Dystrophin

Dystrophin
PDB rendering based on 1dxx.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1DXX, 1EG3, 1EG4, 3UUN
Identifiers
Symbols	DMD; BMD; CMD3B; DXS142; DXS164; DXS206; DXS230; DXS239; DXS268; DXS269; DXS270; DXS272
External IDs	OMIM: 300377 MGI: 94909 HomoloGene: 20856 GeneCards: DMD Gene
Gene Ontology Molecular function • dystroglycan binding • actin binding • structural constituent of cytoskeleton • calcium ion binding • protein binding • zinc ion binding • structural constituent of muscle • myosin binding • vinculin binding • nitric-oxide synthase binding Cellular component • nucleus • cytosol • cytoskeleton • plasma membrane • cell surface • actin cytoskeleton • dystrophin-associated glycoprotein complex • Z disc • cell-substrate junction • filopodium • sarcolemma • costamere • protein complex • neuron projection terminus • membrane raft • postsynaptic membrane Biological process • regulation of heart rate • regulation of transcription, DNA-dependent • muscle organ development • establishment of blood-nerve barrier • flagellum assembly • regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum • regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion • positive regulation of neuron projection development • regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion • regulation of skeletal muscle contraction • myotube cell development • olfactory nerve structural organization • muscle filament sliding • negative regulation of peptidyl-serine phosphorylation • cellular protein localization • peptide biosynthetic process • cellular protein complex assembly • neurotransmitter receptor metabolic process • positive regulation of neuron differentiation • muscle cell homeostasis • muscle fiber development • nucleus localization • cardiac muscle contraction • regulation of ryanodine-sensitive calcium-release channel activity • establishment of glial blood-brain barrier • regulation of cardiac muscle cell action potential • regulation of cellular response to growth factor stimulus • regulation of voltage-gated calcium channel activity • regulation of peptidyl-cysteine S-nitrosylation • positive regulation of sodium ion transmembrane transporter activity Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1756	13405
Ensembl	ENSG00000198947	ENSMUSG00000045103
UniProt	P11532	P11531
RefSeq (mRNA)	NM_000109	NM_007868
RefSeq (protein)	NP_000100	NP_031894
Location (UCSC)	Chr X: 31.14 – 33.36 Mb	Chr X: 82.95 – 85.21 Mb
PubMed search
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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 2.5 megabases (0.08% 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

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, reduces muscle stiffness, increases sarcolemmal deformability, and compromises the mechanical stability of costameres and their connections to nearby myofibrils; as shown in recent studies where biomechanical properties of the sarcolemma and its links through costameres to the contractile apparatus were measured,^[5] 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

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,^[6] after the 1986 discovery of the mutated gene that causes Duchenne muscular dystrophy (DMD) .^[7]

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.^[8]

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.^[9]

Interactions

Dystrophin has been shown to interact with:

• DTNA,^[10]
• SNTA1,^[11][12][13] and
• SNTB1.^[14]

Neanderthal admixture

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.^[15]

References

Other sources

• 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

External links

• GeneReviews/NCBI/NIH/UW entry on Dystrophinopathies
• Dystrophin at the US National Library of Medicine Medical Subject Headings (MeSH)
• LOVD mutation database: DMD, DMD (whole exon changes)

v t e PDB gallery 1dxx: N-TERMINAL ACTIN-BINDING DOMAIN OF HUMAN DYSTROPHIN  1eg3: STRUCTURE OF A DYSTROPHIN WW DOMAIN FRAGMENT IN COMPLEX WITH A BETA-DYSTROGLYCAN PEPTIDE  1eg4: STRUCTURE OF A DYSTROPHIN WW DOMAIN FRAGMENT IN COMPLEX WITH A BETA-DYSTROGLYCAN PEPTIDE