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

Helena Kuivaniemi; Gerard Tromp

doi:10.1016/j.gene.2019.05.003

. Author manuscript; available in PMC: 2020 Jul 30.

Published in final edited form as: Gene. 2019 May 7;707:151–171. doi: 10.1016/j.gene.2019.05.003

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

Helena Kuivaniemi ^a,^*, Gerard Tromp ^a,^b,^c,^d,^e

PMCID: PMC6579750 NIHMSID: NIHMS1529799 PMID: 31075413

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 signalling molecule in would 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.

Keywords: Extracellular matrix, Connective tissue, Vascular disease, Ehlers-Danlos syndrome, Fibrosis

1. 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.

Table 1.

Characteristics of the COL3A1 gene, mRNA and protein in Homo sapiens and Mus musculus.

	Homo sapiens	Mus musculus
Gene symbol	COL3A1	Col3a1
NCBI Gene ID	1281	12825
HGNC/MGI	2201	88453
OMIM	120180
Chromosomal location	2q32.2	1 C1.1 (23.67 cM)
Genome coordinates	Chr2:188974373-189012746^a	Chr1:45311538-45349706
GeneBank (gene)	NC_000002.12	NC_000067.6
Ensembl transcript ID	ENSG00000168542	ENSMUST00000087883.12
RefSeq (mRNA)	NM_000090.3	NM_009930.2
RefSeq (protein)	NP_000081.1	NP_034060.2
Gene length (kbp)	38.4	38.2
mRNA length (nt)	5543	5564
Number of exons	51	51
Number of codingexons	51	51
CCDS code	CCDS2297.1	CCDS35554
Uniprot name	Collagen alpha-1(III) chain	Collagen alpha-1(III) chain
UniProtKB/Swiss-Prot ID	P02461–1 ^b	P08121
Length of protein in amino acids	1466	1464
Mass for single pro-α-chain (kDa)	139	139

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Based on GRCh38.p12.

Annotations in the Uniprot database entry P02461–1 are incomplete and do not incorporate domain expert knowledge. Also, there is no biological evidence that the Uniprot entry P02461–2 or the Ensembl entry COL3A1–202 (ENST00000317840.9) exist and they appear to be purely computational entities. Furthermore, exon coverage data based on RNA-sequencing shows no evidence for extensive alternative splicing. See Figures 1 and 2 for structural domains.

Data sources for Homo sapiens: https://www.ncbi.nlm.nih.gov/gene/1281; https://www.genecards.org/cgi-bin/carddisp.pl?gene=COL3A1; https://www.ncbi.nlm.nih.gov/CCDS/CcdsBrowse.cgi?REQUEST=GENEID&DATA=1281; https://www.uniprot.org/uniprot/P02461#P02461–1; https://www.omim.org/entry/120180?search=col3a1&highlight=col3a1;

Data sources for Mus musculus: https://www.ncbi.nlm.nih.gov/gene/12825; http://www.informatics.jax.org/marker/MGI:88453; https://www.uniprot.org/uniprot/P08121#P08121

2. 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): Chr2:188,974,320189,012,746]. The gene is approximately 38 kb long and has 51 exons, which are numbered 152 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 1,105 (exon 52) (Valkkila et al., 2001). All exons except exon 2 begin with a complete codon, and all exons encoding the triple-helical domain start with a codon for a glycine (Valkkila et al., 2001). The first intron at approximately 11.5 kb is the largest one in the COL3A1 gene, whereas the second largest intron is 1,500 bp and the smallest intron is only 85 bp.

Fig. 1 — Structure of the human *COL3A1* transcripts. The image shows the location of coding sequence (CDS), untranslated regions (UTR), 51 exons, polyA signals and sites, and the different functional domains. Locations of the proline residues that will be hydroxylated are also shown. The same color scheme was used in Figure 2. The annotations shown here differ slightly from those by Uniprot database (P02461–1), which are incomplete and did not incorporate domain expert knowledge. Also, there is no biological evidence that the Uniprot entry P02461–2 or the Ensembl entry COL3A1–202 exist and they appear to be purely computational entities. Furthermore, exon coverage data based on RNA-sequencing shows no evidence for extensive alternative splicing. The figure was generated using GeneBank entry NM_000090.3, and a software package UGENE (Okonechnikov et al., 2012). See Fig. 4 for schematic drawing of the different functional domains.

COL3A1 gene is in tail-to-tail orientation with a gene for another fibrillar collagen, namely COL5A2 (Valkkila et al., 2001). The sequence between these two genes is about 22 kb and it contains several repeat sequences including a LINE-1, two AT, and an Alu repeat (Valkkila et al., 2001). A phylogenetic analysis for the human COL3A1 and COL5A2 genes based on the sequences of the carboxy (C)-terminal domains indicated that these two genes likely evolved from a common ancestor (Valkkila et al., 2001).

Genetic variation present in the COL3A1 gene has been compared between four ethnic groups, namely African American, European, Mexican and Chinese (Chan et al., 2008). DNA samples from 48 unrelated individuals from each of these four groups were analysed for all the exonic and some intronic regions of four collagen genes (COL1A1, COL1A21, COL2A1 and COL3A1). A total of 114 polymorphic sites were identified in COL3A1, only four (Ala679Thr, Thr698Ala, Val1205Ile, and Gln1353His) of which led to an amino acid change. Phylogenetic trees generated using these results demonstrated that the African American group was evolutionary separated from the other three groups when COL3A1 sequences were analysed.

Two transcripts, 4.8 kb and 5.5 kb are generated from the COL3A1 gene using different polyadenylation sites (Fig. 2) (Ala-Kokko et al., 1989).

In the mouse genome, Col3a1 encoding the mouse α1 chain of type III collagen is located on the chromosome 1 [genomic coordinates (GRCm38): Chr1:45311538–45349706]. The gene is similar in size to the human COL3A1 gene with a length of approximately 38 kb and 51 exons. The exon-intron organization is also identical to that of the human COL3A1 gene (Toman and de Crombrugghe, 1994; Valkkila et al., 2001).

3. Protein structure

3.1. 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, the triple helix (Bachinger et al., 1980; Birk and Silver, 1984; Boudko and Engel, 2004). Prior to assembling the super-helix, each monomer is subjected to a number of post-translational modifications that occur while the monomer is being translated. First, on the order of 145 prolyl residues of the 239 in the triple-helical domain are hydroxylated to 4-hydroxyproline by prolyl-4-hydroxylase. Second, some of the lysine residues are hydroxylated or glycosylated, and some lysine as well as hydroxylysine residues undergo oxidative deamination catalysed by lysyl oxidase. Other post-translational modifications occur after the triple helix is formed. The large globular domains from both ends of the molecule are removed by C- and amino(N)-terminalproteinases to generate triple-helical type III collagen monomers called tropocollagen. In addition, crosslinks form between certain lysine and hydroxylysine residues. In the extracellular space in tissues, type III collagen monomers assemble into macromolecular fibrils, which aggregate into fibers, providing a strong support structure for tissues requiring tensile strength (Fig. 3).

There are two types of hydroxylations of proline residues, namely the formation of 4hydroxyproline and 3-hydroxyproline, by two different enzymes (Weis et al., 2010). 4hydroxyprolines are known to stabilize the triple helix, whereas the exact function of 3hydroxyproline is not known, but it could be associated with inter-triple-helical interactions and supramolecular assembly. Between one and six 3-hydroxyprolines in each pro-α-chain are found in human fibrillar procollagens I, II, V, and XI, but none in the human type III procollagen although the chicken type III procollagen has one 3-hydroxyproline at position 986 (Weis et al., 2010).

The C-propeptides are important in the biosynthesis of fibrillar collagens by directing the chain selection, stabilizing the associated α chains by the formation of interchain disulphide bonds, and facilitating the formation of the triple helix (Boudko and Engel, 2004; Bourhis et al., 2012; DiChiara et al., 2018). In type III procollagen, the C-propeptide has eight cysteine residues and an N-glycosylation site. To facilitate the functional analyses, a recombinant form of the C-propeptide of type III collagen was expressed in a baculovirus system (Zafarullah et al., 1997). It was secreted into the medium and was shown to contain the expected inter- and intrachain disulphide bonds. In 2012, Bourhis et al. (2012) reported the crystal structure of the human C-propeptide of type III procollagen (Bourhis et al., 2012).This study provided the threedimensional structure of the homotrimeric propeptide and has facilitated the prediction of functional consequences of COL3A1 mutations occurring in the C-propeptide.

Production of a full-length recombinant COL3A1 protein has been hampered by the large number of posttranslational modifications required in the biosynthesis of collagens (Tomita et al., 1995; Shi et al., 2017). The most successful approach has been the use of a baculovirus expression system (Tomita et al., 1995; Lamberg et al., 1996), which yielded type III collagen molecules with stable triple helix, but their melting temperature was lower than that from cultured skin fibroblasts (Tomita et al., 1995). When the insect cells were co-transfected with human prolyl-4-hydroxylase, the recombinant type III procollagen was disulphide-bonded and the pepsin-digested collagen had a thermal stability of 41°C in a trypsin-chymotrypsin assay, a result comparable to that for a native type III collagen (Lamberg et al., 1996). In subsequent experiments using a yeast expression system, an intriguing finding was that co-expression of type III procollagen together with prolyl-4-hydroxylase, a key enzyme responsible for hydroxylating proline residues during collagen biosynthesis, markedly increased the amount of active prolyl-4-hydroxylase even though there was no change in the mRNA levels (Vuorela et al., 1997). The authors concluded that the increase in this activity was most likely due to an increased association of enzyme subunits to form the active enzyme tetramer and that in the absence of a collagen substrate the enzyme subunits rapidly dissociated.

The crystal structure has been determined for a synthetic triple-helical peptide with 42 amino acids (aa) that correspond to aa 991–1032 in the type III procollagen and contain the so called C-terminal cysteine knot, the region with a disulphide bond (Boudko et al., 2008). The analyses of the structure demonstrated that the multiple non-imino acids in this peptide, are part of direct intra- and interhelical contacts, and could interact with other extracellular matrix components (Boudko et al., 2008).

