| DES | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | DES , CSM1, CSM2, LGMD2R, desmin, LGMD1D, CMD1F, CDCD3, LGMD1E | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 125660 MGI: 94885 HomoloGene: 56469 GeneCards: DES | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Desmin is a protein that in humans is encoded by the DES gene. [5] [6] Desmin is a muscle-specific, type III intermediate filament [7] that integrates the sarcolemma, Z disk, and nuclear membrane in sarcomeres and regulates sarcomere architecture. [8] [9]
Desmin is a 53.5 kD protein composed of 470 amino acids, encoded by the human DES gene located on the long arm of chromosome 2. [10] [11] There are three major domains to the desmin protein: a conserved alpha helix rod, a variable non alpha helix head, and a carboxy-terminal tail. [12] Desmin, as all intermediate filaments, shows no polarity when assembled. [12] The rod domain consists of 308 amino acids with parallel alpha helical coiled coil dimers and three linkers to disrupt it. [12] The rod domain connects to the head domain. The head domain 84 amino acids with many arginine, serine, and aromatic residues is important in filament assembly and dimer-dimer interactions. [12] The tail domain is responsible for the integration of filaments and interaction with proteins and organelles. Desmin is only expressed in vertebrates, however homologous proteins are found in many organisms. [12] Desmin is a subunit of intermediate filaments in cardiac muscle, skeletal muscle and smooth muscle tissue. [13] In cardiac muscle, desmin is present in Z-discs and intercalated discs. Desmin has been shown to interact with desmoplakin [14] and αB-crystallin. [15]
Desmin was first described in 1976, [16] first purified in 1977, [17] the gene was cloned in 1989, [6] and the first knockout mouse was created in 1996. [18] The function of desmin has been deduced through studies in knockout mice. Desmin is one of the earliest protein markers for muscle tissue in embryogenesis as it is detected in the somites. [12] Although it is present early in the development of muscle cells, it is only expressed at low levels, and increases as the cell nears terminal differentiation. A similar protein, vimentin, is present in higher amounts during embryogenesis while desmin is present in higher amounts after differentiation. This suggests that there may be some interaction between the two in determining muscle cell differentiation. However desmin knockout mice develop normally and only experience defects later in life. [13] Since desmin is expressed at a low level during differentiation another protein may be able to compensate for desmin's function early in development but not later on. [19]
In adult desmin-null mice, hearts from 10 week-old animals showed drastic alterations in muscle architecture, including a misalignment of myofibrils and disorganization and swelling of mitochondria; findings that were more severe in cardiac relative to skeletal muscle. Cardiac tissue also exhibited progressive necrosis and calcification of the myocardium. [20] A separate study examined this in more detail in cardiac tissue and found that murine hearts lacking desmin developed hypertrophic cardiomyopathy and chamber dilation combined with systolic dysfunction. [21] In adult muscle, desmin forms a scaffold around the Z-disk of the sarcomere and connects the Z-disk to the subsarcolemmal cytoskeleton. [22] It links the myofibrils laterally by connecting the Z-disks. [12] Through its connection to the sarcomere, desmin connects the contractile apparatus to the cell nucleus, mitochondria, and post-synaptic areas of motor endplates. [12] These connections maintain the structural and mechanical integrity of the cell during contraction while also helping in force transmission and longitudinal load bearing. [22] [23]
In human heart failure, desmin expression is upregulated, which has been hypothesized to be a defense mechanism in an attempt to maintain normal sarcomere alignment amidst disease pathogenesis. [24] There is some evidence that desmin may also connect the sarcomere to the extracellular matrix (ECM) through desmosomes which could be important in signalling between the ECM and the sarcomere which could regulate muscle contraction and movement. [23] Finally, desmin may be important in mitochondria function. When desmin is not functioning properly there is improper mitochondrial distribution, number, morphology and function. [25] [26] Since desmin links the mitochondria to the sarcomere it may transmit information about contractions and energy need and through this regulate the aerobic respiration rate of the muscle cell.
Desmin-related myofibrillar myopathy (DRM or desminopathy) is a subgroup of the myofibrillar myopathy diseases [27] and is the result of a mutation in the gene that codes for desmin which by changing the protein structure [28] prevents it from forming protein filaments, and rather, forms aggregates of desmin and other proteins throughout the cell. [8] [12] Desmin (DES) mutations have been associated with restrictive, [29] dilated, [30] [31] idiopathic, [32] [33] arrhythmogenic [34] [35] [36] [37] and non-compaction cardimyopathy. [38] [39] The N-terminal part of the 1A desmin subdomain is a genetic hot spot region for mutations affecting filament assembly. [40] Some of these DES mutations cause an aggregation of desmin within the cytoplasm. [40] [41] [42] A mutation p.A120D was discovered in a family, where several members had sudden cardiac death. [43] In addition, DES mutations cause frequently cardiac conduction diseases. [44]
Desmin has been evaluated for role in assessing the depth of invasion of urothelial carcinoma in TURBT specimens. [45]
Intermediate filaments (IFs) are cytoskeletal structural components found in the cells of vertebrates, and many invertebrates. Homologues of the IF protein have been noted in an invertebrate, the cephalochordate Branchiostoma.
Arrhythmogenic cardiomyopathy (ACM), arrhythmogenic right ventricular dysplasia (ARVD), or arrhythmogenic right ventricular cardiomyopathy (ARVC), most commonly is an inherited heart disease.
Titin is a protein that in humans is encoded by the TTN gene. Titin is a giant protein, greater than 1 µm in length, that functions as a molecular spring that is responsible for the passive elasticity of muscle. It comprises 244 individually folded protein domains connected by unstructured peptide sequences. These domains unfold when the protein is stretched and refold when the tension is removed.
