DES (gene)

Desmin is a is_associated_with::protein that in humans is encoded by the DES is_associated_with::gene. Desmin is a muscle-specific, type III is_associated_with::intermediate filament that integrates the sarcolemma, Z disk and nuclear membrane in is_associated_with::sarcomeres and regulates sarcomere architecture (PMID 23860255).

Structure
Desmin is a 53.5 kD protein comprised of 470 amino acids (See human DES sequence features here). There are three major domains to the desmin protein: a conserved is_associated_with::alpha helix rod, a variable non alpha helix head, and a carboxy-terminal tail. Desmin, as all is_associated_with::intermediate filaments, shows no polarity when assembled. The rod domain consists of 308 amino acids with parallel alpha helical coiled coil dimers and three linkers to disrupt it. 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. 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. Desmin is a subunit of intermediate filaments in is_associated_with::cardiac muscle, is_associated_with::skeletal muscle and is_associated_with::smooth muscle tissue. In cardiac muscle, desmin is present in Z-discs and is_associated_with::intercalated discs. Desmin has been shown to interact with is_associated_with::desmoplakin and αB-crystallin (PMID 1628387).

Function
Desmin was first described in 1976, first purified in 1977, the is_associated_with::gene was cloned in 1989, and the first is_associated_with::knockout mouse was created in 1996. 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 is_associated_with::somites. 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, is_associated_with::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. 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.

In adult desmin-null mice, hearts from 10 wk-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 (PMID 8794866). A separate study examined this in more detail in cardiac tissue and found that murine hearts lacking desmin developed hypertophic cardiomyocytes and chamber dilation and systolic dysfunction (PMID 10591032). In adult muscle, desmin forms a scaffold around the Z-disk of the sarcomere and connects the Z-disk to the subsarcolemmal cytoskeleton. It links the is_associated_with::myofibrils laterally by connecting the Z-disks. Through its connection to the sarcomere, desmin connects the contractile apparatus to the is_associated_with::cell nucleus, is_associated_with::mitochondria, and post-synaptic areas of motor endplates. These connections maintain the structural and mechanical integrity of the cell during contraction while also helping in force transmission and longitudinal load bearing. In human heart failure, desmin expression is upregulated, which has been hyopthesized to be a defense mechanism in an attempt to maintain normal sarcomere alignment (PMID 10785506). There is some evidence that desmin may also connect the sarcomere to the is_associated_with::extracellular matrix (ECM) through desmosomes which could be important in signalling between the ECM and the sarcomere which could regulate muscle contraction and movement. Finally, desmin may be important in is_associated_with::mitochondria function. When desmin is not functioning properly there is improper mitochondrial distribution, number, morphology and function. 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.

Clinical Significance
Desmin-related myopathy (DRM or Desminopathy) 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 is_associated_with::protein filaments, instead forming aggregates of desmin and other proteins throughout the cell. Recently, mutations were identified in patients suffered by an arrhythmogenic right ventricular cardiomyopathy (ARVC). Some of these DES mutations like p.N116S or p.E114del cause an aggregation of desmin within the cytoplasma. A mutation p.A120D was discovered in family where several members had a sudden cardiac death. It is also associated with is_associated_with::Sarcoma botryoides (rhabdomyosarcoma variant) - a vaginal malignancy composed of spindle-shaped cells that affects girls < 4 years of age.