3.2. Structure of type III preprocollagen, procollagen and collagen

The triple-helical conformation, which is a characteristic feature of all fibrillar collagens, is possible because of the presence of a glycine as every third amino acid in the sequence of about 1,000 amino acids. This (Gly-Xaa-Yaa)_n sequence is repeated 343 times in the type III collagen molecule. Proline or hydroxyproline is often found in the X- and Y-position giving the triple helix stability (Fig. 2 and Fig. 4).

Fig. 4 — Structural domains of type III procollagen molecule. Type III collagen is synthesized by cells as a preprocollagen. The signal peptide (not shown here), which is 24 amino acids (aa) long, is cleaved off to form the procollagen chain. The total length of each of the α chains of type III procollagen is 1466 aa. Three α chains form a homotrimer as the type III procollagen molecule. The large globular domains from both ends of the molecule are removed by carboxyterminal (C) and aminoterminal (N) proteinases to form type III collagen. Several co- and post-translational modifications also take place.

The exact amino acid sequence was first determined by partial amino acid sequencing of bovine (Glanville and Fietzek, 1976; Fietzek et al., 1979; Brandt et al., 1984) and human (Gilbert et al., 1978; Seyer and Kang, 1981) type III collagen. Recombinant DNA technology then made it possible to obtain complementary DNA (cDNA) clones from chicken (Yamada et al., 1983), mouse (Wood et al., 1987), and human (Loidl et al., 1984; Chu et al., 1985; Miskulin et al., 1986; Mankoo and Dalgleish, 1988; Toman et al., 1988; Ala-Kokko et al., 1989; Janeczko and Ramirez, 1989) samples to determine the nucleotide sequence of the type III preprocollagen transcripts (Fig. 2). The cDNA and amino acid sequences between human, mouse and bovine type III collagen are very similar (Ala-Kokko et al., 1989).

Comparison of the human type III procollagen cDNA sequence to those of other two major fibrillar collagen chains, the α1 and α2 chains of type I procollagen, revealed that the triple-helical domain of the type III procollagen is 15 amino acid longer (1,029 aa) than the triplehelical domains (1,014 aa) of the two other α chains (Ala-Kokko et al., 1989). There were also differences in the lengths of the other functional domains, the largest difference being in the length of the N-propeptides, which is only 57 aa in the α2 chain of type I procollagen, but 139 and 129 aa in the α1 chains of type I and type III procollagen, respectively (Ala-Kokko et al., 1989). The codon usage for glycine, proline and alanine in the triple-helical domain was similar between the type I and type III collagen in that it favoured U as the third base (Ala-Kokko et al., 1989).

4. 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 al., 1995). In another study that analysed COL3A1 mRNA levels in human fetal tissues, the expression patterns of COL1A1 and COL3A1 were quite different in the developing skeletal tissues and the authors suggested that this might mean that they are under different regulatory mechanisms (Sandberg et al., 1989).

Many early studies were not able to extract type III collagen from bone, and concluded that bone did not contain type III collagen. The first study to show that human bone does contain type III collagen was a histological analysis by Keene et al. (Keene et al., 1991) and used monoclonal antibodies. Type III collagen-containing fibers were found in all samples from donors between ages of 30 weeks to 80 years. Type III collagen was detected throughout the cortex, but was concentrated at the Haversian canal surface and the bone-periosteal interface.

A detailed mRNA expression analysis based on RNA-sequencing of 27 different human organs and tissues from 95 individuals was carried out by Fagerberg et al (Fagerberg et al., 2014). COL3A1 mRNA had a high level of expression in the gall bladder, placenta, bladder and endometrium (Fig. 5A). It was also detected in various parts of the gastrointestinal track, fat, heart, prostate, skin, spleen and testis. Unfortunately the sample collection did not contain blood vessels.

Fig. 5 — Distribution of *COL3A1* mRNA in human (A) and mouse (B) tissues. RNA-sequencing data by Faderberg et al. (Fagerberg et al., 2014) for the human and Yue et al. (Yue et al., 2014) for the mouse tissues were used to generate these figures.

A similar analysis was carried out in the mouse using 69 samples from different tissues and developmental stages (Yue et al., 2014). The results showed that Col3a1 expression was high in the bladder, mammary gland, placenta, fat and in the limbs of E14.5 mouse embryos (Fig. 5B). Col3a1 mRNA was also detectable in the gastrointestinal track, heart, kidney, lung, ovary, and mouse embryonic brain and liver, but not in the adult mouse brain or liver.

Expression of type III collagen has also been studied in different benign and malignant tumors using immunostaining (d’Ardenne et al., 1984). All tumor samples were positive for type III collagen. Of the benign tumors, leiomyomas, and giant cell tumors of tendon sheaths had the highest level of type III collagen expression, whereas among the malignant tumors, leiomyosarcomas, fibrosarcomas, and sarcomas had the highest expression.

5. 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 and it has been suggested that its role is to act as a modifier of the fibril network composed of type II collagen together with other minor collagens during tissue healing (Wu et al., 2010). Type III collagen molecules appear to be cross-linked to the surface of type II collagen fibrils. Interestingly, most of the type III collagen molecules found to be present in the cartilage were not fully processed (see section 3) and contained disulphide-bonded N-terminal propeptides.

One of the earliest studies on type III collagen in 1975 showed that it influences the aggregation of human platelets (Balleisen et al., 1975). Follow-up studies demonstrated that one peptide generated by a cyanogen bromide treatment of calf skin type III collagen could facilitate platelet adhesion in human blood (Fauvel et al., 1978). The peptide was broken down further by chymotrypsin and hydroxylamine to narrow down the amino acid residues responsible for this function. Further evidence on the interaction between collagens and platelets was provided by Balleisen et al. (Balleisen et al., 1979), when they demonstrated that aggregation of platelets could be inhibited by coating the collagen fibrils with antibodies directed towards types I, II and III collagens thereby preventing the direct physical contact between platelets and collagens. Chiang et al. (Chiang et al., 1993) isolated a 47-kDa membrane protein from platelets and showed that it interacted with type III collagen. It is now known that platelets interact with type III collagen through specific glycoproteins and non-integrin receptors (Monnet and FauvelLafeve, 2000). Jarvis et al. (Jarvis et al., 2008) used 57 synthetic peptides, the sequence of which was derived from the sequence of COL3A1 and which could form a triple-helix, and tested their ability to interact with human and mouse platelets. A peptide with three hydroxyproline residues was found to bind to glycoprotein VI in platelets.

Type III collagen also functions in cell adhesion, migration, proliferation and differentiation through its interaction with integrins, which are cell surface receptors (Kim et al., 2005). The sites present in type III procollagen and showing high affinity to bind integrins are located in the C-terminal region (Kim et al., 2005).

It is likely that future research will identify additional binding sites in the type III collagen molecule for its interaction partners. This is facilitated by the Collagen Toolkit designed by the investigators at Cambridge University in the United Kingdom (https://collagentoolkit.bio.cam.ac.uk/ ). The toolkit contains 57 overlapping peptides corresponding to the triple-helical domain of type III collagen. The peptides can be used in a 96well format for mapping binding sites.

Based on measurements in the fluid collected from surgical wounds, peritoneum and serum of patients who underwent surgical procedures, the N-terminal propeptide levels of type III procollagen (PIIINP) increased 2–3 days after surgery (Haukipuro et al., 1987). At day 5 after the surgery, the serum PIIINP levels were 1000-fold higher in surgical patients than in nonsurgical patients. These findings suggest that type III collagen is required for wound healing.

6. 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 6.3).

Several studies have demonstrated that hypoxia alters type III collagen expression. Duval et al (2009) showed that hypoxia led to a decrease in both mRNA and protein levels of COL3A1 in cultured chondrocytes (Duval et al., 2009). A similar response was seen when using transient expression of the hypoxia-inducible factor 1ɑ (HIF-1ɑ), and the authors concluded that the effect is mediated by HIF-1ɑ. Zhang et al. (2018) found an opposite result when using cultured rat pulmonary microvascular endothelial cells under hypoxia (Zhang et al., 2018). In this experimental system hypoxia led to an increase in Col3a1 mRNA levels.

Samokhin et al. (2018) studied the molecular interactions in human pulmonary arterial hypertension using an in silico approach, and generated a “fibrosome” consisting of proteinprotein interactions important for lung fibrosis (Samokhin et al., 2018). Next, they incorporated into this network genes known to be regulated by aldosterone. This in silico analysis resulted in identifying NEDD9 as the key molecule in regulating gene expression that leads to pulmonary fibrosis, vascular remodeling, and pulmonary hypertension. The authors then went on to verify the findings experimentally and demonstrated that hypoxia increased NEDD9 and COL3A1 expression in human pulmonary artery endothelial cells, and that this was independent of TGFβ1 signaling. Nedd9-deficient mice exposed to hypoxia had decreased amounts of Col3a1 and decreased systolic pressure of the right ventricle. They concluded that NEDD9 targets COL3A1 to promote endothelial fibrosis and pulmonary arterial hypertension and that oxidative modification of a cysteine residue in NEDD9 and paracrine signaling of exosomes were the two mechanisms responsible for this.

In response to hypoxia, injury or metabolic stress cells release adenosine, a purine generated from ATP and ADP. Shaikh et al (2016) showed that in human skin fibroblasts adenosine acts through its receptors and stimulates COL3A1 expression via the canonical and non-canonical Wnt/β-catenin signaling pathway (Shaikh et al., 2016). Interestingly, the Wnt/β-catenin pathway was not involved in type I collagen expression in this experimental system.

When investigating the potential mechanisms leading to chronic allergic airway inflammation in a mouse model, Kilic et al (2011) discovered that a protein called the nerve growth factor induced the expression of type III collagen (Kilic et al., 2011). A treatment of the mice with an antibody against the nerve growth factor prevented this induction. The nerve growth factor was shown to signal through the MAPK pathway. Inhibition of this pathway in mouse lung fibroblasts prevented induction of COL3A1 expression by the nerve growth factor.

Yamane et al. (2018) investigated the role of branched amino acids leucine and isoleucine in the expression of Col1a1 and Col3a1 in the skin of mice deficient in branchedchain ɑ-ketoacid dehydrogenase kinase, which inactivates the enzyme involved in catabolizing branched amino acids (Yamane et al., 2018). Leucine and isoleucine levels were low in these mice. Col1a1 and Col3a1 mRNA and protein levels were also low compared to wild type mice. The authors found indirect evidence that the activity of the mammalian target of rapamycin (mTOR) was also decreased. Branched amino acids are known to signal via mTOR.

Epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF; also called FGF2) enhanced the expression of COL3A1 mRNA and protein in human skin fibroblasts via MAPK signaling (Shen et al., 2018). Using human amniotic fibroblast cultures and explants of amniotic tissue, Mi et al (2018) demonstrated that cortisol decreased COL3A1 protein, but not mRNA levels (Mi et al., 2018). Further studies revealed that the reduction in protein levels was likely due to degradation mediated by the ubiquitin-proteasome pathway. Yuan et al. (2018) treated cultured human skin fibroblasts with TGFβ1 and found that the mRNA levels of COL3A1 were increased (Yuan et al., 2018).

A study by Chen et al. (2018) investigated the role of long non-coding RNAs (lncRNAs) in hypertrophic scars and found that one lncRNA had lower levels (Chen et al., 2018). In cultured skin fibroblasts overexpressing this same lncRNA reduced COL3A1 mRNA levels.

Thiele et al (2004) identified two mRNA-binding proteins called heterogeneous nuclear ribonucleoproteins (hnRNP) A1 and K that bind to sequences in the 3’UTR of COL3A1 mRNA (Thiele et al., 2004). Their experiments demonstrated that hnRNP K stabilized the COL3A1 mRNA, which resulted in increased expression. They also showed that TGFβ1 activates the synthesis of these hnRNPs as well as the synthesis of type III collagen in cardiac fibroblasts. Other studies have shown that the response to TGFβ1 varies based on the embryological origin of the cells (see Kuivaniemi et al., 2015); thus it is not possible to say if the regulatory mechanisms are the same in other vascular beds.

7. 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 found in various organs.

7.1. COL3A1 defects in patients with vEDS and other forms of EDS

vEDS (OMIM130050; ICD-10: Q79.6), previously known as the arterial-ecchymotic EDS, Sack-Barabas syndrome, EDSIV and EDS type 4, is the most serious form of EDS, since patients often die suddenly due to a rupture of large arteries or other hollow organs (Pope et al., 1977; Byers, 1993 [updated 2019]; Pope et al., 1996; Pepin et al., 2014; Byers et al., 2017; Malfait et al., 2017; Malfait, 2018). Other clinical manifestations of vEDS can include cigarette paper-like scarring of the skin, large ecchymoses over bony protuberances due to bruising, skin so thin that subcutaneous vessels are readily visible, joint laxity that is usually confined to fingers, pneumothorax, acrogeria, talipes equinovarus, keratoconus, gingival recession and fragility, and early-onset varicose veins, but the clinical picture of vEDS can be quite heterogenous even among members of the same family (Pope et al., 1977; Pope et al., 1996; Malfait et al., 2017). The median life expectancy is 50 years, and most patients develop major complications before the age of 30 years. Penetrance is 100% for mutations with autosomal dominant inheritance, but shows age-dependence. Patients with heterozygous null mutations usually have milder phenotype and these mutations have a lower penetrance of approximately 50% (Byers, 1993 [updated 2019]).

The inheritance mode of vEDS is autosomal dominant. Approximately 50% of the vEDS patients have no family history of the disease and the disease is due to de novo mutations (Byers, 1993 [updated 2019]). Prevalence estimate is 1–9/100,000, but it is likely that many vEDS cases are undiagnosed. It is estimated that there are approximately 1,500 vEDS cases in the USA (Byers, 1993 [updated 2019]).

Clinical diagnosis of vEDS is often difficult without genetic testing for COL3A1 mutations. vEDS diagnosis should be suspected in individuals with spontaneous ruptures of arteries, uterus or bowel at young age and the diagnosis confirmed by DNA sequencing. Once a mutation has been identified in the patient, testing for the at-risk relatives should also be offered (Byers, 1993 [updated 2019]).

Clinical management of vEDS patients often requires a multidisciplinary team of medical experts including primary care physicians, genetic counsellors, human geneticists, radiologists, vascular surgeons, general surgeons, gastroenterologists, and obstetricians. Evaluations should include blood pressure monitoring, and arterial screening by ultrasound, magnetic resonance or computed tomography imaging to detect dissections and dilatations (Byers, 1993 [updated 2019]; Eagleton, 2016; Byers et al., 2017; Malfait, 2018). Procedures such as arteriograms, colonoscopies and elective surgeries should be avoided due to tissue fragility, which could lead to complications. When surgical treatment is needed, if feasible, it should be performed by surgeons experienced in treating vEDS patients and familiar with the higher risks associated with the care of these patients (Eagleton JVS 2016).

Only one clinical trial for a potential drug therapy to prevent vascular events in vEDS patients has been published (Ong et al., 2010). In this study, carried out in France and Belgium, celiprolol, a cardioselective β-blocker with β₂-agonist vasodilatation effects, was used. Altogether 53 vEDS patients, 33 (62%) of whom were later confirmed to have vEDS based on genetic testing, were randomly assigned to treatment (n=25) or no treatment (n=28) groups. The trial was ended early at 64 months due to the small number of patients available for follow-up who had not developed any of the vascular events. Although the authors concluded that celiprolol reduced the risk of arterial complication, the study has been criticized for its small size, and the fact that about third of the patients did not have COL3A1 mutations (Byers, 1993 [updated 2019]).

Female vEDS patients are at increased risk for pregnancy-related complications based on a study on 616 pregnancies of 283 women with confirmed COL3A1 defects (Murray et al., 2014) and should be followed in a high-risk obstetric program (Byers, 1993 [updated 2019]). In this study, a total of 30 (4.9%) pregnancies resulted in the death of the mother due to an arterial dissection or rupture, a uterine rupture, or complications during a cesarean section. All of the deaths occurred in women who had protein-altering COL3A1 mutations, whereas no deaths were seen in the 51 pregnancies among the 27 women with COL3A1 null mutations. The authors of this study also compared the overall death rates of these women who had been pregnant to those who had not, but had a genetically-confirmed vEDS diagnosis (n=243 nulliparous vEDS patients) and found that the overall survival rates were similar in these two groups of women (Murray et al., 2014).

7.1.1. Protein analyses with skin fibroblasts taken from patients with vEDS

Before DNA analyses became feasible, skin biopsies were taken from patients suspected of having vEDS and biochemical analyses were carried out using cultured skin fibroblasts (Pope et al., 1975; Byers et al., 1981; Stolle et al., 1985). These analyses involved culturing cells in the presence of a radioactive proline, which was incorporated into the newly synthesized collagens. It was then feasible to analyse the secreted and intracellular proteins separately and assess intracellular accumulation and secretion of collagens which have a high proline content.

Additional analyses included “stress tests” in which the proteins were subjected to a proteinase digestion at different temperatures (Stolle et al., 1985; Tromp et al., 1989a; Tromp et al., 1989b; Kontusaari et al., 1990b; Narcisi et al., 1993; Anderson et al., 1997). Properly folded type III procollagen can withstand a trypsin-chymotrypsin treatment to 41°C, but procollagen molecules containing mutations will break down at lower temperatures due to unfolding of cooperative blocks within the triple helix and expose the proteinase-sensitive sites of the molecule. Another test was to carry out digestion with collagenase, which cleaves normal type III procollagen at a very specific site at aa 781 of the triple-helical domain (Fig. 6). The procollagen can also be digested by pepsin, which will remove the globular propeptides, the end result being collagen (Kontusaari et al., 1990b; Nuytinck et al., 1992; Narcisi et al., 1993).

Fig. 6 — Thermal unfolding of type III collagen from a patient with a Gly619Arg mutation in *COL3A1.* Skin fibroblasts were obtained from the patient and a control. The effect of a single base missense mutation was tested on the type III collagen protein by using a proteinase assay. The type III collagen was first digested with collagenase which cleaves the molecule at aa 781. This was then followed by digestion with trypsin and chymotrypsin. A large fraction of the patient’s type III collagen was digested to a fragment of approximately 620 aa at temperatures 20–36°C. In comparison the type III collagen isolated from control fibroblasts stayed intact and did not break down until at 38°C. Reproduced with permission from (Kontusaari et al., 1990b).

Increased amounts and intracellular accumulation of this normally secreted protein are also often found (Anderson et al., 1997) in addition to the synthesis of an overmodified type III collagen showing retarded migration on a polyacrylamide gel (Nuytinck et al., 1992; Richards et al., 1992; Narcisi et al., 1993). In some cases, the type III collagen protein was digested with cyanogen bromide and the various peptides analysed to map the defect (Nuytinck et al., 1992; Richards et al., 1992).

7.1.2. DNA analyses and a mutation database for patients with vEDS

The first COL3A1 DNA study based on a preliminary Southern blot analysis of a vEDS patient identified an approximately 3.3-kb deletion in COL3A1 in 1988 (Superti-Furga et al., 1988). In a subsequent publication three years later, DNA sequencing of the breakpoints of the deletion demonstrated that it was much larger and included 16 exons and approximately 7.5 kb of genomic DNA (Lee et al., 1991). Based on a large number of studies that have screened for mutations in COL3A1 in patients with vEDS, large deletions and insertions are not a common type of mutations in these patients.

The first glycine mutation in the triple-helical domain was reported in 1989 in a study that was also the first detailed DNA analysis of a COL3A1 mutation using DNA sequencing both on the genomic and cDNA level (Tromp et al., 1989a). This mutation changed a glycine at aa position 790 to a serine (Gly790Ser; numbering from the beginning of the triple-helical domain) (Tromp et al., 1989a).

A total of 63 COL3A1 mutations were summarized in a review article published in 1997 (Kuivaniemi et al., 1997). About 20 years later, over 650 different mutations have been reported, which are listed in a COL3A1-specific database (see https://eds.gene.le.ac.uk/home.php?select_db=COL3A1). In 2014, 410 different mutations were reported from a single Medical Genetics Laboratory at the University of Washington, USA (Pepin et al., 2014). Based on this study and the COL3A1 mutation database, the most common type of mutation is a missense mutation substituting a bulkier amino acid for a glycine in the triple-helical domain. The second most common type of mutations in vEDS are COL3A1 RNA splicing mutations (Kuivaniemi et al., 1990; Schwarze et al., 1997).

