Elsevier

Gene

Volume 707, 30 July 2019, Pages 151-171
Gene

Review
Type III collagen (COL3A1): Gene and protein structure, tissue distribution, and associated diseases

https://doi.org/10.1016/j.gene.2019.05.003Get rights and content

Highlights

  • Type III collagen is a structural component of blood vessels, uterus and bowel.

  • Type III collagen regulates type I collagen fibril formation.

  • Mutations in COL3A1 cause vascular Ehlers-Danlos syndrome.

  • Mutations in COL3A1 can also cause frontoparietal polymicrogyria.

  • Accumulation of type III collagen is found in fibrotic diseases.

Abstract

Collagen alpha-1(III) chain, also known as the alpha 1 chain of type III collagen, is a protein that in humans is encoded by the COL3A1 gene. Three alpha 1 chains are required to form the type III collagen molecule which has a long triple-helical domain. Type III collagen, an extracellular matrix protein, is synthesized by cells as a pre-procollagen. It is found as a major structural component in hollow organs such as large blood vessels, uterus and bowel. Other functions of type III collagen include interaction with platelets in the blood clotting cascade and it is also an important signaling molecule in wound healing. Mutations in the COL3A1 gene cause the vascular type of Ehlers-Danlos syndrome (vEDS; OMIM 130050). It is the most serious form of EDS, since patients often die suddenly due to a rupture of large arteries. Inactivation of the murine Col3a1 gene leads to a shorter life span in homozygous mutant mice. The mice die prematurely from a rupture of major arteries mimicking the human vEDS phenotype. The biochemical and cellular effects of COL3A1 mutations have been studied extensively. Most of the glycine mutations lead to the synthesis of type III collagen with reduced thermal stability, which is more susceptible for proteinases. Intracellular accumulation of this normally secreted protein is also found. Ultrastructural analyses have demonstrated dilated rough endoplasmic reticulum and changes in the diameter of collagen fibers. Other clinical conditions associated with type III collagen are several types of fibroses in which increased amounts of type III collagen accumulate in the target organs.

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

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