On Duchenne Muscular Dystrophy - Research Paper Example

Duchenne muscular dystrophy gene s Introduction Duchenne muscular dystrophy is a recessive X-linked for of the muscular dystrophy that usually affects about in every 3,600 boys that results in muscle degeneration and eventual death (van Deutekom & van Ommen, 2003). The disease is caused by a mutation in the dystrophin gene (Woodhead, 2007). It is a mutation that alters the gene expression by affecting the promoter. This is the largest gene which is located on the human X chromosome. It codes for the protein dystrophin which is a very crucial structural component within the muscle tissue that offers structural stability to the dystroglycan complex of the cell membrane. Even though both sexes carry the mutation, the females rarely exhibit the signs of the disease. The symptoms may be visible in early infancy and appear in male children before the age of 6. Laboratory testing can establish the children who carry the active mutation at birth (Dalkilic & Kunkel, 2003). At first, progressive proximal muscle weakness of the pelvis and legs that are associated with a loss in muscle mass. Eventually, this weakness spreads to the neck, arms and other areas. The early signs consist of enlargement of the deltoid and calf muscle, difficulties in standing without help, and low endurance. As the condition progresses, there is wasting of the muscle tissue. By the age of 12, most patients are usually dependent on the wheel chair. Symptoms that occur in the later stage include abnormal development of the bone that leads to deformities of the skeleton. As a result of muscle deteroriation, there is occurrence of the loss of movement, in the long run it leads to paralysis. The average life expectancy for the DMD patients is about 25 years. Diagnosis of the disease The diagnoses of the disease include DNA testing, muscle biopsy, and prenatal tests. First, the muscle-specific isoform of the dysrtophin gene is made up of 79 exons. DNA tests and analysis determine the particular type of mutation of the exon (s) that is affected. Secondly, muscle biopsy entails extraction of a small sample of muscle tissue. A dye is then applied to reveal the presence of the dystrophin. Lastly, prenatal tests establish if the unborn child has the most common mutations. The X-linked recessive gene carries the DMD. Males have one X chromosome implying that one copy of the mutated gene will lead to DMD. The mutation is transferred by the mother since fathers cannot pass the X-linked traits to their sons. When the mother is a carrier, one of her X chromosomes has a DMD mutation. In that respect, there is 50 % chance that the female child will actually inherit that mutation as one of her X chromosomes and be a carrier. Moreover, there is also a 50 % chance that a male child will have DMD if he inherits that mutation as his one X chromosome (Goemans et al., 2011). Treatment of the disease Currently, there is no cure for DMD. Generally, the treatments are directed towards controlling the onset of symptoms and maximise life quality. They comprise of the following: first, corticosteroids, for instance, deflazacort and prednisolone have been found to enhance the energy and strength as well deferring severity of some symptoms (Kinali, Manzur, & Muntoni, 2008); Secondly, the randomised control trials have indicated that beta2-agonists usually increase muscle strength. However, they usually do not modify the progression of the disease. The follow-up time for majority of RCTs on beta2-agonists is about 12 months and, therefore, results cannot be extrapolated beyond that time frame (van Deutekom & van Ommen, 2003); thirdly, there in encouragement of the mild, non-jarring physical activity such as swimming. Inactivity like bed rest has been found to worsen the muscle disease; the next treatment for DMS is physical therapy. It assists in maintaining muscle flexibility, strength and function. This will enable the children to attain their maximum physical potential. In that respect, occupational and physical therapists address the patient problems by making use of meaningful occupations and grading the activity by using various methods of assessments and resources like bracing, splinting, manual muscle testing, postural intervention, and equipment prescription (Stone et al, 2007); fifth, orthopedic appliances, for example wheelchairs and braces may improve mobility and the ability for self-care; lastly, suitable respiratory support as the disease progresses is very vital such as the modern respirators that deliver an adjustable amount of air to the DMD patient with respiratory