7.1.3. Mutations in the C-propeptide of COL3A1

Missense and nonsense mutations in the C-terminal propeptide of type III procollagen possibly also cause vEDS, although the detailed functional studies to prove this are still needed (Stembridge et al., 2015).The C-propeptide is important for the assembly of the three pro-α chains (Boudko and Engel, 2004; Bourhis et al., 2012), but knowledge about the role of each aa in the sequence is limited and it is, therefore, difficult to interpret the results. One of the patients in the study by Stembridge et al. (Stembridge et al., 2015) was a female patient with a Pro1440Leu mutation in the C-terminal propeptide of type III procollagen (Stembridge et al., 2015). She had thin skin, easy bruisability, mild joint laxity, periodontal disease with gum recession, and a typical acrogeria, but no vascular or bowel ruptures by the age of 27 years. Her father, who was mosaic for the same mutation, showed mild joint laxity (see section 7.1.5.). Cultured skin fibroblasts of the patient produced less type III collagen than control fibroblasts. Protein modelling was suggestive of leucine destabilizing the structure. Another patient was a 39-year old male with easy bruisability, hyperextensible skin, ruptured ligament of the diaphragm, and bilateral inguinal hernia, but again no vascular complications (Stembridge et al., 2015). Protein analysis of cultured skin fibroblasts revealed type III collagen deficiency, and DNA sequencing of genomic DNA revealed an Arg1432Leu missense mutation. The patient’s more mildly affected sister had the same mutation. The third patient studied by Stembridge et al. (Stembridge et al., 2015) was a 26-year old female with a generalized joint laxity, easy bruisability, unusual facial appearance, and a slightly enlarged pulmonary artery. DNA sequencing found a nonsense mutation. Protein analyses demonstrated slightly reduced amounts of type III procollagen. The fourth patient had skin and joint manifestations, as well as a gastric paresis with atony, and was diagnosed with the benign hypermobility or EDS type III. DNA sequencing revealed a Lys1313Arg missense mutation, but based on protein analyses performed on cultured skin fibroblasts the amount of type III procollagen was normal. Protein modelling showed no adverse consequences. The authors concluded the variant was a benign variant.

7.1.4. RNA splicing mutations in COL3A1

The most frequently seen pattern of abnormal splicing is exon skipping, but other forms of aberrant splicing have also been detected (Fig. 7) (Kuivaniemi et al., 1990; Schwarze et al., 1997). The normal COL3A1 gene does not undergo alternative splicing. RNA splicing mutations that lead to exon skipping, and thereby remove one entire exon, produce a transcript that encodes a protein with multiple triplets of amino acids deleted, since each exon in the triplehelical region starts with a complete glycine codon. The resultant mutant protein is, therefore, shorter by the number of amino acids encoded by that exon, but the Gly-Xaa-Yaa triplets stay in frame and there are no premature termination codons.

In a study that described the first RNA splicing mutations in COL3A1 in 1990 (Kuivaniemi et al., 1990), three single nucleotide changes were found, each mutating the first G in a different intron (introns 16, 20 and 42) to an A (Fig. 7). The patterns of RNA splicing were studied by S1 nuclease probe protection experiments and cDNA sequencing and were found to differ(Kontusaari et al. 1990a; Kuivaniemi et al. 1990).. The intron 16 mutation led to an abnormal splicing that skipped exon 16, whereas an identical mutation in intron 20 produced two different RNA species, one of which was generated by an efficient use of a cryptic splice and the other with no splicing of intron 20 and retaining the entire intron in the resulting transcript. The third mutation located in intron 42 led to an efficient use of a near-by cryptic splice site which added only 30 nucleotides to the transcript and kept it in frame (Kuivaniemi et al., 1990). The same intron 42 mutation was later found in another unrelated patient and the splicing pattern was the same in both patients (Schwarze et al., 1997). Interestingly, two different mutations in the 5^th nucleotide of intron 42 in two additional vEDS patients also produced the same abnormal splicing (Giunta and Steinmann, 2000; Okita et al., 2010) suggesting that the inclusion of 30 intronic nucleotides into the mRNA is an efficient form of splicing for intron 42. Okita et al. (Okita et al., 2010) showed that the mutation led to a decreased amount of type III collagen synthesis by the patient’s skin fibroblasts.

A single-base mutation in COL3A1 that changed the 5^th nucleotide of intron 37 from G to A led to abnormal RNA splicing, which produced skipping of exon 37 (Wu et al., 1993). Quantification of the RNA splicing patterns showed that 70% of the mutant allele was spliced through exon skipping and 30% was spliced normally, when the skin fibroblasts were grown at 37°C. Interestingly, the amount of abnormal splicing increased at a lower temperature and was approximately 90% at 31°C.

Studies on RNA splicing defects in COL3A1 have led to a better understanding of the mechanism of RNA splicing in large multi-exon genes such as the collagen genes (Fig. 7). It is plausible to speculate that the order of splicing of different introns varies and that the size of the intron also influences the splicing pattern favoured when the normally occurring splice site is mutated (Kuivaniemi et al., 1990; Schwarze et al., 1997). Another factor likely to play a role is the presence of cryptic splice sites, sequences near the normally used splice sites, which are activated when the normal splice site becomes weaker through a mutation (Kuivaniemi et al., 1990). The use of cryptic splice sites in an intron leads to an incorporation of additional nucleotides into the transcript (Fig. 7). These extra sequences usually contain premature termination sites for translation and are detected by nonsense-mediated mRNA decay, the result of which is the degradation of the abnormal RNA molecules and no protein synthesis.

7.1.5. Germline and somatic cell mosaicism in the relatives of patients with COL3A1 mutations

Germline and somatic cell mosaicism refers to a situation where a mutation occurred during the embryogenesis of the individual and therefore, the mutation is not present in all the cells of that individual. Depending on the cell lineage in which the mutation occurred and the number of cells with the mutation, the disease phenotype may or may not manifest in that individual. It has been estimated that approximately 15% of the phenotypically normal parents of vEDS patients are mosaic (Byers, 1993 [updated 2019]). This is an important finding that must be taken into consideration in genetic counselling, since the risk for a mosaic parent to have another affected child is higher than that for a genetically normal parent. Prenatal testing is available for at-risk individuals (Byers, 1993 [updated 2019]).

Several of the COL3A1 mosaic cases have been studied in detail (Kontusaari et al., 1992; Richards et al., 1992; Milewicz et al., 1993; Palmeri et al., 2003; Stembridge et al., 2015). One such case was a typical female vEDS patient with arterial ruptures, pneumothorax, easy bruisability, and skin changes, who was found to have a single base mutation leading to a Gly1018Asp change in the triple-helical domain (Kontusaari et al., 1992). The parents had no signs of vEDS when last examined in their 70’s. When the inheritance of the mutation was investigated, a surprising finding was that the mother also carried the same mutation in nearly all of her blood leukocytes. Analyses of saliva and hair samples from the mother revealed that approximately 40% of the oral epithelial cells and 0 to 100% of the DNA from 28 hair roots tested individually contained the single base mutation. Based on these results, the mutation must have occurred after the first cell division of the embryo, but before the differentiation of three major germ layers, the endoderm, mesoderm and ectoderm (Kontusaari et al., 1992).

Another example of a mosaicism was in a family where the vEDS patient had a 2-kb deletion in the COL3A1, and the patient’s phenotypically normal father also had this same deletion in some of his cells (Milewicz et al., 1993). Approximately 80% of his cultured skin fibroblasts, but only 20% of his blood leukocytes, carried the deletion. The deletion was also found in his sperm cells, but due to a small sample, quantification was not possible (Milewicz et al., 1993). The authors interpreted the results to mean that the mutation occurred during his embryologic development before the lineage allocation happens.

The third example of a mosaicism was described in the unaffected 77-year old maternal grandmother of a male vEDS patient with a Gly847Glu mutation (Richards et al., 1992). The patient had a spontaneous carotid-cavernous sinus aneurysm and his mother died at the age of 50 years from a bowel rupture. The patient’s brother had thin skin and joint laxity. The amount of type III collagen synthesized by the patient, his brother and mother was reduced. Additional biochemical work on the patient’s skin fibroblasts showed that the type III collagen was overmodified. In addition, cyanogen bromide peptide mapping demonstrated differences from the normal pattern. A genetic test using allele specific hybridization on genomic DNA isolated from blood demonstrated that all three affected family members and the maternal grandmother were positive for the missense mutation. The findings on the grandmother were confirmed with a second blood sample and hair samples. Quantification of the amount of the mutant-to-normal allele ratio was approximately 0.5 suggesting that about 2/3 of the grandmother’s cells carried the mutant allele.

The fourth example of a mosaicism was reported in a study on a family in which the index patient and her mother had neurological manifestations with leg and hand contractures, epilepsy and stroke in addition to acrogeria and coiled cerebral vessels and dissections (Palmeri et al., 2003). They harboured a missense mutation at aa 883 that converted a glycine to a valine. The asymptomatic maternal grandmother with a slight ectasia of thoracic aorta was found to be a mosaic for the same mutation.

The fifth example of a mosaicism was described in the father of a female patient with a Pro1440Leu mutation in the C-terminal propeptide of type III procollagen (Stembridge et al., 2015). The father showed mild joint laxity, whereas the patient had thin skin, easy bruisability, mild joint laxity, periodontal disease with gum recession, and a typical acrogeria, but no vascular or bowel ruptures by the age of 27 years.

7.1.6. Biochemical and cellular effects of COL3A1 mutations

The biochemical and cellular effects of COL3A1 mutations have been investigated extensively using cultured skin fibroblasts established from skin biopsies (Tromp et al., 1989b; Kontusaari et al., 1990b; Kontusaari et al., 1992; Richards et al., 1992; Narcisi et al., 1993; Anderson et al., 1997; Okita et al., 2010). This is an ideal system to study the consequences of the mutations, since skin biopsies are easy to obtain and type III procollagen is expressed in these cells (see section 7.1.1. for details).

Most patients are heterozygous for the mutation and therefore, produce both normal and abnormal α chains of the type III procollagen. Since three α chains are required to form a triplehelical structure, there can be normal and mutant homotrimers, but also trimers that have either one or two mutant α chains together with two or one normal α chains. Altogether only oneeighth of the trimers are completely normal and only one-eighth of the trimers are completely abnormal. For structural stability, the heterotrimers with both normal and mutant α chains folded together are the most problematic ones with aberrant fibril formation leading to reduced strength.

