Desmin is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''DES''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. Desmin is a muscle-specific, type III intermediate filament that integrates the sarcolemma, Z disk, and nuclear membrane in

sarcomere A sarcomere (Greek σάρξ ''sarx'' "flesh", μέρος ''meros'' "part") is the smallest functional unit of striated muscle tissue. It is the repeating unit between two Z-lines. Skeletal striated muscle, Skeletal muscles are composed of tubular ...

s and regulates sarcomere architecture.

Structure

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. There are three major domains to the desmin protein: a conserved

alpha helix An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix). The alpha helix is the most common structural arrangement in the Protein secondary structure, secondary structure of proteins. It is al ...

rod, a variable non alpha helix head, and a carboxy-terminal tail. Desmin, as all 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 cardiac muscle,

skeletal muscle Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...

and smooth muscle tissue. In cardiac muscle, desmin is present in Z-discs and intercalated discs. Desmin has been shown to interact with desmoplakin and αB-crystallin.

Function

Desmin was first described in 1976, first purified in 1977, the

was cloned in 1989, and the first 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 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, 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 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. 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. 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

myofibril A myofibril (also known as a muscle fibril or sarcostyle) is a basic rod-like organelle of a muscle cell. Skeletal muscles are composed of long, tubular cells known as Skeletal muscle#Skeletal muscle cells, muscle fibers, and these cells contain ...

s laterally by connecting the Z-disks. Through its connection to the sarcomere, desmin connects the contractile apparatus to the

cell nucleus The cell nucleus (; : nuclei) is a membrane-bound organelle found in eukaryote, eukaryotic cell (biology), cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, have #Anucleated_cells, ...

, 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 hypothesized to be a defense mechanism in an attempt to maintain normal sarcomere alignment amidst disease pathogenesis. 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. Finally, desmin may be important in 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 myofibrillar 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 by changing the protein structure prevents it from forming protein filaments, and rather, forms aggregates of desmin and other proteins throughout the cell. Desmin (''DES'') mutations have been associated with restrictive, dilated, idiopathic, arrhythmogenic and non-compaction cardimyopathy. Even within the same family the observed cardiac phenotype could be broad and diverse. The N-terminal part of the 1A desmin subdomain is a genetic hot spot region for mutations affecting filament assembly. Some of these ''DES'' mutations cause an aggregation of desmin within the

cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...

. Some mutations like p.A120D or p.R127P were discovered in families, where several members had sudden cardiac death. In addition, ''DES'' mutations cause frequently cardiac conduction diseases. Desmin has been evaluated for role in assessing the depth of invasion of urothelial carcinoma in TURBT specimens.

References

External links

GeneReviews/NIH/NCBI/UW entry on Myofibrillar Myopathy
* * LOVD mutation database
DES
{{Tumor markers Tumor markers