Dystrophin-associated protein complex

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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. [1] 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.

Contents

Structure

The dystrophin-associated protein complex includes dystrophin. [2] [3] Dystrophin binds to actin of the cytoskeleton, and also to proteins in the extracellular matrix. [3]

The dystrophin-associated protein complex also contains dystrophin-associated proteins. [2] This includes a four subunit sarcoglycan complex, which is fixed to dystrophin in muscle cells. [4]

In the epithelia of the kidney, dystrophin may be replaced with utrophin. [3]

Aquaporin 4 may be connected to the dystrophin-associated protein complex. [5]

Function

The dystrophin-associated protein complex is important for cell structure and cell signalling. [3] It is one of two protein complexes found in the costamere in striated muscle fibres.

Clinical significance

Many forms of muscular dystrophy are associated with disorders of the dystrophin-associated protein complex. [6]

Muscular dystrophy, the result of mutations in the genes that encode for dystrophin and the associated proteins that binds to it can arise in various forms. [7] The most common form is known as Duchenne muscular dystrophy (DMD). [8] DMD is usually discovered in early childhood and is most often seen occurring in males. There are several associated symptoms that can be observed in such patients including but not limited to a delay in walking and sitting, difficulty in breathing and heart failure. [9] [10] These symptoms are found as a result of the inability to synthesize dystrophin and associate protein complexes that leave muscles weak and unable to repair any damaged sustained. These perpetually weak muscles prohibit normal physical activity. [8]

Therapy

There has been extensive research to discover treatment for DMD. The most common drug treated against DMD is known to be Deflazacort yielding the greatest benefits with the most acceptable side effects. Physical therapy consists of varying exercises that aim to increase muscle strength and durability so to facilitate normal physical activity and is recommended to begin as early as possible after diagnosis. Contracture intervention is recommended for patients in the middle ambulatory stage. However, surgical approach to DMD is declining as less invasive treatment becomes available. While treatment for DMD has been observed to improve muscle function and quality of life, a cure to the debilitating disease remains to be found. [7] [11]

Therapeutic Microdystrophin

Related Research Articles

<span class="mw-page-title-main">Muscular dystrophy</span> Diseases in which skeletal muscle breaks down over time

Muscular dystrophies (MD) are a genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. The disorders differ as to which muscles are primarily affected, the degree of weakness, how fast they worsen, and when symptoms begin. Some types are also associated with problems in other organs.

<span class="mw-page-title-main">Dystrophin</span> Rod-shaped cytoplasmic protein

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

<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.

<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">Actin, cytoplasmic 2</span> Protein-coding gene in the species Homo sapiens

Actin, cytoplasmic 2, or gamma-actin is a protein that in humans is encoded by the ACTG1 gene. Gamma-actin is widely expressed in cellular cytoskeletons of many tissues; in adult striated muscle cells, gamma-actin is localized to Z-discs and costamere structures, which are responsible for force transduction and transmission in muscle cells. Mutations in ACTG1 have been associated with nonsyndromic hearing loss and Baraitser-Winter syndrome, as well as susceptibility of adolescent patients to vincristine toxicity.

<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">Integrin alpha 7</span>

Alpha-7 integrin is a protein that in humans is encoded by the ITGA7 gene. Alpha-7 integrin is critical for modulating cell-matrix interactions. Alpha-7 integrin is highly expressed in cardiac muscle, skeletal muscle and smooth muscle cells, and localizes to Z-disc and costamere structures. Mutations in ITGA7 have been associated with congenital myopathies and noncompaction cardiomyopathy, and altered expression levels of alpha-7 integrin have been identified in various forms of muscular dystrophy.

<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.

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.

<span class="mw-page-title-main">Viltolarsen</span> Pharmaceutical drug

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.

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

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.

Delandistrogene moxeparvovec, sold under the brand name Elevidys, is a recombinant gene therapy used for the treatment of Duchenne muscular dystrophy. It is designed to deliver into the body a gene that leads to production of Elevidys micro-dystrophin that contains selected domains of the dystrophin protein present in normal muscle cells. It is an adeno-associated virus vector-based gene therapy that is given by intravenous infusion.