It is also possible to carry out ultrastructural analyses of skin samples taken from the patient and use light and electron microscopy for the analysis. These studies have demonstrated a dilated rough endoplasmic reticulum and changes in the diameter of collagen fibers (Nuytinck et al., 1992; Smith et al., 1997).

More recent studies have used microarray-based transcriptomics to determine which biological pathways are affected by COL3A1 mutations in cultured skin fibroblasts (Chiarelli et al., 2018). Expression profiles of skin cells from two patients who were each heterozygous for the missense mutations, Gly237Arg and Gly612Asp, and a third patient with an RNA slicing mutation in intron 14 were compared to expression profiles of nine healthy age-matched controls (Chiarelli et al., 2018). Altogether 969 genes were differentially expressed, 281 with increased and 688 with decreased expression, between the vEDS and control groups. Fibrillin-2 (FBN2) was the most differentially expressed gene with decreased expression. Several of the genes with increased expression in the patient cells were involved in transcriptional regulation and re-organization of the actin cytoskeleton. The genes with decreased expression belonged to such functional categories as cell cycle processes, cell division, histones, cell movement and intracellular trafficking, DNA damage response, and ribosomal RNA processing. A pathway enrichment analysis revealed that cell cycle was the most affected pathway. The proteasome system was also affected by having several of the differentially expressed genes.

7.1.7. Genotype-phenotype correlations among vEDS patients

In a series of 1,231 vEDS cases from a single laboratory, 630 index cases and their 601 affected relatives were analysed for clinical features and COL3A1 defects (Pepin et al., 2014). The median survival age among men and women was 46 and 54 years, respectively. The causes of deaths included vascular complications such as rupture and dissection, and bowel perforations.

In this study, a total of 410 different COL3A1 mutations deemed to be causative were found among the 572 index cases (Pepin et al., 2014). Biochemical analysis of cultured skin fibroblasts had been carried out in the remaining 58 index cases before genetic testing was available and found to produce abnormal type III procollagen. The 410 different mutations included 356 glycine substitutions, 164 RNA splicing mutations and 52 other types of mutations (insertions, duplications or deletions). In 27 vEDS patients the mutated allele led to an unstable RNA through nonsense-mediated decay, and did not produce protein (null mutations or haploinsufficiency).

Survival of vEDS patients with null mutations was 10–15 years longer than in individuals harbouring RNA splicing or glycine mutations (Pepin et al., 2014). Interestingly, survival among the patients with glycine mutations differed based on the substituting amino acid; a substitution of a valine or an aspartic acid meant worse survival than a substitution of a serine (Pepin et al., 2014).

In another smaller series from France, 215 vEDS patients from 146 different families and with 126 different variants were investigated (Frank et al., 2015). The overall findings were similar to those from the larger series described above in that patients with glycine substitutions (n=127) had poorer prognosis than patients with mutations leading to haploinsufficiency (n=14) (Frank et al., 2015). There was, however, no difference between male and female vEDS patients in the age when a major clinical complication occurred. Interestingly, in this series the vEDS patients with RNA splicing defects had earlier age at diagnosis than patients with glycine substitutions (Frank et al., 2015). The authors speculated that this could be due to differences in the clinical practices between France and the USA.

7.2. Genetic studies for other human diseases

7.2.1. COL3A1 mutations in patients with brain disorders

Several patients with severe brain anomalies in addition to connective tissue manifestations have been reported to harbour a pathogenic variant in both COL3A1 alleles (Plancke et al., 2009; Jorgensen et al., 2015; Horn et al., 2017; Vandervore et al., 2017). In human genetics this is known as a compound heterozygosity, but they are now called “biallelic variants” in the literature. Interestingly, the results from imaging and histological analyses of the brain in the affected individuals resemble those seen in patients with bilateral frontoparietal polymicrogyria (OMIM 606854), who have mutations in GRP56 (Ke et al., 2008). Since type III collagen is a ligand for GRP56, it is plausible that those mutations in COL3A1 that interfere with the receptor-ligand interaction or eliminate type III collagen altogether, manifest as this neurological phenotype. It is also noteworthy, that the Col3a1^+/− mice manifest similar brain phenotype (see section 8.1). One of these patients had an Arg428Stop nonsense mutation in the paternal and a deletion of one C in Pro686 leading to premature termination in the maternal allele of COL3A1. As a consequence, the patient had no functional type III collagen, and would be expected to have a very severe phenotype. Each parent was heterozygous for one of these variants and showed no clinical phenotype (Horn et al., 2017). Four other patients, a sister and a brother, and two unrelated patients with delayed speech and motor development and frontoparietal polymicrogyria were reported to be homozygous for the same Pro49Ala variant (Horn et al., 2017; Vandervore et al., 2017). Even though the variant was classified as pathogenic or likely pathogenic based on in silico scoring algorithms, and it is intriguing that it was present in four patients, it is difficult to be certain that it is the cause of the disease, since biological functional studies did not yield any significant findings (Vandervore et al., 2017). In another study by Jorgensen et al. (Jorgensen et al., 2015), two siblings were compound heterozygotes for a mutation causing a premature termination at aa 596 and a missense mutation in the C-terminal propeptide that changed a glycine to a glutamic acid. One of these patients died suddenly at the age of 15 of arterial dissections at three different sites, and the other had a dissection in the internal carotid artery and cerebral cortical dysplasia (micropolygyria). The four family members who were heterozygous for the premature termination mutation had no clinical manifestations, whereas the one family member who was heterozygous for the missense mutation had thin, translucent skin, small joint hypermobility, pulmonary emphysema and reduced aortic elasticity, which are typical signs of vEDS (Jorgensen et al., 2015).

7.2.2. Studies for other human diseases using COL3A1 genetic variants

Since type III collagen is such an important structural component for the integrity of blood vessels, several studies have investigated the possibility that genetic variants in the COL3A1 gene increase the person’s risk for developing aneurysms. Despite of few isolated reports with positive findings (Kontusaari et al., 1990b; Anderson et al., 1996; van Keulen et al., 1999), larger studies using a comprehensive DNA sequencing analysis of the entire triple-helical domain of type III procollagen in patients with abdominal aortic aneurysms (Tromp et al., 1993) and intracranial aneurysms (Kuivaniemi et al., 1993) found no mutations that could explain the disease. Subsequently, an approach called genetic association study (Romero et al., 2002) in which the frequencies of the two alleles of COL3A1 polymorphisms were compared in cases and controls, was used. No association was found between aneurysms and the COL3A1 polymorphisms (Ogata et al., 2005; Hinterseher et al., 2011). Furthermore, family-based DNA linkage studies (Shibamura et al., 2004; Tromp et al., 2014) and genome-wide association studies (Tromp et al., 2014; Jones et al., 2017) for abdominal aortic aneurysms and intracranial aneurysms with large sample sets have found no evidence that COL3A1 variants contribute to the susceptibility of these conditions. Unlike the candidate gene approaches which rely on prior knowledge about the pathobiology of the disease and are based on educated guesses, these genome-wide approaches are unbiased and decipher the entire human genome to find statistical evidence for a linkage or an association. It should be noted that such studies require large sample sets with thousands of cases and controls to obtain reliable estimates of the disease risk (Romero et al., 2002).

COL3A1 has been tested as a potential susceptibility gene for several other clinical conditions (Muckian et al., 2002; Lv et al., 2014; Reichert et al., 2018). One recent study investigated two COL3A1 single nucleotide polymorphisms (SNPs), rs3134646 and rs1800225, among 422 patients with diverticulosis and 285 controls(Reichert et al., 2018). The rs3134646 was associated with diverticulosis, but rs1800225 not, with an odds ratio of 1.82 (95% confidence interval of 1.04–3.20) and p = 0.04. Due to the small sample size and only borderline significance, the results will need validation and replication.

In another genetic association study, three COL3A1 SNPs (rs2138533, rs11887092, and rs1800255) were analysed for their contribution to the recurrence and prognosis of stroke in the Chinese population (Lv et al., 2014). A total of 1,544 stroke patients from three different subtypes of stroke were included in the study and followed up for 4.5 years. All three variants were associated with the risk for stroke recurrence and prognosis independently from conventional risk factors. Patients who had the A allele of rs1800255, had a lower risk for reoccurrence of stroke, but an increased risk for all-cause mortality in the atherothrombotic stroke subgroup. Again, due to the small sample size, the results although statistically significant, can only be considered suggestive and need further validation.

Muckian et al. (Muckian et al., 2002) assessed the role of genetic variability in COL3A1 in coronary artery disease using a highly polymorphic intronic tandem repeat as a marker. This repeat is located in intron 25 and has between three and 13 copies of a 15-bp repeat (Mays et al., 1992). Four of the alleles are common and were used in the study. The rationale for selecting COL3A1 as the candidate gene for the study, was that it is expressed in vascular wall and is known to interact with platelets. They genotyped DNA samples obtained from individuals who were part of three different cardiovascular studies and had a total of 1,851 cases with either acute coronary syndrome and myocardial infarction, unstable coronary syndrome, or stable angina, in addition to 306 controls. The authors concluded that COL3A1 variants modulate the risk for coronary artery disease. As with all small human genetic studies, the results require confirmation in an independent data set. Furthermore, in complex phenotypes such as the coronary artery disease, the contribution of any single genetic variant is expected to be small and explain only a small fraction of the increased or decreased risk.

