDNAs for portions of the Duchenne muscular dystrophy gene". Nature. 323 (6089): 646–50. Bibcode:1986Natur.323..646M. doi:10.1038/323646a0. PMID   3773991. S2CID   4317085.
  16. ↑ Burghes AH, Logan C, Hu X, Belfall B, Worton RG, Ray PN (1987). "A cDNA clone from the Duchenne/Becker muscular dystrophy gene". Nature. 328 (6129): 434–7. Bibcode:1987Natur.328..434B. doi:10.1038/328434a0. PMID   3614347. S2CID   4364629.
  17. ↑ Šimčíková D, Heneberg P (December 2019). "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports. 9 (1): 18577. Bibcode:2019NatSR...918577S. doi:10.1038/s41598-019-54976-4. PMC   6901466 . PMID   31819097.
  18. ↑ Aartsma-Rus A, Van Deutekom JC, Fokkema IF, Van Ommen GJ, Den Dunnen JT (August 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. S2CID   42303520.
  19. ↑ Sharma P, Tran T, Stelmack GL, McNeill K, Gosens R, Mutawe MM, Unruh H, Gerthoffer WT, Halayko AJ (January 2008). "Expression of the dystrophin-glycoprotein complex is a marker for human airway smooth muscle phenotype maturation". American Journal of Physiology. Lung Cellular and Molecular Physiology. 294 (1): L57–68. doi:10.1152/ajplung.00378.2007. PMID   17993586.
  20. 1 2 Blake DJ, Weir A, Newey SE, Davies KE (April 2002). "Function and genetics of dystrophin and dystrophin-related proteins in muscle". Physiological Reviews. 82 (2): 291–329. doi:10.1152/physrev.00028.2001. PMID   11917091.
  21. ↑ Sicinski P, Geng Y, Ryder-Cook AS, Barnard EA, Darlison MG, Barnard PJ (June 1989). "The molecular basis of muscular dystrophy in the mdx mouse: a point mutation". Science. 244 (4912): 1578–80. Bibcode:1989Sci...244.1578S. doi:10.1126/science.2662404. PMID   2662404.
  22. 1 2 Stedman HH, Sweeney HL, Shrager JB, Maguire HC, Panettieri RA, Petrof B, et al. (August 1991). "The mdx mouse diaphragm reproduces the degenerative changes of Duchenne muscular dystrophy". Nature. 352 (6335): 536–9. Bibcode:1991Natur.352..536S. doi:10.1038/352536a0. PMID   1865908. S2CID   4302451.
  23. ↑ "Duchenne Muscular Dystrophy and Becker Muscular Dystrophy: Diagnostic Principles". Duchenne Muscular Dystrophy. CRC Press. 2006-02-27. pp. 105–118. doi:10.3109/9780849374456-7. ISBN   978-0-429-16351-7.
  24. ↑ Valentine BA, Cooper BJ, de Lahunta A, O'Quinn R, Blue JT (December 1988). "Canine X-linked muscular dystrophy. An animal model of Duchenne muscular dystrophy: clinical studies". Journal of the Neurological Sciences. 88 (1–3): 69–81. doi:10.1016/0022-510X(88)90206-7. PMID   3225630. S2CID   6902011.
  25. ↑ Valentine BA, Cooper BJ, Cummings JF, de Lahunta A (June 1990). "Canine X-linked muscular dystrophy: morphologic lesions". Journal of the Neurological Sciences. 97 (1): 1–23. doi: 10.1016/0022-510x(90)90095-5 . PMID   2370557. S2CID   31250421.
  26. ↑ Winand NJ, Edwards M, Pradhan D, Berian CA, Cooper BJ (September 1994). "Deletion of the dystrophin muscle promoter in feline muscular dystrophy". Neuromuscular Disorders. 4 (5–6): 433–45. doi:10.1016/0960-8966(94)90082-5. PMID   7881288. S2CID   38556669.
  27. 1 2 Carpenter JL, Hoffman EP, Romanul FC, Kunkel LM, Rosales RK, Ma NS, et al. (November 1989). "Feline muscular dystrophy with dystrophin deficiency". The American Journal of Pathology. 135 (5): 909–19. PMC   1880103 . PMID   2683799.
  28. ↑ Gaschen FP, Hoffman EP, Gorospe JR, Uhl EW, Senior DF, Cardinet GH, Pearce LK (July 1992). "Dystrophin deficiency causes lethal muscle hypertrophy in cats". Journal of the Neurological Sciences. 110 (1–2): 149–59. doi:10.1016/0022-510x(92)90022-d. PMID   1506854. S2CID   21156994.
  29. ↑ "Chugai In-Licenses Gene Therapy Delandistrogene Moxeparvovec (SRP-9001) for Duchenne Muscular Dystrophy | News". 16 December 2021.
  30. ↑ Mendell JR, Sahenk Z, Lehman K, Nease C, Lowes LP, Miller NF, et al. (September 2020). "Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy: A Nonrandomized Controlled Trial". JAMA Neurology. 77 (9): 1122–1131. doi:10.1001/jamaneurol.2020.1484. PMC   7296461 . PMID   32539076.
  31. ↑ "Delandistrogene moxeparvovec - Roche/Sarepta Therapeutics". AdisInsight. Springer Nature Switzerland AG.
  32. ↑ Sadoulet-Puccio HM, Rajala M, Kunkel LM (November 1997). "Dystrobrevin and dystrophin: an interaction through coiled-coil motifs". Proceedings of the National Academy of Sciences of the United States of America. 94 (23): 12413–8. Bibcode:1997PNAS...9412413S. doi: 10.1073/pnas.94.23.12413 . PMC   24974 . PMID   9356463.
  33. ↑ Ahn AH, Freener CA, Gussoni E, Yoshida M, Ozawa E, Kunkel LM (February 1996). "The three human syntrophin genes are expressed in diverse tissues, have distinct chromosomal locations, and each bind to dystrophin and its relatives". The Journal of Biological Chemistry. 271 (5): 2724–30. doi: 10.1074/jbc.271.5.2724 . PMID   8576247.
  34. ↑ Yang B, Jung D, Rafael JA, Chamberlain JS, Campbell KP (March 1995). "Identification of alpha-syntrophin binding to syntrophin triplet, dystrophin, and utrophin". The Journal of Biological Chemistry. 270 (10): 4975–8. doi: 10.1074/jbc.270.10.4975 . PMID   7890602.
  35. ↑ Gee SH, Madhavan R, Levinson SR, Caldwell JH, Sealock R, Froehner SC (January 1998). "Interaction of muscle and brain sodium channels with multiple members of the syntrophin family of dystrophin-associated proteins". The Journal of Neuroscience. 18 (1): 128–37. doi:10.1523/jneurosci.18-01-00128.1998. PMC   6793384 . PMID   9412493.
  36. ↑ Ahn AH, Kunkel LM (February 1995). "Syntrophin binds to an alternatively spliced exon of dystrophin". The Journal of Cell Biology. 128 (3): 363–71. doi:10.1083/jcb.128.3.363. PMC   2120343 . PMID   7844150.
  37. ↑ Khan R (January 25, 2011). "Neandertal admixture, revisiting results after shaken priors". Discover Magazine. Archived from the original on January 27, 2013. Retrieved March 27, 2013.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.