Collagen VI (ColVI) is a type of
collagen
Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...
primarily associated with the
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
of
skeletal muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
.
ColVI maintains regularity in muscle function and stabilizes the cell membrane.
It is synthesized by a complex, multistep pathway that leads to the formation of a unique network of linked microfilaments located in the
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
(ECM). ColVI plays a vital role in numerous cell types, including
chondrocyte
Chondrocytes (, from Greek χόνδρος, ''chondros'' = cartilage + κύτος, ''kytos'' = cell) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteog ...
s,
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s,
myocyte
A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a muscl ...
s,
fibroblast
A fibroblast is a type of cell (biology), biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and plays a critical role in wound ...
s, and
cardiomyocytes
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that ...
.
ColVI molecules are made up of three alpha chains: α1(VI), α2(VI), and α3(VI). It is encoded by 6 genes:
COL6A1
Collagen alpha-1(VI) chain is a protein that in humans is encoded by the ''COL6A1'' gene.
Function
The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix ...
,
COL6A2,
COL6A3, COL6A4,
COL6A5, and COL6A6.
[Collagen VI at a glance
Matilde Cescon, Francesca Gattazzo, Peiwen Chen, Paolo Bonaldo
J Cell Sci 2015 128: 3525-3531; doi: 10.1242/jcs.169748] The chain lengths of α1(VI) and α2(VI) are about 1,000 amino acids. The chain length of α3(VI) is roughly a third larger than those of α1(VI) and α2(VI), and it consists of several spliced variants within the range of 2,500 to 3,100 amino acids.
The first two alpha chains subunits of ColVI have a molecular weight of 140-150 KDa and the third polypeptide chain is larger with a molecular weight of 250-300kDa.
ColVI is also found in the skin, lungs, blood vessels, cornea and intervertebral disc. It also forms part of the peripheral nerves, brain,
myocardium
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that ...
and adipose tissue.
Function
Collagen VI plays many different roles in the cell depending on which tissue in which it is expressed. ColVI maintains a mechanical function in the cell, which is typical of most types of Collagen, by providing stability and structural support in the
ECM. ColVI allows muscle cells to connect with the
ECM by interacting with perlecan in the basal lamina. ColVI also functions as a cytoprotective agent:
# ColVI plays an important role in cancer by acting as a chemotherapy resistance modulator.
#ColVI inhibits oxidative damage and apoptosis.
#ColVI regulates cell differentiation and autophagic machinery.
# With the assistance of other collagens, proteoglycans, matrilineal, fibronectins, and glycoproteins, ColVI anchors the basement membrane of the skin to the extracellular matrix.
Expression in Various Tissues
Muscle Tissue
ColVI is one of the primary components of muscle
extra cellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structu ...
. It has been shown to play an integral role in building the
basement membrane
The basement membrane is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between Epithelium, epithelial tissues including mesot ...
of
myofiber
A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a musc ...
endoymsium. The crucial role of ColVI in skeletal muscle can be seen by the fact that mutations in the genes responsible for encoding ColVI cause diseases affecting the function of skeletal muscle, including Ullrich congenital muscular dystrophy and Bethlem myopathy. Absence of ColVI in muscle cells results in muscle cell dysfunction due to defects in the regulation of the
autophagic
Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...
pathway. ColVI is also a key component of muscle cell generation, and has been shown to have the ability to regenerate itself.
[Urciuolo, A., Quarta, M., Morbidoni, V., Gattazzo, F., Molon, S., Grumati, P., Montemurro, F., Tedesco, F. S., Blaauw, B., Cossu, G. et al. (2013). Collagen VI regulates satellite cell self-renewal and muscle regeneration. Nat. Commun. 4, 1964. doi:10.1038/ncomms2964]
Nervous Tissue
ColVI is expressed in both the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
and
peripheral nervous system
The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain ...
.
Central Nervous System
The presence of ColVI in the brain was originally discovered in
meningeal
In anatomy, the meninges (, ''singular:'' meninx ( or ), ) are the three membranes that envelop the brain and spinal cord. In mammals, the meninges are the dura mater, the arachnoid mater, and the pia mater. Cerebrospinal fluid is located in th ...
cells. ColVI has also been linked to the development of
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
.
[Cheng, J. S., Dubal, D. B., Kim, D. H., Legleiter, J., Cheng, I. H., Yu, G.-Q., Tesseur, I., Wyss-Coray, T., Bonaldo, P. and Mucke, L. (2009). Collagen VI protects neurons against Aβ toxicity. Nat. Neurosci. 12, 119-121. doi:10.1038/nn.2240] When treated with AB-
peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
A ...
s, mice without the COL6A1 gene were observed to have an increase in
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
compared to wild type mice, suggesting that ColVI plays a neuroprotective role against AB-peptide toxicity.