7.3. Altered COL3A1 mRNA and protein levels, or degradation in human diseases

Accumulation of type III collagen is a hallmark of several chronic human diseases that involve fibrotic processes including systemic sclerosis, cardiac fibrosis, lung fibrosis, liver cirrhosis and renal fibrosis (Table 2) (Jimenez et al., 1986; Krieg et al., 1986; Rosenbloom et al., 2016; Fogo et al., 2017; Karsdal et al., 2017; Ricard-Blum et al., 2018). Thus, a large number of studies have investigated the potential of using the determination of the PIIINP levels (Risteli et al., 1988) in the urine and serum as a biomarker for the presence of fibrosis. The N-terminal propeptide is cleaved off enzymatically during the biosynthesis of type III collagen (Fig. 3) and it has been proposed that its levels are a surrogate marker for the amount of type III collagen in a given tissue. Another serum test (C3M), developed more recently, measures the levels of a 10aa neoepitope of type III collagen generated by digestion with matrix metalloproteinase 9 (Barascuk et al., 2010). This test does not recognize intact type III collagen, but is specific for the short peptide, and can thus be used to measure type III collagen degradation. A third test (C3C) was developed to measure fragments of type III collagen generated by cathepsins B, L, S and K by ELISA and was tested in patients with chronic obstructive pulmonary disease (COPD) (Rasmussen et al., 2017). This test recognizes a neo-epitope located in aa 642–651 of the αchain of type III collagen. COPD patients (n=68) had significantly elevated levels of C3C in their serum compared to healthy controls (n=20). Serum tests of these three assays and any new tests to be developed would provide an important clinical advancement for diagnostics and monitoring treatment responses since they are minimally invasive tests.

Table 2.

Human diseases associated with altered levels of COL3A1 mRNA, protein or its degradation products.

Condition	Tissue	Method	Results	Study^a (PMID)
Dilated cardiomyopathy	Heart	Gel electrophoresis, IHC	COL3A1 protein increased	Marijianowski et al (JACC 1995); 7722119

Idiopathic restrictive cardiomyopathy	Heart	IHC	COL3A1 protein increased	Hayashi et al Int J Cardiology 1998; 9688428

Hypertrophic cardiomyopathy	Heart	IHC	COL3A1 protein increased	Kitamura et al Clin Cardiol 2001;11303702

Ischemic cardiomyopathy	Heart	IHC	COL3A1 protein increased	Herpel et al Histopathology 2006; 16681691

Valvular cardiomyopathy	Heart	IHC	COL3A1 protein increased	Herpel et al Histopathology 2006; 16681691

Myocardial infarction	Serum	RIA	PIIINP increased 2 days after infarction, but level is within normal limits	Manhenke et al (Eur Heart J 2014); 24255130

Renal fibrosis	Urine and serum	RIA	PIIINP increased	(Soylemezoglu et al., 1997); 9306339
Progression of kidney disease	Urine	RIA	PIIINP increased with progression of disease	(Ix et al., 2015); 25655067
Diabetic nephropathy	Kidney tissue	IHC, in situ RNA hybridization	COL3A1 mRNA and protein increased	(Razzaque et al., 1995); 8822111
Type III collagen glomerulopathy	Kidney tissue	IHC, EM	COL3A1 protein increased	(Fogo et al., 2017); 28532638
Liver fibrosis	Serum	RIA	ELF increased	(Tanwar et al., 2017); 27906753
Chronic obstructive pulmonary disease	Serum	ELISA	C3C increased	(Rasmussen et al., 2017); 28076408
Cryptogenic fibrosing alveolitis	Lung tissue and serum	Gel electrophoresis, RIA	COL3A1 protein and PIIINP increased. Higher PIIINP correlated with response to treatment	(Kirk et al., 1984); 6495240
Progressive systemic sclerosis	Fibroblasts isolated from skin	Gel electrophoresis, Northern, dot-blot	Total collagen increased; COL3A1 mRNA increased	(Jimenez et al., 1986); 3800922
Systemic sclerosis	Serum	RIA	ELF and PIIIINP increased	(Abignano et al., 2019); 30239834
Dupuytren’s disease	Aponeurosis		COL3A1 protein increased	391658
Peyronie’s disease	Penis	Gel electrophoresis	COL3A1 protein increased	(Somers et al., 1989); 2918606
Crohn’s disease	Fibroblasts isolated from intestine		COL3A1 protein increased	(Stallmach et al., 1992); 1587410
Crohn’s disease subtypes	Serum	ELISA	C3M levels higher in penetrating disease	(van Haaften et al., 2017); 28481042
Osteoarthritis	Cartilage	IHC, in situ RNA hybridization	Present in osteoarthritic, but not in normal cartilage	(Aigner et al., 1993); 7680669
Hyperthyroidism	Serum	RIA	PIIINP increased	(Inui et al., 1992); 1576745
Glioma	Tumor tissue	qRT-PCR, IHC	COL3A1 mRNA increased	(Gao et al., 2018); 30008884
Bladder cancer progression	Tumor tissue	Microarray; qRT-PCR; IHC	COL3A1 mRNA and protein increased	(Yuan et al., 2017); 29050298
Breast cancer	Tumor tissue	IHC	PIIINP	(Kauppila et al., 1998); 10211114
Breast cancer: progression and survival	Serum	ELISA	PIIINP increased with progression of disease and shorter survival	(Lipton et al., 2018); 29923614

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C3C, test measuring fragments of type III collagen generated by cathepsins B, L, S and K; C3M, test for measuring levels of a 10-aa neoepitope of type III collagen generated by digestion with matrix metalloproteinase 9; ELF, enhanced liver fibrosis, a panel of three markers including PIIINP, hyaluronic acid and fibronectin; ELISA, enzyme-linked immunosorbent assay; EM, electron microscopy; IHC, immunohistochemistry; PIIINP, N-terminal propeptide of type III procollagen; qRT-PCR, quantitative reverse transcriptase PCR; RIA, radioimmunoassay

Only one representative study for each disease, since a large number of studies have been reported.

7.3.1. Cardiac diseases

The role of extracellular matrix proteins in the pathophysiology of some of the major cardiovascular diseases has been studied extensively (Prabhu and Frangogiannis, 2016; Frangogiannis, 2017). Extracellular matrix accumulation in the heart tissue leads to cardiac fibrosis, scarring that results from an injury, such as a myocardial infarction, and leads to impaired function of the heart muscle (Krenning et al., 2010). Many studies, however, do not distinguish what collagen type was studied and just refer to collagen. Studies that have investigated type III collagen specifically include those on the hypertrophic (Hayashi et al., 1998; Kitamura et al., 2001) and dilated cardiomyopathy (Marijianowski et al., 1995; Hayashi et al., 1998; Bonapace et al., 2006; Herpel et al., 2006; Sivakumar et al., 2008), as well as pulmonary vascular disease (Frangogiannis, 2017), and replacement fibrosis following myocardial infarction (Herpel et al., 2006; Prabhu and Frangogiannis, 2016). Type III collagen changes have also been studied in a rare cardiomyopathy called idiopathic restrictive cardiomyopathy (Hayashi et al., 1998).

Marijianowski et al (1995) studied the amount and distribution of type I and III collagen in heart tissue samples obtained from patients with dilated cardiomyopathy (n=19) and agematched controls (n=17) who died of non-cardiovascular diseases (Marijianowski et al., 1995). Using biochemical and histological methods, they found that both collagen types were increased in the diseased heart tissues, but the increase was more pronounced in type I collagen and therefore the type I-to-III –ratio increased. The authors speculated that this finding could be clinically relevant and explain part of the disease characteristics, since type III collagen gives more elastic properties to the tissue and type I collagen is more rigid. The findings of increased type III collagen levels being associated with dilated cardiomyopathy have subsequently been validated in other studies (Hayashi et al., 1998; Sivakumar et al., 2008).

Herpel et al (2006) investigated several extracellular matrix proteins in heart tissue samples obtained from patients diagnosed with dilated (n=15), ischemic (n=17) and valvular cardiomyopathy (n=7) using immunostaining (Herpel et al., 2006). They showed that the different types of cardiomyopathies all had myocardial interstial fibrosis, but that they differed in the distribution of various extracellular matrix proteins. The amount of type III collagen was the greatest in samples from patients with dilated cardiomyopathy, and lowest in those from patients with valvular disease. Bonapace et al (2006) studied aortic stiffness in 89 patients diagnosed with dilated cardiomyopathy and found that serum PIIINP levels were correlated with clinical parameters measuring aortic stiffness (Bonapace et al., 2006).

Idiopathic restrictive cardiomyopathy is a rare disease manifesting as a diastolic dysfunction. Histologically the disease is characterized by fibrosis in the heart tissue and hypertrophy of myocytes making the heart tissue stiff. Hayashi et al (Hayashi et al., 1998) carried out a histological analysis of endomyocardial biopsy samples (n=7) from these patients and compared the findings to those from patients diagnosed with coronary artery disease (n=5), hypertrophic cardiopathy (n=11) and dilated cardiomyopathy (n=14). The results revealed a marked increase in the amount of type III collagen deposited in the myocardial interstitium. Kitamura et al (2001) analyzed histologically 35 heart tissue specimens from 35 patients with hypertrophic cardiomyopathy (Kitamura et al., 2001). The amount of type III collagen protein detected in immunostaining correlated with several cardiac metrics measuring diastolic function and demonstrated that increased amount of fibrosis was associated with poorer cardiac function. Interestingly, the amount of type I collagen did not correlate with these metrics.

Thiele et al (Thiele et al., 2004) found that the mRNA levels of hnRNP E1, K and A1 were elevated in heart tissue samples from patients diagnosed with aortic stenosis (n=18), and E1 and K were elevated in patients with ischemic cardiomyopathy (n=6), compared to control heart tissue samples (n=20) taken from hearts harvested for transplantation. As described in section 6, A1 and K bind to sequences in the 3’UTR of COL3A1 mRNA to stabilize the transcript.

PIIINP has been tested as a potential marker for heart disease, but the results have been contradictory. In a large community-based study of 967 well-characterized participants, no correlation was found between serum PIIINP levels and various cardiovascular risk factors such as hypertension or diabetes (Wang et al., 2007). There was also no correlation between echocardiographically-determined left ventricular or atrial mass and PIIINP levels (Wang et al., 2007). Manhenke et al (2011) measured several biomarkers, including PIIINP, in serum samples from 233 patients who had suffered a myocardial infarction within the past three days (Manhenke et al., 2014). The patients were then followed up for two years. Several of the other biomarkers including type I collagen markers, but not PIIINP, changed during the follow-up that included treatment with either losartan or captopril. In this study PIIINP showed no prognostic value. The same authors (Manhenke et al., 2014) analyzed 42 patients with first-time mmyocardial infarction that produced ST-elevation in an electrocardiogram. The patients underwent percutaneous coronary intervention with stent implantation. In agreement with their earlier study, PIIINP levels stayed within normal limits during the entire time. There was, however, an increase in PIIINP levels during the first two days after the infarction, but the levels did not exceed the normal limits.