Hereditary inclusion body myopathies (HIBM) are a group of rare genetic disorders which have different symptoms. Generally, they are neuromuscular disorders characterized by muscle weakness developing in young adults. Hereditary inclusion body myopathies comprise both autosomal recessive and autosomal dominant muscle disorders that have a variable expression (phenotype) in individuals, but all share similar structural features in the muscles.
MYH7 is a gene encoding a myosin heavy chain beta (MHC-β) isoform expressed primarily in the heart, but also in skeletal muscles. This isoform is distinct from the fast isoform of cardiac myosin heavy chain, MYH6, referred to as MHC-α. MHC-β is the major protein comprising the thick filament in cardiac muscle and plays a major role in cardiac muscle contraction.
Restrictive cardiomyopathy (RCM) is a form of cardiomyopathy in which the walls of the heart are rigid. Thus the heart is restricted from stretching and filling with blood properly. It is the least common of the three original subtypes of cardiomyopathy: hypertrophic, dilated, and restrictive.
Desmoplakin is a protein in humans that is encoded by the DSP gene. Desmoplakin is a critical component of desmosome structures in cardiac muscle and epidermal cells, which function to maintain the structural integrity at adjacent cell contacts. In cardiac muscle, desmoplakin is localized to intercalated discs which mechanically couple cardiac cells to function in a coordinated syncytial structure. Mutations in desmoplakin have been shown to play a role in dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, where it may present with acute myocardial injury; striate palmoplantar keratoderma, Carvajal syndrome and paraneoplastic pemphigus.
Cardiac muscle troponin T (cTnT) is a protein that in humans is encoded by the TNNT2 gene. Cardiac TnT is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration.
Ryanodine receptor 2 (RYR2) is one of a class of ryanodine receptors and a protein found primarily in cardiac muscle. In humans, it is encoded by the RYR2 gene. In the process of cardiac calcium-induced calcium release, RYR2 is the major mediator for sarcoplasmic release of stored calcium ions.
Alpha-crystallin B chain is a protein that in humans is encoded by the CRYAB gene. It is part of the small heat shock protein family and functions as molecular chaperone that primarily binds misfolded proteins to prevent protein aggregation, as well as inhibit apoptosis and contribute to intracellular architecture. Post-translational modifications decrease the ability to chaperone. Mutations in CRYAB cause different cardiomyopathies, skeletal myopathies mainly myofibrillar myopathy, and also cataracts. In addition, defects in this gene/protein have been associated with cancer and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.
Alpha-actinin-2 is a protein which in humans is encoded by the ACTN2 gene. This gene encodes an alpha-actinin isoform that is expressed in both skeletal and cardiac muscles and functions to anchor myofibrillar actin thin filaments and titin to Z-discs.
Desmocollin-2 is a protein that in humans is encoded by the DSC2 gene. Desmocollin-2 is a cadherin-type protein that functions to link adjacent cells together in specialized regions known as desmosomes. Desmocollin-2 is widely expressed, and is the only desmocollin isoform expressed in cardiac muscle, where it localizes to intercalated discs. Mutations in DSC2 have been causally linked to arrhythmogenic right ventricular cardiomyopathy.
Myosin heavy chain, α isoform (MHC-α) is a protein that in humans is encoded by the MYH6 gene. This isoform is distinct from the ventricular/slow myosin heavy chain isoform, MYH7, referred to as MHC-β. MHC-α isoform is expressed predominantly in human cardiac atria, exhibiting only minor expression in human cardiac ventricles. It is the major protein comprising the cardiac muscle thick filament, and functions in cardiac muscle contraction. Mutations in MYH6 have been associated with late-onset hypertrophic cardiomyopathy, atrial septal defects and sick sinus syndrome.
Myotilin is a protein that in humans is encoded by the MYOT gene. Myotilin also known as TTID is a muscle protein that is found within the Z-disc of sarcomeres.
Plakophilin-2 is a protein that in humans is encoded by the PKP2 gene. Plakophilin 2 is expressed in skin and cardiac muscle, where it functions to link cadherins to intermediate filaments in the cytoskeleton. In cardiac muscle, plakophilin-2 is found in desmosome structures located within intercalated discs. Mutations in PKP2 have been shown to be causal in arrhythmogenic right ventricular cardiomyopathy.
Ankyrin repeat domain-containing protein 1, or Cardiac ankyrin repeat protein is a protein that in humans is encoded by the ANKRD1 gene also known as CARP. CARP is highly expressed in cardiac and skeletal muscle, and is a transcription factor involved in development and under conditions of stress. CARP has been implicated in several diseases, including dilated cardiomyopathy, hypertrophic cardiomyopathy, and several skeletal muscle myopathies.
LIM domain binding 3 (LDB3), also known as Z-band alternatively spliced PDZ-motif (ZASP), is a protein which in humans is encoded by the LDB3 gene. ZASP belongs to the Enigma subfamily of proteins and stabilizes the sarcomere during contraction, through interactions with actin in cardiac and skeletal muscles. Mutations in the ZASP gene has been associated with several muscular diseases.
Myopalladin is a protein that in humans is encoded by the MYPN gene. Myopalladin is a muscle protein responsible for tethering proteins at the Z-disc and for communicating between the sarcomere and the nucleus in cardiac and skeletal muscle
Desmin-related myofibrillar myopathy, is a subgroup of the myofibrillar myopathy diseases and is the result of a mutation in the gene that codes for desmin which prevents it from forming protein filaments, instead forming aggregates of desmin and other proteins throughout the cell.