problems (Dunckley et al. 1998). Methods mRNA for dystrophin gene was found to be the mRNA Dp427- GenBank NM 004007 (from the lymphocyte promoter) The DNA was done using the DNA Sequence Quality -Phred. It provided base calling, high quality sequence region evaluation, chromatogram display, and presentation of up to 5 sequences at the same time. I used SEQERR to detect the frame shift error that occurred in the coding regions. With regard to protein sequence, the protein sequence of dystrophin gene was searched using SWISSPORT. To help in the discrimination between disease-causing and non-disease causing amino acid substitutions, protein-derived sequence alignments were prepared. These alignments include dystrophins from other species, dystrophin-related proteins such as utrophin and DRP2 as well as dystrobrevin. Alignments with proteins and of the individual repeats from the central rod domain and showed homology with specific dystrophin domains such as actin and spectrin. With regard to the homologs of the DMD gene, the gene is conserved in mouse, chimpanzee, dog, chicken, mosquito and fruit fly. The protein homology was found using the BLAST method. For instance, dystrophin Dp427m isoform [Homo sapiens]. The tools/website that was used to website you used to find protein domains was via the Pro Scan Query. Dystrophin is a rod-shaped protein that measures about 150 nm. It consists of 3684 amino acids which have a calculated molecular weight of 427 kDa. Dystophin gene has four domains: a cysteine-rich domain, N-terminal actin-binding domain, a unique C-terminal domain, and twenty four spectrin-like triple helix repeats. DMD is caused by the mutation at locus Xp21 of the dystophin gene. The recessive mutations occur at the gene for muscle protein dysophin. As cited by Templeton (2012), the mutation was detected using the direct sequencing and automated DHPLC screening. Results The Duchenne muscular dystrophy gene is located on the short arm of the X chromosome (Xp21.2-p21.1).Dystrophin is responsible for connecting the cystosekeleton of every muscle fiber to the underlying extracellular matrix via a protein complex that contains numerous subunits. The absence of dystrophin allows excessive calcium to penetrate the cell membrane. These changes in the signalling pathways result to water entering the mitochondria to burst. As a result, the bones become weak. DMD is caused by mutations that occur in the gene that encodes the 427-kDa cytoskeletal protein of the dystrophin. Dystrophin is a protein that is located between the plasma membrane and the outermost layer of the myofilaments in the muscle fiber. It is a cohesive protein that connects the filaments to another support protein residing on each muscle fiber’s plasma membranes’ inside surface (Dunckley et al, 2003). Figure showing DMD gene (Dunckley et al, 2003). The human DMD is the largest known X chromosome. The genomic DNA of puffer fish corresponds to the complete dystrophin gene. Besides, nearly all the positions and phases are conserved between the DMD and its mammalian counterparts. The gene of the puffer fish shows 56% identity and 71 % similarity to the human dystrophin...... an analysis of the intron sequences of the murine and human and genes found out that they are extremely conserved in size and that the same faction of the total intron length is represented by repetitive element. This means that the homologs are very close. Dystrophin shows similarity in its domain structure, gene structure and amino acids sequence (50% identity to another cytoskeletal protein, utrophin and Dystrophin-glycoprotein complex. At the protein level, evidence shows that utrophin-like proteins are highly conserved throughout metazoans, showing a fundamental role in animal biology In the muscle, dystrophin is a part of a large complex connecting the actin cytoskeleton and the plasma membrane (sarcolemma) as well as the extracellular matrix. In the complex, the other proteins are collectively known as dystrophin-associated proteins. During cycles of contraction and relaxation, the absence of dystrophin or some components of the dystrophin-associated proteins’s complex leads to progressive damage to muscle fibers. The recent studies found that the dystrophin-DAPs complex can also be involved in muscle signaling and other tissues (Wagner, Lechtzin, & Judge, 2007). To maintain muscle integrity, the dystrophin protein offers a structural link between the extracellular matrix and the muscle cytoskeleton. Mutation occurs at the locus Xp21 of the dystrophin gene causes DMD in humans. It is a mutation that alters the gene expression