In 2012, Fertin et al (2012) carried out a systematic review on 59 published studies (Fertin et al., 2012) investigating the usefulness of biomarkers predicting which myocardial infarction patients develop left ventricular remodeling that leads to heart failure. PIIINP was one of the biomarkers studied, but it was measured in only three studies for a total of 210 patients. In all three studies the serum PIIINP levels were correlated with left ventricular remodeling.

7.3.2. Other diseases

The histological hallmarks of chronic renal failure are glomerulosclerosis and tubulointerstial fibrosis due to the accumulation of connective tissue proteins (Soylemezoglu et al., 1997). Based on histological analyses tubular epithelial cells in patients with diabetic nephropathy synthesize increased amounts of type III collagen (Razzaque et al., 1995). Individual studies on renal fibrosis have concluded that PIIINP levels in the urine and serum correlate with the amount of fibrosis present in the kidneys (Soylemezoglu et al., 1997). A recent systematic review (Mansour et al., 2017) that included only studies in which renal biopsy was used to verify the kidney disease, however, concluded that PIIINP levels were not independently associated with a chronic kidney disease after adjusting for proteinuria. In another communitybased study of 958 individuals ≥65 years, urine PIIINP levels were found to increase with the progression of the kidney disease and higher PIIINP levels were also associated with death (Ix et al., 2015).

For liver diseases, PIIINP assay is part of the “Enhanced Liver Fibrosis” (ELF) panel, which includes assays for three molecules: hyaluronic acid, PIIINP, and tissue inhibitor of matrix metalloproteinase-1 (Tanwar et al., 2017). The ELF panel has been used as a surrogate marker of liver fibrosis allowing a minimally invasive blood sampling method to be used instead of obtaining a liver biopsy (Tanwar et al., 2017). ELF score and PIIINP levels were also shown to be correlated with skin and lung fibrosis in patients with systemic sclerosis (Abignano et al., 2019).

Collagen accumulation and metabolism has also been studied extensively in fibrotic lung diseases. For example, Kirk et al. (Kirk et al., 1984) carried out a study on patients diagnosed with cryptogenic fibrosing alveolitis. They showed that the serum PIIINP concentrations were increased in these patients compared to normal controls or patients with non-fibrotic lung diseases. With biochemical analyses of lung tissue samples they were able to demonstrate that the serum PIIINP levels correlated with the type III to type I collagen ratios in the lung. Interestingly, those patients with the highest serum PIIINP levels before the treatment had the best response to treatment measured by improvements in lung function tests forced vital capacity and transfer coefficient values.

Another disease with type III collagen accumulation is Dupuytren’s disease, in which type III collagen is present in increased amounts in the aponeurosis (Menzel et al., 1979; Somers et al., 1989). Collagen III accumulation has been seen in yet another fibrotic condition called Peyronie’s disease, in which scar tissue forms in the tunica albuginea of the penis as a result of currently unknown mechanism and leads to a severely impaired function (Somers et al., 1989).

Elevated levels of type III collagen have also been seen in patients with Crohn’s disease. One study showed increased amounts of type III collagen in fibroblast cultures originating from patients’ intestine (Stallmach et al., 1992). In another study C3M levels were higher in serum samples from patients with the penetrating form of Crohn’s disease indicating increased breakdown of type III collagen by matrix metalloproteinase 9 (van Haaften et al., 2017). The best marker to differentiate between the different subtypes of Crohn’s disease was the ratio of type III collagen to C3M, reflecting an imbalance between the synthesis and the breakdown of type III collagen. Another study was able to differentiate between Crohn’s disease and ulcerative colitis using serum biomarkers including the C3M assay (Mortensen et al., 2015).

Type III collagen expression has also been studied in non-fibrotic diseases. In a study that investigated 33 patients with hyperthyroidism, the serum levels of PIIINP were found to be elevated compared to 26 controls (Inui et al., 1992). The authors pointed out that the liver function of these patients was normal.

Aigner et al (Aigner et al., 1993) had an unexpected finding in that type III collagen was present in dedifferentiated chondrocytes in cartilage samples taken from patients with late stage osteoarthritis, when the well-established expression profile of chondrocytes includes type II, IX and XI collagens, but no type III collagen. In this study immunostaining was used to investigate protein expression and in situ RNA hybridization to determine the location and extent of mRNA expression. Interestingly, these cells also expressed type II collagen, but no type I collagen. Normal chondrocytes did not express any type III collagen (Aigner et al., 1993). Another group, however, detected type III collagen even in normal human articular cartilage specimens taken from individuals between ages 17 and 81 years (Wotton and Duance, 1994).

Type III collagen expression has also been evaluated in cancer. In one study where 33 glioma tissues samples were analyzed, a significant increase in COL3A1 mRNA levels was found and the increased expression correlated with the tumor grade with high grade gliomas showing the highest levels of expression (Gao et al., 2018). Immunohistological staining of glioma tissues demonstrated the same results on the protein level. In follow-up studies in which COL3A1 expression in a cell culture system was silenced by siRNA, the proliferation and migration of glioma cells was suppressed.

In another cancer study, overexpression of COL3A1 was found to be associated with a poor prognosis of bladder cancer (Yuan et al., 2017). Similarly, increased levels of PIIINP were associated with a poor prognosis and a shorter overall survival of breast cancer patients (Lipton et al., 2018).

8. 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.

Table 3.

Comparison of Col3a1 models

Feature	Col3a1 KO	Col3a1 deletion	Transgenic with Gly182Ser mutation	Tsk/+ (Cys-to-Ser in PIIINP)
Original publication	Liu et al. 1997 (Liu et al., 1997)	Smith et al. 2011 (Smith et al., 2011)	D’hondt et al. 2018 (D’Hondt et al., 2018)	Long et al. 2015 (Long et al., 2015)
Method used to create model	Homologous recombination with a targeting vector that contains neo resulting in a deletion of the promoter and exon 1 sequences	Deletion occurred spontaneously; 185 kb; removes Col3a1 promoter and exons 1–39	Transgenic mouse lines with and without Gly182Ser mutation to overexpress Col3a1	Mutagenesis with ethylnitrosurea
Phenotype in homozygous mice	Early death in 95%; remaining 5% had arterial aneurysm and rupture at age 6 months	Early death	Mice overexpressing Col3a1 with Gly182Ser mutation die at 13–14 weeks due to severe skin wounds	Embryonic death
Phenotype in heterozygous mice	Appeared grossly normal; but stress test showed decreased strength in aorta and bowel	28% have thoracic aortic dissection		Tight skin resembling systemic sclerosis in humans
Vascular phenotype	Arterial aneurysm and rupture at age 6 months	Thoracic aortic dissection (no aneurysm) in 28% of heterozygote mice	Grossly normal, but in stress test aorta showed reduced tensile strength
Bowel phenotype	Enlarged with spontaneous rupture	Normal	Normal	Normal
Skin phenotype	Severe wounds	Normal	Thin and fragile with severe wounds in male mice	Tight skin resembling systemic sclerosis in humans
Light microscopy findings	Heterozygote mice have reduced amount of collagen and fragmentation of internal elastic lamina in aorta	Heterozygote mice have reduced amount of collagen	Thinner aortic adventitia	Excessive deposition of ECM proteins in skin
Electron microscopy findings	Abnormal type I collagen fibrils	Abnormal collagen fibrils	Abnormal collagen fibrils	Thick collagen fibrils
Biochemical analyses	Col3a1 mRNA levels decreased	Col5a1 and Tgfβ mRNA levels normal	Less Col3a1 protein in transgenic Gly182Ser mice; thermal stability normal	Col3a1 mRNA levels increased
Differences between male and female mice	Males more often affected	Male mice died of dissection twice as frequently as female mice	Male transgenic mice express more Col3a1

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EMC, extracellular matrix; KO, knockout

8.1. Inactivation by knockout of the murine Col3a1 gene

Inactivation of the murine Col3a1 gene was carried out by homologous recombination in embryonic stem cells using a targeting vector in which the Col3a1 promoter and the first exon were deleted and replaced by the neomycin gene (Liu et al., 1997). Approximately 95% of the homozygous mutant mice died early on, with most deaths occurring in the first two days after birth, but heterozygous mice appeared phenotypically normal (Liu et al., 1997). The homozygous mice that survived were smaller than their wild-type littermates, and they died at the age of about 6 months from a rupture of major arteries or the bowel, mimicking the human vEDS phenotype. These mice also had skin lesions, such as open wounds. Histological analysis using light microscopy did not reveal any obvious abnormalities in the analyzed tissues. Electron microscopy, however, demonstrated abnormal collagen fibers in the skin, aorta, liver, lung, heart and bowel (Liu et al., 1997). These studies provided important information to our basic understanding of the fibrillogenesis of collagen by demonstrating that lack of type III collagen led to disorganized type I collagen fibrils with variable diameters (Liu et al., 1997). Type III collagen thus appears to regulate the type I collagen fibril formation.

The homozygous Col3a1^−/− mice were also studied for potential brain defects, since COL3A1 is a ligand for GPR56, which harbors mutations in patients with bilateral frontoparietal polymicrogyria, a severe brain malformation (Jeong et al., 2012). In histological analyses all Col3a1^−/− mice showed a severe malformation of the brain cortex at E18.5. The defects were described as cobblestone like cortical malformations and included pial breakdown in the basement membrane, neuronal overmigration, radial glial detachment, and formation of marginal zone heterotopias. None of the heterozygous Col3a1^+/− or wildtype mice had these malformations. Based on these findings, type III collagen appears to be important for brain development.

The heterozygous mutant mice of the same Col3a1 knock-out mouse model were studied further by Cooper et al. (Cooper et al., 2010). Less collagen and reduced amounts of Col3a1 mRNA were found in the abdominal aorta and the wall strength was reduced. Similarly, the bowel walls from these mice showed increased compliance and decreased strength, which was tested by applying pressure and determining when the bowel wall burst. Histological lesions found in the internal elastic lamina of the aortae were more severe in older mice and more common in male mice (Cooper et al., 2010). In conclusion, the heterozygous mice lack the clinical features of vEDS, but do display several histological signs of Col3a1 deficiency. A 9month doxycycline treatment of heterozygous (Col3a1^+/−) mice reduced the number of histological lesions in the aorta (Tae et al., 2012). This was most likely due to a decrease in Mmp9 expression, since doxycycline is a known inhibitor of MMPs.

