Dystrophin
Encyclopedia
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 the longest human gene known on DNA level, covering 2.4 megabases (0.08% of the human genome) at locus
Xp21
. However, it does not encode the longest protein known in humans, which is titin
. The primary transcript
measures about 2,400 kilobases and takes 16 hours to transcribe; the mature mRNA measures 14.0 kilobases. The 79 exons code for a protein of over 3500 amino acid residues.
collectively referred to as muscular dystrophy
. The large cytosolic protein was first identified in 1987 by Louis M. Kunkel,
after the 1986 discovery of the mutated gene that causes Duchenne muscular dystrophy
(DMD)
.
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.
Mutation
s 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.
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.
with SNTB1
, Syntrophin, alpha 1 and DTNA
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
, and a vital part of a protein complex
Protein complex
A multiprotein complex is a group of two or more associated polypeptide chains. If the different polypeptide chains contain different protein domain, the resulting multiprotein complex can have multiple catalytic functions...
that connects the cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
of a muscle fiber to the surrounding extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
through the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
. This complex is variously known as the costamere
Costamere
The costamere is a structural-functional component of striated muscle cells which connects the sarcomere of the muscle to the cell membrane.Costameres are sub-sarcolemmal protein assemblies circumferentially aligned in register with the Z-disk of peripheral myofibrils...
or the dystrophin-associated protein complex
Dystrophin-associated protein complex
The dystrophin-associated protein complex is a multiprotein complex that includes dystrophin and the dystrophin-associated proteins.Many forms of muscular dystrophy are associated with disorders of the dystrophin-associated protein complex....
. Many muscle proteins, such as α-dystrobrevin
Dystrobrevin
Dystrobrevin is a protein that binds to dystrophin in the costamere of skeletal muscle cells. There are at least two isoforms of dystrobrevin in man, α-dystrobrevin and β-dystrobrevin....
, syncoilin
Syncoilin
Syncoilin is a muscle-specific intermediate filament, first isolated as a binding partner to α-dystrobrevin, as determined by a yeast two-hybrid assay.Later, a yeast two-hybrid method was used to demonstrate that syncoilin is a binding partner of desmin...
, synemin
Synemin
Synemin, also called desmuslin, is an intermediate filament and, like other IFs, primarily functions to integrate mechanical stress and maintain structural integrity in eukaryotic cells. While it has been observed in a variety of cell types, it has been best studied in the sarcomere of skeletal...
, sarcoglycan
Sarcoglycan
The sarcoglycans are a family of transmembrane proteins involved in the protein complex responsible for connecting the muscle fibre cytoskeleton to the extracellular matrix, preventing damage to the muscle fibre sarcolemma through shearing forces.The dystrophin glycoprotein complex is a...
, dystroglycan
Dystroglycan
Dystroglycan is a protein that in humans is encoded by the DAG1 gene.Dystroglycan is one of the dystrophin-associated glycoproteins, which is encoded by a 5.5 kb transcript in Homo sapiens by chromosome 3. There are two exons that are separated by a large intron...
, and sarcospan
Sarcospan
Sarcospan, discovered by the research group of Kevin Campbell, is a 25-kDa transmembrane protein located in the dystrophin-associated protein complex of skeletal muscle cells. It contains four transmembrane spanning helices with both N- and C-terminal domains located intracellularly...
, colocalize with dystrophin at the costamere.
The Dystrophin gene is the longest human gene known on DNA level, covering 2.4 megabases (0.08% of the human genome) at locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
Xp21
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
. However, it does not encode the longest protein known in humans, which is titin
Titin
Titin , also known as connectin, is a protein that in humans is encoded by the TTN gene. Titin is a giant protein that functions as a molecular spring which is responsible for the passive elasticity of muscle. It is composed of 244 individually folded protein domains connected by unstructured...
. The primary transcript
Primary transcript
A primary transcript is an RNA molecule that has not yet undergone any modification after its synthesis. For example, a precursor messenger RNA is a primary transcript that becomes a messenger RNA after processing, and a primary microRNA precursor becomes a microRNA after processing....
measures about 2,400 kilobases and takes 16 hours to transcribe; the mature mRNA measures 14.0 kilobases. The 79 exons code for a protein of over 3500 amino acid residues.
Pathology
Dystrophin deficiency has been definitively established as one of the root causes of the general class of myopathiesMyopathy
In medicine, a myopathy is a muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. "Myopathy" simply means muscle disease...
collectively referred to as muscular dystrophy
Muscular dystrophy
Muscular dystrophy is a group of muscle diseases that weaken the musculoskeletal system and hamper locomotion. Muscular dystrophies are characterized by progressive skeletal muscle weakness, defects in muscle proteins, and the death of muscle cells and tissue.In the 1860s, descriptions of boys who...
. The large cytosolic protein was first identified in 1987 by Louis M. Kunkel,
after the 1986 discovery of the mutated gene that causes Duchenne muscular dystrophy
Duchenne muscular dystrophy
Duchenne muscular dystrophy is a recessive X-linked form of muscular dystrophy, which results in muscle degeneration, difficulty walking, breathing, and death. The incidence is 1 in 3,000 boys. Females and males are affected, though females are rarely affected and are more often carriers...
(DMD)
.
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.
Mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s 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
Becker's muscular dystrophy
Becker muscular dystrophy is an X-linked recessive inherited disorder characterized by slowly progressive muscle weakness of the legs and pelvis....
(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.
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.
Interactions
Dystrophin has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with SNTB1
SNTB1
Beta-1-syntrophin is a protein that in humans is encoded by the SNTB1 gene.-Interactions:SNTB1 has been shown to interact with Dystrophin.-Further reading:...
, Syntrophin, alpha 1 and DTNA
DTNA
Dystrobrevin alpha is a protein that in humans is encoded by the DTNA gene.-Interactions:DTNA has been shown to interact with Dystrophin.-Further reading:...
.
External links
- GeneReviews/NCBI/NIH/UW entry on Dystrophinopathies
- LOVD mutation database: DMD, DMD (whole exon changes)