ReviewType III collagen (COL3A1): Gene and protein structure, tissue distribution, and associated diseases
Introduction
Type III collagen, first identified and described in 1971 (Miller et al., 1971), is an important structural protein, classified as one of the major fibrillar collagens (Prockop and Kivirikko, 1995). It constitutes about 5–20% of the entire collagen content in the human body (Miller, 1988). Its essential role in the structural integrity of arteries, uterus and bowel has been clearly demonstrated by studies on patients who harbour mutations in the COL3A1 gene (Byers, 1993 [updated 2019]; Byers et al., 2017; Malfait et al., 2017; Malfait, 2018). The cardinal clinical manifestations of these patients include spontaneous, life-threatening arterial, uterine and bowel ruptures (Byers, 1993 [updated 2019]; Byers et al., 2017; Malfait et al., 2017; Malfait, 2018). Other clinical phenotypes associated with COL3A1 missense and nonsense mutations include severe brain anomalies suggesting that COL3A1 is essential for the normal brain development.
This review summarizes the information on the human (COL3A1) and mouse (Col3a1) gene, transcripts and protein, and discusses the disease phenotypes associated with type III collagen mutations and altered protein levels, as well as mouse models. Table 1 lists the characteristics of the human (COL3A1) and mouse (Col3a1) gene, transcripts and protein, and provides links to available resources.
Section snippets
Chromosomal location and intron-exon organization of COL3A1 and Col3a1
In the human genome, COL3A1 encoding the α1 chain of type III collagen is located on the long arm of chromosome 2 [2q32.2; genomic coordinates (GRCh38): Chr2:188,974,320-189,012,746]. The gene is approximately 38 kb long and has 51 exons, which are numbered 1–52 to match the numbering of exons in the genes for other fibrillar collagens (Fig. 1) (Valkkila et al., 2001). The sizes of the exons vary from 45 nt (exons 13, 15, 18 and 30) to 1105 (exon 52) (Valkkila et al., 2001). All exons except
Biosynthesis of type III preprocollagen
Type III collagen is synthesized by cells as a pre-procollagen, which undergoes multiple co- and posttranslational modifications (Fig. 3). The signal peptide is cleaved off producing a procollagen molecule (Fig. 2). Three identical type III procollagen chains come together in the C-terminal ends, and the structure is stabilized by the formation of disulphide bonds. Each individual chain folds into left-handed helix and the three chains are then wrapped together into a right-handed superhelix,
Tissue distribution
Type III collagen is found as a major structural component in hollow organs such as large blood vessels, uterus and bowel, tissues that must withstand stretching. It is also found in many other tissues in association with type I collagen. During the development of an embryo, type I and III collagen seem to be expressed in a coordinated manner based on a comprehensive survey of different developmental stages (E7.5 to E17.5) of the mouse embryo using in situ RNA hybridization (Niederreither et
Function
Type III collagen provides tensile strength and integrity for many organs, but it has also been reported to have several other functions. In tissues the diameter of type III collagen fibrils is smaller than that of type I collagen (Birk and Silver, 1984). Type I and III collagens sometimes appear in the same fibrils and in that situation type III collagen regulates the fibril diameter (Fleischmajer et al., 1990; Cameron et al., 2002). Type III collagen is also found in the adult human cartilage
Regulation of COL3A1 expression
Several lines of evidence suggest that COL3A1 expression is regulated also on the posttranscriptional level. The biological pathways involved in the regulation of COL3A1 expression include the transforming growth factor (TGF) β1, Wnt/β-catenin, and the p38 mitogen-activated protein kinase (MAPK) pathway. These studies have important implication for the developing new treatment strategies for fibrosis in different organs (see Section 7.3).