Further, ColVI has been suggested to play an anti-apoptotic role in other parts of the nervous system, as seen in studies analyzing the effects of
UV-induced apoptosis.
Peripheral Nervous System
ColVI is expressed by
Schwann cell
Schwann cells or neurolemmocytes (named after German physiologist Theodor Schwann) are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensh ...
s in the
peripheral nervous system
The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain ...
. It is present in the
connective tissue
Connective tissue is one of the four primary types of animal tissue, along with epithelial tissue, muscle tissue, and nervous tissue. It develops from the mesenchyme derived from the mesoderm the middle embryonic germ layer. Connective tiss ...
of the
endoneurium
The endoneurium (also called endoneurial channel, endoneurial sheath, endoneurial tube, or Henle's sheath) is a layer of delicate connective tissue around the myelin sheath of each myelinated nerve fiber in the peripheral nervous system. Its comp ...
,
perineurium
The perineurium is a protective sheath that surrounds a nerve fascicle. This bundles together axons targeting the same anatomical location. The perineurium is composed from fibroblasts.
In the peripheral nervous system, the myelin sheath of each ...
, and
epineurium
The epineurium is the outermost layer of dense irregular connective tissue surrounding a peripheral nerve. It usually surrounds multiple nerve fascicles as well as blood vessels which supply the nerve. Smaller branches of these blood vessels p ...
.
[Chen, P., Cescon, M., Megighian, A. and Bonaldo, P. (2014a). Collagen VI regulates peripheral nerve myelination and function. FASEB J. 28, 1145-1156. doi:10.1096/fj.13-239533] ColVI has been shown to be expressed by immature Schwann cells when they begin to differentiate into myelinating cells, suggesting that ColVI plays an integral role in regulating Schwann cell differentiation. ColVI also plays a key role in the peripheral nervous system myelination and maintains proper functioning of the
sciatic nerve
The sciatic nerve, also called the ischiadic nerve, is a large nerve in humans and other vertebrate animals which is the largest branch of the sacral plexus and runs alongside the hip joint and down the lower limb. It is the longest and widest si ...
.
Adipose Tissue
ColVI also plays a key role in the extracellular matrix of
white adipose tissue
White adipose tissue or white fat is one of the two types of adipose tissue found in mammals. The other kind is brown adipose tissue. White adipose tissue is composed of monolocular adipocytes.
In humans, the healthy amount of white adipose ti ...
. Lack of ColVI in the extracellular matrix of white adipose tissue leads to molecular characteristic notably seen in
obese
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...
individuals. Endotrophin, a
peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
A ...
generated by ColVI in white adipose tissue, has been shown to promote the growth of
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
cells. Further, therapeutic transplantation of adipose-derived
stem cell
In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...
s has been shown to secrete and assemble ColVI
microfibril A microfibril is a very fine fibril, or fiber-like strand, consisting of glycoproteins and cellulose. It is usually, but not always, used as a general term in describing the structure of protein fiber, e.g. hair and sperm tail. Its most frequently o ...
s.
Role of Collagen VI in Knee Function
Studies have revealed that the mutation or deletion of genes encoding for
collagen
Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...
VI can result in numerous
musculoskeletal disorder
Musculoskeletal disorders (MSDs) are injuries or pain in the human musculoskeletal system, including the joints, ligaments, muscles, nerves, tendons, and structures that support limbs, neck and back. MSDs can arise from a sudden exertion (e.g., li ...
s, e.g. hip
osteoarthritis
Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of disability in the w ...
, tissue fibrosis, tissue ossification, and muscular dystrophies. The deletion of the COL6A1 gene in mice was used to determine the function of collagen VI in the
bone
A bone is a Stiffness, rigid Organ (biology), organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red blood cell, red and white blood cells, store minerals, provid ...
and
cartilage
Cartilage is a resilient and smooth type of connective tissue. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck an ...
of knee joints. The absence of collagen VI impacted the structure and shape of the knee joint, but did not critically affect physicality of the cartilage.
Associated Disorders
Defects in Collagen VI are associated with
Ullrich congenital muscular dystrophy
Ullrich congenital muscular dystrophy is a form of congenital muscular dystrophy. It is associated with variants of type VI collagen, it is commonly associated with muscle weakness and respiratory problems, though cardiac issues are not associated ...
and
Bethlem myopathy.
Phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
s associated with Ullrich congenital muscular dystrophy are typically more severe than phenotypes associated with Bethlem myopathy. Rare cases of collagen VI related myopathies with phenotypes of intermediate severity have been reported.