References

  1. ↑ Charvet B, Ruggiero F, Le Guellec D (April 2012). "The development of the myotendinous junction. A review". Muscles, Ligaments and Tendons Journal. 2 (2): 53–63. PMC   3666507 . PMID   23738275.
  2. 1 2 Dystrophin-Associated+Protein+Complex at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  3. 1 2 3 4 Welling PA (2008-01-01). "Chapter 12 - Scaffolding Proteins in Transport Regulation". In Alpern RJ, Herbert SC (eds.). Seldin and Giebisch's The Kidney (Fourth Edition). San Diego: Academic Press. pp. 325–341. doi:10.1016/b978-012088488-9.50015-2. ISBN   978-0-12-088488-9.
  4. ↑ Kirschner J, Lochmüller H (2011-01-01). "Sarcoglycanopathies". In Griggs RC, Amato AA (eds.). Muscular Dystrophies. Handbook of Clinical Neurology. Vol. 101. Elsevier. pp. 41–46. doi:10.1016/b978-0-08-045031-5.00003-7. ISBN   9780080450315. PMID   21496623.
  5. ↑ Binder DK (2017-01-01). "Chapter 17 - Water Homeostasis Dysfunction in Epilepsy". In Badaut J, Plesnila N (eds.). Brain Edema. San Diego: Academic Press. pp. 315–335. doi:10.1016/b978-0-12-803196-4.00017-5. ISBN   978-0-12-803196-4.
  6. ↑ Ehmsen J, Poon E, Davies K (July 2002). "The dystrophin-associated protein complex". Journal of Cell Science. 115 (Pt 14): 2801–2803. doi:10.1242/jcs.115.14.2801. PMID   12082140.
  7. 1 2 Lovering RM, Porter NC, Bloch RJ (December 2005). "The muscular dystrophies: from genes to therapies". Physical Therapy. 85 (12): 1372–1388. doi:10.1093/ptj/85.12.1372. PMC   4496952 . PMID   16305275.
  8. 1 2 Passamano L, Taglia A, Palladino A, Viggiano E, D'Ambrosio P, Scutifero M, et al. (October 2012). "Improvement of survival in Duchenne Muscular Dystrophy: retrospective analysis of 835 patients". Acta Myologica. 31 (2): 121–125. PMC   3476854 . PMID   23097603.
  9. ↑ Gao QQ, McNally EM (July 2015). "The Dystrophin Complex: Structure, Function, and Implications for Therapy". Comprehensive Physiology. 5 (3): 1223–1239. doi:10.1002/cphy.c140048. ISBN   9780470650714. PMC   4767260 . PMID   26140716.
  10. ↑ Ryder S, Leadley RM, Armstrong N, Westwood M, de Kock S, Butt T, et al. (April 2017). "The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: an evidence review". Orphanet Journal of Rare Diseases. 12 (1): 79. doi: 10.1186/s13023-017-0631-3 . PMC   5405509 . PMID   28446219.
  11. ↑ Wagner KR, Lechtzin N, Judge DP (February 2007). "Current treatment of adult Duchenne muscular dystrophy". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. The Muscular Dystrophies: Molecular Basis and Therapeutic Strategies. 1772 (2): 229–237. doi: 10.1016/j.bbadis.2006.06.009 . PMID   16887341.
  12. ↑ "Dec 16,2021 | Chugai In-Licenses Gene Therapy Delandistrogene Moxeparvovec (SRP-9001) for Duchenne Muscular Dystrophy | News".
  13. ↑ Mendell, Jerry R.; Sahenk, Zarife; Lehman, Kelly; Nease, Carrie; Lowes, Linda P.; Miller, Natalie F.; Iammarino, Megan A.; Alfano, Lindsay N.; Nicholl, Amanda; Al-Zaidy, Samiah; Lewis, Sarah; Church, Kathleen; Shell, Richard; Cripe, Linda H.; Potter, Rachael A.; Griffin, Danielle A.; Pozsgai, Eric; Dugar, Ashish; Hogan, Mark; Rodino-Klapac, Louise R. (1 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 . Retrieved 9 November 2022.
  14. ↑ "Delandistrogene moxeparvovec - Roche/Sarepta Therapeutics - AdisInsight". adisinsight.springer.com.
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