Several studies have demonstrated that hypoxia alters
Diseases associated with COL3A1 mutations and variants, or altered levels of COL3A1 protein
Mutations in the COL3A1 gene cause the vascular type of Ehlers-Danlos syndrome (vEDS; OMIM 130050), which is a rare, life-threatening genetic disease. A few patients with arterial aneurysms without clear signs of EDS have also been found to have COL3A1 mutations (Kontusaari et al., 1990b). Other disease phenotypes associated with COL3A1 include a brain abnormality characterized by frontoparietal polymicrogyria, and many fibrotic diseases, in which increased amounts of type III collagen are
Col3a1 mutant mice
Currently there are four different Col3a1 mouse models (Liu et al., 1997; Smith et al., 2011; Long et al., 2015; D'Hondt et al., 2018). As can be seen in Table 3, which summarizes the characteristics of these models, none of them are ideal models of the human vEDS. They have, however, become useful models for studying the function of type III collagen in various tissues and organs.
Conclusions
Nearly 50 years of research into the structure and function of type III collagen has demonstrated that it is an essential structural component of blood vessels, uterus and bowel. Without type III collagen mice die in utero and with mutated forms of it humans develop serious clinical manifestations leading to a premature death due to a spontaneous rupture of an artery, bowel or uterus. Furthermore, some COL3A1 mutations lead to a severe brain abnormality and developmental delay. Increased
Conflict of interest statement
The authors declare that they have no commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
This review and the corresponding Gene Wiki article are written as part of the Gene Wiki Review series–a series resulting from a collaboration between the journal GENE and the Gene Wiki Initiative. The Gene Wiki Initiative is supported by National Institutes of Health (GM089820). Additional support for Gene Wiki Reviews is provided by Elsevier, the publisher of GENE.
HK is supported by the Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa. GT is supported by the
References (168)
- et al.
A novel assay for extracellular matrix remodeling associated with liver fibrosis: an enzyme-linked immunosorbent assay (ELISA) for a MMP-9 proteolytically revealed neo-epitope of type III collagen
Clin. Biochem.
(2010) - et al.
Collagen fibrillogenesis in vitro: comparison of types I, II, and III
Arch. Biochem. Biophys.
(1984) - et al.
Structure formation in the C terminus of type III collagen guides disulfide cross-linking
J. Mol. Biol.
(2004) - et al.
Crystal structure of human type III collagen Gly991-Gly1032 cystine knot-containing peptide shows both 7/2 and 10/3 triple helical symmetries
J. Biol. Chem.
(2008) - et al.
Structure of type I and type III heterotypic collagen fibrils: an X-ray diffraction study
J. Struct. Biol.
(2002) - et al.
Natural variation in four human collagen genes across an ethnically diverse population
Genomics
(2008) - et al.
Collagen-platelet interaction: separate receptor sites for types I and III collagen
Thromb. Res.
(1993) - et al.
Isolation of cDNA and genomic clones encoding human pro-alpha 1 (III) collagen. Partial characterization of the 3′ end region of the gene
J. Biol. Chem.
(1985) - et al.
Type III collagen affects dermal and vascular collagen fibrillogenesis and tissue integrity in a mutant Col3a1 transgenic mouse model
Matrix Biol.
(2018) Arterial complications of vascular Ehlers-Danlos syndrome
J. Vasc. Surg.
(2016)
Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics
Mol. Cell. Proteomics
Platelet-collagen interaction: adhesion of human blood platelets to purified (CB4) peptide from type III collagen
Thromb. Res.
Usefulness of circulating biomarkers for the prediction of left ventricular remodeling after myocardial infarction
Am. J. Cardiol.
Dermal collagen fibrils are hybrids of type I and type III collagen molecules
J. Struct. Biol.
AJKD atlas of renal pathology: type III collagen glomerulopathy
Am. J. Kidney Dis.
Amino acid sequence to the N-terminal non-triple helical cross link region of type III collagen
FEBS Lett.
Collagen subtypes and matrix metalloproteinase in idiopathic restrictive cardiomyopathy
Int. J. Cardiol.
Genes and abdominal aortic aneurysm
Ann. Vasc. Surg.
Increased serum concentration of type IV collagen peptide and type III collagen peptide in hyperthyroidism
Clin. Chim. Acta
Identification of a major GpVI-binding locus in human type III collagen
Blood
The good and the bad collagens of fibrosis - their role in signaling and organ function
Adv. Drug Deliv. Rev.