[Marakhonov, A. V., Tabakov, V. Y., Zernov, N. V., Dadali, E. L., Sharkova, I. V., & Skoblov, M. Y. (2018). Two novel COL6A3 mutations disrupt extracellular matrix formation and lead to myopathy from Ullrich congenital muscular dystrophy and Bethlem myopathy spectrum. ''Gene,'' ''672'', 165-171. doi:10.1016/j.gene.2018.06.026] Whole genome sequencing
Whole genome sequencing (WGS), also known as full genome sequencing, complete genome sequencing, or entire genome sequencing, is the process of determining the entirety, or nearly the entirety, of the DNA sequence of an organism's genome at a s ...
reveals that these intermediate phenotypes most likely result from a premature translation
termination codon
In molecular biology (specifically protein biosynthesis), a stop codon (or termination codon) is a codon (nucleotide triplet within messenger RNA) that signals the termination of the translation process of the current protein. Most codons in mess ...
caused by a variation in the
COL6A3 gene, as well as an amino acid substitution in the
N2-terminal domain caused by
nonsense-mediated decay
Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that exists in all eukaryotes. Its main function is to reduce errors in gene expression by eliminating mRNA transcripts that contain premature stop codons. Translation of these aberrant ...
.
Biopsied muscle tissue samples in individuals with Ullrich congenital muscular dystrophy and Bethlem myopathy showed a significant decrease in protein levels of Beclin1 and VNIP3, demonstrating that mutated ColVI causes defect in the regulation of autophagic pathways.
There are few treatments that have been developed to treat Ullrich congenital muscular dystrophy or Bethlem myopathy at the genetic level; the primary methods of treating these disorders are surgery and physical therapy.
Ullrich congenital muscular dystrophy
Ullrich congenital muscular dystrophy (UCMD) is a condition that primarily affects the function of skeletal muscles. UCMD has been associated with mutations in the
COL6A1
Collagen alpha-1(VI) chain is a protein that in humans is encoded by the ''COL6A1'' gene.
Function
The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix ...
,
COL6A2, and
COL6A3 gene.
[Collagen VI involvement in Ullrich syndrome
E. Mercuri, Y. Yuva, S. C. Brown, M. Brockington, M. Kinali, H.Jungbluth, L. Feng, C. A. Sewry, F. Muntoni
Neurology May 2002, 58 (9) 1354-1359; DOI:10.1212/WNL.58.9.1354] The most common pattern of inheritance for UCMD is
autosomal recessive
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
, although an
autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
pattern of inheritance is observed in rare cases.
Symptoms
* Severe weakness and
atrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply t ...
of skeletal muscles
*
Contracture
In pathology, a contracture is a permanent shortening of a muscle or joint. It is usually in response to prolonged hypertonic spasticity in a concentrated muscle area, such as is seen in the tightest muscles of people with conditions like spasti ...
s in knees and elbows
* Hyper-mobility in wrists and ankles
* Rigid spine
Treatments
The most common treatment for individuals affected by Ullrich congenital muscular dystrophy is physical therapy, with an emphasis on the mobilization and stabilization of affected joints. Surgical interventions may be needed to correct
contracture
In pathology, a contracture is a permanent shortening of a muscle or joint. It is usually in response to prolonged hypertonic spasticity in a concentrated muscle area, such as is seen in the tightest muscles of people with conditions like spasti ...
s or
scoliosis
Scoliosis is a condition in which a person's spine has a sideways curve. The curve is usually "S"- or "C"-shaped over three dimensions. In some, the degree of curve is stable, while in others, it increases over time. Mild scoliosis does not t ...
.
Bethlem myopathy
Bethlem myopathy is the mildest form of Collagen VI related myopathies. Related symptoms include
ligamentous laxity
Ligamentous laxity, or ligament laxity, is a cause of chronic body pain characterized by loose ligaments. When this condition affects joints in the entire body, it is called ''generalized joint hypermobility'', which occurs in about ten percent o ...
,
hypotonia
Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases a ...
in infancy, and difficulty breathing due to weakness in respiratory muscles. Bethlem myopathy affects approximately 1 in 200,000 people.
[Okada, M., Kawahara, G., Noguchi, S., Sugie, K., Murayama, K., Nonaka, I., . . . Nishino, I. (2007). Primary collagen VI deficiency is the second most common congenital muscular dystrophy in Japan. ''Neurology,'' ''69''(10), 1035-1042. doi:10.1212/01.wnl.0000271387.10404.4e]
References
Further reading
*
{{Scleroprotein disease
Collagens