| Structural highlights
Disease
[DMD_HUMAN] Defects in DMD are the cause of Duchenne muscular dystrophy (DMD) [MIM:310200]. DMD is the most common form of muscular dystrophy; a sex-linked recessive disorder. It typically presents in boys aged 3 to 7 year as proximal muscle weakness causing waddling gait, toe-walking, lordosis, frequent falls, and difficulty in standing up and climbing up stairs. The pelvic girdle is affected first, then the shoulder girdle. Progression is steady and most patients are confined to a wheelchair by age of 10 or 12. Flexion contractures and scoliosis ultimately occur. About 50% of patients have a lower IQ than their genetic expectations would suggest. There is no treatment.[1] [2] [3] [4] Defects in DMD are the cause of Becker muscular dystrophy (BMD) [MIM:300376]. BMD resembles DMD in hereditary and clinical features but is later in onset and more benign.[5] Defects in DMD are a cause of cardiomyopathy dilated X-linked type 3B (CMD3B) [MIM:302045]; also known as X-linked dilated cardiomyopathy (XLCM). Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.[6] [7] [8]
Function
[DMD_HUMAN] Anchors the extracellular matrix to the cytoskeleton via F-actin. Ligand for dystroglycan. Component of the dystrophin-associated glycoprotein complex which accumulates at the neuromuscular junction (NMJ) and at a variety of synapses in the peripheral and central nervous systems and has a structural function in stabilizing the sarcolemma. Also implicated in signaling events and synaptic transmission.[9]
Publication Abstract from PubMed
Dystrophin and utrophin link the F-actin cytoskeleton to the cell membrane via an associated glycoprotein complex. This functionality results from their domain organization having an N-terminal actin-binding domain followed by multiple spectrin-repeat domains and then C-terminal protein-binding motifs. Therapeutic strategies to replace defective dystrophin with utrophin in patients with Duchenne muscular dystrophy require full-characterization of both these proteins to assess their degree of structural and functional equivalence. Here the high resolution structures of the first spectrin repeats (N-terminal repeat 1) from both dystrophin and utrophin have been determined by x-ray crystallography. The repeat structures both display a three-helix bundle fold very similar to one another and to homologous domains from spectrin, alpha-actinin and plectin. The utrophin and dystrophin repeat structures reveal the relationship between the structural domain and the canonical spectrin repeat domain sequence motif, showing the compact structural domain of spectrin repeat one to be extended at the C-terminus relative to its previously defined sequence repeat. These structures explain previous in vitro biochemical studies in which extending dystrophin spectrin repeat domain length leads to increased protein stability. Furthermore we show that the first dystrophin and utrophin spectrin repeats have no affinity for F-actin in the absence of other domains.
The crystal structures of dystrophin and utrophin spectrin repeats: implications for domain boundaries.,Muthu M, Richardson KA, Sutherland-Smith AJ PLoS One. 2012;7(7):e40066. Epub 2012 Jul 20. PMID:22911693[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Prior TW, Papp AC, Snyder PJ, Burghes AH, Bartolo C, Sedra MS, Western LM, Mendell JR. A missense mutation in the dystrophin gene in a Duchenne muscular dystrophy patient. Nat Genet. 1993 Aug;4(4):357-60. PMID:8401582 doi:http://dx.doi.org/10.1038/ng0893-357
- ↑ Prior TW, Bartolo C, Papp AC, Snyder PJ, Sedra MS, Burghes AH, Mendell JR. Identification of a missense mutation, single base deletion and a polymorphism in the dystrophin exon 16. Hum Mol Genet. 1994 Jul;3(7):1173-4. PMID:7981690
- ↑ Lenk U, Oexle K, Voit T, Ancker U, Hellner KA, Speer A, Hubner C. A cysteine 3340 substitution in the dystroglycan-binding domain of dystrophin associated with Duchenne muscular dystrophy, mental retardation and absence of the ERG b-wave. Hum Mol Genet. 1996 Jul;5(7):973-5. PMID:8817332
- ↑ Goldberg LR, Hausmanowa-Petrusewicz I, Fidzianska A, Duggan DJ, Steinberg LS, Hoffman EP. A dystrophin missense mutation showing persistence of dystrophin and dystrophin-associated proteins yet a severe phenotype. Ann Neurol. 1998 Dec;44(6):971-6. PMID:9851445 doi:10.1002/ana.410440619
- ↑ Eraslan S, Kayserili H, Apak MY, Kirdar B. Identification of point mutations in Turkish DMD/BMD families using multiplex-single stranded conformation analysis (SSCA). Eur J Hum Genet. 1999 Oct-Nov;7(7):765-70. PMID:10573008 doi:10.1038/sj.ejhg.5200370
- ↑ Ortiz-Lopez R, Li H, Su J, Goytia V, Towbin JA. Evidence for a dystrophin missense mutation as a cause of X-linked dilated cardiomyopathy. Circulation. 1997 May 20;95(10):2434-40. PMID:9170407
- ↑ Feng J, Yan JY, Buzin CH, Sommer SS, Towbin JA. Comprehensive mutation scanning of the dystrophin gene in patients with nonsyndromic X-linked dilated cardiomyopathy. J Am Coll Cardiol. 2002 Sep 18;40(6):1120-4. PMID:12354438
- ↑ Feng J, Yan J, Buzin CH, Towbin JA, Sommer SS. Mutations in the dystrophin gene are associated with sporadic dilated cardiomyopathy. Mol Genet Metab. 2002 Sep-Oct;77(1-2):119-26. PMID:12359139
- ↑ Haenggi T, Fritschy JM. Role of dystrophin and utrophin for assembly and function of the dystrophin glycoprotein complex in non-muscle tissue. Cell Mol Life Sci. 2006 Jul;63(14):1614-31. PMID:16710609 doi:10.1007/s00018-005-5461-0
- ↑ Muthu M, Richardson KA, Sutherland-Smith AJ. The crystal structures of dystrophin and utrophin spectrin repeats: implications for domain boundaries. PLoS One. 2012;7(7):e40066. Epub 2012 Jul 20. PMID:22911693 doi:http://dx.doi.org/10.1371/journal.pone.0040066
|