Biochemical characterization of genetic mutations of GPR56 in patients with bilateral frontoparietal polymicrogyria (BFPP)
Biochem. Biophys. Res. Commun.
A novel binding site in collagen type III for integrins alpha1beta1 and alpha2beta1
J. Biol. Chem.
Type III collagen aminopropeptide levels in serum of patients with progressive systemic scleroderma
J. Invest. Dermatol.
Identical G+1 to A mutations in three different introns of the type III procollagen gene (COL3A1) produce different patterns of RNA splicing in three variants of Ehlers-Danlos syndrome. IV. An explanation for exon skipping some mutations and not others
J. Biol. Chem.
Characterization of human type III collagen expressed in a baculovirus system. Production of a protein with a stable triple helix requires coexpression with the two types of recombinant prolyl 4-hydroxylase subunit
J. Biol. Chem.
The Tsk2/+ mouse fibrotic phenotype is due to a gain-of-function mutation in the PIIINP segment of the Col3a1 gene
J. Invest. Dermatol.
Vascular aspects of the Ehlers-Danlos syndromes
Matrix Biol.
Dilated cardiomyopathy is associated with an increase in the type I/type III collagen ratio: a quantitative assessment
J. Am. Coll. Cardiol.
A 15 base-pair AT-rich variable number tandem repeat in the type III procollagen gene (COL3A1) as an informative marker for 2q31-2q32.3
Matrix
Collagen types and anticollagen-antibodies in Dupuytren's disease
Hand
Identification of three genetically distinct collagens by cyanogen bromide cleavage of insoluble human skin and cartilage collagen
Biochem. Biophys. Res. Commun.
A new platelet receptor specific to type III collagen. Type III collagen-binding protein
J. Biol. Chem.
Genetic variability in the extracellular matrix as a determinant of cardiovascular risk: association of type III collagen COL3A1 polymorphisms with coronary artery disease
Blood
Pregnancy-related deaths and complications in women with vascular Ehlers-Danlos syndrome
Genet. Med.
Coordinate patterns of expression of type I and III collagens during mouse development
Matrix Biol.
European multicentre study validates enhanced liver fibrosis test as biomarker of fibrosis in systemic sclerosis
Rheumatology (Oxford)
Independent expression of fibril-forming collagens I, II, and III in chondrocytes of human osteoarthritic cartilage
J. Clin. Invest.
Structure of cDNA clones coding for the entire prepro alpha 1 (III) chain of human type III procollagen. Differences in protein structure from type I procollagen and conservation of codon preferences
Biochem. J.
Multiple defects in type III collagen synthesis are associated with the pathogenesis of abdominal aortic aneurysms
Ann. N. Y. Acad. Sci.
A glycine (415)-to-serine substitution results in impaired secretion and decreased thermal stability of type III procollagen in a patient with Ehlers-Danlos syndrome type IV
Hum. Mutat.
Folding mechanism of the triple helix in type-III collagen and type-III pN-collagen. Role of disulfide bridges and peptide bond isomerization
Eur. J. Biochem.
Comparative investigation on the influence of human and bovine collagen types I, II and III on the aggregation of human platelets
Klin. Wochenschr.
Inhibition of collagen-induced platelet aggregation by antibodies to distinct types of collagens
Biochem. J.
Aortic stiffness correlates with an increased extracellular matrix turnover in patients with dilated cardiomyopathy
Am. Heart J.
Structural basis of fibrillar collagen trimerization and related genetic disorders
Nat. Struct. Mol. Biol.
Complete amino acid sequence of the N-terminal extension of calf skin type III procollagen
Biochem. J.
[updated 2019]. Vascular Ehlers-Danlos syndrome
Altered secretion of type III procollagen in a form of type IV Ehlers-Danlos syndrome. Biochemical studies in cultured fibroblasts
Lab. Investig.
Diagnosis, natural history, and management in vascular Ehlers-Danlos syndrome
Am. J. Med. Genet. C Semin. Med. Genet.
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