by affecting the promoter. This means that the mutated is normal to the original sequence. Data on mutations imply that there are clear differences in relation to the distribution, frequency and parental origin of the various types of mutations such as deletion, point mutation and duplication. An estimated 60% of mutations that cause DMD are deletions of huge gene segments including one or more exon (Koenig at al., 2003). The mutation occurs at the functionally important site. Discussion The mutation in the dystrophin gene leads to DMD (Hoffma, Brown, & Kunkel, 1997). Duchenne muscular dystrophy can be observed clinically from the moment a person takes his first steps. By the time the person is 9-12 years old; his ability to walk is usually completely disintegrated. DMD patients are usually paralyzed from the neck down by the age of 21 (Goyenvalle et al. 2004). Muscle wasting commences in the legs and pelvis progress sing to the muscles of the shoulders and neck. It is then followed by loss of respiratory muscles and arm muscles. Calf muscle enlargement is quite obvious. In relation to the diagnosis, the diagnoses of the disease include DNA testing, muscle biopsy, and prenatal tests. Occupational and physical therapists address the patient problems by making use of meaningful occupations and grading the activity by using various methods of assessments and resources like bracing, splinting, manual muscle testing, range of motion, postural intervention, and equipment prescription. Splints prevent deformity and improve function. It also assists in supporting and keeping limbs stretched that prevents or delays the onset of contractures. Manual muscle testing is utilised in evaluating muscular strength. On the other hand, the range of motion measure movement around a joint. Next proper seating and positioning is very crucial in preventing spinal curvatures. The adaptive equipments and devices include walkers, transfer boards, hand held shower heads, bath benches, wheel chairs, braces and pressure-relieving mattresses (Richardson & Frank, 2009). Reference List Dalkilic, I., & Kunkel, L., M. (2003). Muscular dystrophies: genes to pathogenesis. Curr Opin Genet Dev 13: 231–238 Dunckley, M; Manoharan, M; Villiet, P; Eperon, IC; Dickson, G (1998). "Modification of splicing in the dystrophin gene in cultured Mdx muscle cells by antisense oligoribonucleotides". Human Molecular Genetics 7 (7): 1083–90. Goemans, N. M.; Tulinius, M.; Van Den Akker, J. T.; Burm, B. E.; Ekhart, P. F.; Heuvelmans, N.; Holling, T.; Janson, A. A.; Platenburg, G. J.; Sipkens, J. A.; Sitsen, J. M. A.; Aartsma-Rus, A.; Van Ommen, G. J. B.; Buyse, G.; Darin, N.; Verschuuren, J. J.; Campion, G. V.; De Kimpe, S. J.; Van Deutekom, J. C. (2011). "Systemic Administration of PRO051 in Duchennes Muscular Dystrophy". New England Journal of Medicine 364 (16): 1513–1522. Goyenvalle A, Vulin A, Fougerousse F, et al. (2004). "Rescue of dystrophic muscle through U7 snRNA-mediated exon skipping". Science 306 (5702): 1796–9. Hoffman EP, Brown RH, Kunkel L. 1997. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell, 51:919-928 Kinali, M., Manzur, A., & Muntoni, F. 2008. "Recent developments in the management of Duchenne muscular dystrophy". Paediatrics and Child Health 18 (1): 22–26. Koenig M, Hoffman EP, Bertelson CJ, Monaco AP, Feener C, Kunkel L. 2003. Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell, 50:509-517 Koenig M, Monaco AP, & Kunkel LM. 1998. The complete sequence of dystrophin predicts a rod-shaped cytoskeletal protein. Cell 22;53(2):219–228. Richardson, M; Frank, A (2009). "Electric powered wheelchairs for those with muscular dystrophy: Problems of posture, pain and deformity". Disability and Rehabilitation: Assistive Technology 4 (3): 181–188. Sironi M., Cagliani R., Pozzoli U., Bardoni A., Comi G.P., Giorda R., Bresolin N.(2002) The dystrophin gene is alternatively spliced throughout its coding sequence. FEBS Lett. 517:163–166 Stone, K; Tester, C; Howarth, A; Johnston, R; Traynor, N; McAndrew (2007). Occupational therapy and Duchenne muscular dystrophy. New Jersey: John Wiley & Sons Ltd. Templeton, N. S. (2012). Gene and Cell Therapy: Therapeutic Mechanisms and Strategies. New York: CRC Press. van Deutekom J., C, & van Ommen GJ (2003). Advances in Duchenne muscular dystrophy gene therapy. Nat Rev Genet 4: 774–783. Wagner, K; Lechtzin, N; Judge, D (2007). "Current treatment of adult Duchenne muscular dystrophy". Biochimica et Biophysica Acta 1772 (2):229-237. Woodhead, Avril (2007). Molecular Biology of Aging. New York: Plenum Press. pp. 327–328. 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