The Col3a1 knock-out mouse model has been studied for many different organ systems and biological processes including the bladder function and healing of bone fractures. The amount of type III collagen was reduced and the collagen fiber diameter more varied in the bladder tissues of Col3a1^+/−mice compared to wild-type mice (Stevenson et al., 2006). In functional tests using bladder muscle strips removed from the mice, the muscle removed from heterozygous mice generated less tension and were more compliant suggesting that there is a critical level of type III collagen required for normal bladder function.

A detailed analysis of the skeletons of the wild-type, Col3a1^+/− and Col3a1^−/− mice at age 6–8 weeks was carried out using microcomputer tomography (Volk et al., 2014). The results demonstrated a reduction in several bone phenotypes including the bone volume, bone volume fraction, connectivity density, structure model index and trabecular thickness in the Col3a1^+/− compared to the wild-type mice. In cell culture experiments, mesenchymal progenitor cells isolated from the Col3a1^−/− mice had decreased activity of alkaline phosphatase and impaired mineralization. The authors concluded that these findings implied that type III collagen is involved in the formation of the trabecular bone. Furthermore, using a bilateral tibial fracture model in the heterozygous (Col3a1^+/−) mice reduced levels of Col3a1 were shown to impair the bone formation and alter remodelling during the healing of the fractures (Miedel et al., 2015). Based on immunofluorescent staining, fracture callus contained considerable amounts of type III collagen, whereas very little or no type III collagen was detected in the uninjured cortical bone.

8.2. A large deletion of the murine Col3a1 gene

Another mouse model with a large 185-kb deletion encompassing the promoter region and the first 39 exons of the Col3a1 gene was first discovered by its phenotype of sudden deaths due to thoracic aortic dissections (Smith et al., 2011). The underlying genetic defect in these mice was detected by genetic mapping and DNA sequencing. In follow-up studies investigating 225 mice heterozygous for the deletion, aortic dissection was seen in 28% and it was twice as common in male as female mice. No skin or bowel problems were detected in any of the mice. Mice homozygous for the deletion appeared to die before birth, since no homozygous mice were found. Histological analyses of the aortic wall showed reduced amounts of collagen in the media, but not in the adventitia layer. Transmission electron microscopy images demonstrated abnormal collagen fibers (Smith et al., 2011).

8.3. Transgenic mice overexpressing a mutated form of Col3a1

The third currently available mouse model includes transgenic mice overexpressing Col3a1 with a Gly182Ser mutation (D’Hondt et al., 2018). A control transgenic mouse line overexpressing the normal Col3a1 was also produced. The mice with the Gly182Ser transgene developed severe skin wounds, demonstrated vascular fragility in the form of reduced tensile strength and died prematurely at the age of 13–14 weeks (D’Hondt et al., 2018). Both skin and aorta contained abnormal collagen fibrils, and there was less type III collagen in the aortic wall (D’Hondt et al., 2018). The collagen type III:I ratio in the skin changed from 0.5 in the nontransgenic mice to 1.0 in the transgenic mice overexpressing normal Col3a1, to 0.3 in the transgenic mice with the Gly182Ser mutation. There were no differences in the extent of posttranslational modifications or the thermal stability of the collagens produced between the two transgenic mouse lines (D’Hondt et al., 2018). The diameter of collagen fibers was more variable and the fibers were generally thicker in the Gly182Ser transgenic mice than in the other mouse lines.

8.4. Tsk2/+ mice with a missense mutation

The tight skin (Tsk2/+) mice resemble the human disease systemic sclerosis. They were identified in a screening after mutagenic agent ethylnitrosurea was used to generate mutations in the mouse genome (Long et al., 2015). The defect was genetically mapped to mouse chromosome 1, which harbors Col3a1. Sequencing of RNA and genomic DNA identified a total of 265 sequence variants in both wild-type and Tsk2/+ mice and they were thus excluded from further analyses. Thirteen sequence variants were found in all four Tsk2/+ mice, but ten of them were also found in another strain of mice and were excluded. Of the remaining three sequence variants present only in the Tsk2/+ mice, two were in introns, and one was a missense variant in Col3a1 that converted a cysteine to a serine in the N-terminal propeptide. This Cys-to-Ser change mutates one of the cysteine residues that are normally part of intrachain disulphide bonds. Based on the RNA-sequencing data, Col3a1 had the highest number of reads from the genes located in the candidate interval, indicating that its expression was increased, which is in agreement with previous biochemical studies. Complementation experiments were carried out in which the Tsk2/+ mice were crossed with Col3a1^−/+ mice to prove that the sequence variant found in Col3a1 is Tsk2. The result showed that the Tsk2 gene was not able to rescue the Col3a1-knockout phenotype.

9. 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 amounts of type III collagen are found in many acquired human fibrotic diseases such as kidney and liver fibrosis, and systemic sclerosis. Type III collagen is known to interact with type I and II collagens in the fibril formation and is an important regulator of fibril diameter; increase in type III collagen content will lead to the formation of thinner fibrils. Type III collagen is also a critical component in platelet aggregation and thus initiating the blood clotting cascade.

There are still several unanswered questions about the function of type III collagen, e.g., what are the molecules it interacts with, is it possible to create a computational model that predicts the effects of a COL3A1 mutation accurately, and how do we prevent overexpression of type III collagen and fibrotic processes. It is also not clear why some COL3A1 mutations lead to vEDS, whereas others manifest as a severe brain abnormality. The classic vEDS manifests as an autosomal dominant disease, but in the case of the brain abnormality, all reported cases have had two mutant COL3A1 alleles suggesting an autosomal recessive inheritance pattern. To facilitate answering these important research questions with implications to human health, additional animal models are required.

Supplementary Material

NIHMS1529799-supplement-1.xlsx^{(63KB, xlsx)}

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.

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 South African Tuberculosis Bioinformatics Initiative (SATBBI), a Strategic Health Innovation Partnership grant from the South African Medical Research Council and South African Department of Science and Technology.

The authors are grateful to the two anonymous expert reviewers for helpful suggestions.

The corresponding Gene Wiki entry for this review can be found here: https://en.wikipedia.org/wiki/Collagen,_type_III,_alpha_1

List of abbreviations

A: adenosine
aa: amino acid(s)
Alu: a type of repeat sequence in the genome
Arg428Stop: an arginine at amino acid position 428 has changed to a stop codon
Arg1432Leu: an arginine at amino acid position 1432 has changed to a leucine
AT: a type of repeat sequence in the genome
bFGF: basic fibroblast growth factor
bp: base pair(s)
C: cytidine
C3C: fragments of type III collagen generated by digestion with cathepsins B, L, S, and K
C3M: a 10-aa neopeptide of type III collagen generated by digestion with matrixmetalloproteinase 9
CCDS: Consensus Coding Sequence
CDS: coding seqeunce
COPD: chronic obstructive pulmonary disease
C-terminal: carboxyterminal
cDNA: DNA complementary to RNA
E18.5: developmental stage of a mouse embryo at 18.5 days
ECM: extracellular matrix
EGF: epidermal growth factor
ELF: enhanced liver fibrosis, a panel of three biomarkers for liver fibrosis
ELISA: enzyme-linked immunosorbent assay
EM: electron microscope
G: guanosine
Gly182Ser: a glycine at amino acid position 182 has changed to a serine
Gly237Arg: a glycine at amino acid position 237 has changed to an arginine
Gly612Asp: a glycine at amino acid position 612 has changed to an aspartic acid
Gly-Xaa-Yaa: a triplet in the triple-helical domain of type III collagen showing glycine as every third amino acid
GRCh38: Genome Reference Consortium Human Build 38
GRCm38: Genome Reference Consortium Mouse Build 38
GRP56: G protein-coupled receptor 56
HGNC: Human Genome Nomenclature Committee
HIF-1α: hypoxia-inducible factor alpha 1
hnRNP: heterogeneous nuclear ribonucleoprotein
ICD-10: International Classification of Diseases 10^th revision
IHC: immunohistochemistry
kb: kilobase(s) or 1000 bp
kDa: kilodalton(s)
KO: knock-out
LINE: a type of repeat sequence in the genome
Lys1313Arg: a lysine at amino acid position 1313 has changed to an arginine
MAPK: mitogen-activated protein kinase
MGI: Mouse Genome Informatics
mTOR: mammalian target of rapamycin
NCBI: National Center for Biotechnology Information
NEDD9: neural precursor cell expressed, developmentally down-regulated 9
nt: nucleotide(s)
N-terminal: aminoterminal
OMIM: online inheritance in man database
PIIINP: aminoterminal propeptide of type III procollagen
polyA: polyadenylation site
Pro49Ala: a proline at amino acid position 49 has changed to an alanine
Pro686: a proline at amino acid position 686
Pro1440Leu: a proline at amino acid position 1440 has changed to a leucine
qRT-PCR: quantitative reverse transcriptase polymerase chain reaction
RIA: radioimmunoassay
T: thymidine
TGFβ: transforming growth factor beta
Tsk2/+: tight skin mouse with a mutation in Col3a1
UTR: untranslated region(s)
vEDS: vascular Ehlers-Danlos syndrome

Footnotes

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Conflict of interest statement

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PERMALINK

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

Helena Kuivaniemi

Gerard Tromp

Abstract

1. Introduction

Table 1.

2. Chromosomal location and intron-exon organization of COL3A1 and Col3a1

Fig. 1.

Fig. 2.

3. Protein structure

3.1. Biosynthesis of type III preprocollagen

Fig. 3.

3.2. Structure of type III preprocollagen, procollagen and collagen

Fig. 4.

4. Tissue distribution

Fig. 5.

5. Function

6. Regulation of COL3A1 expression

7. Diseases associated with COL3A1 mutations and variants, or altered levels of COL3A1 protein

7.1. COL3A1 defects in patients with vEDS and other forms of EDS

7.1.1. Protein analyses with skin fibroblasts taken from patients with vEDS

Fig. 6.

7.1.2. DNA analyses and a mutation database for patients with vEDS

7.1.3. Mutations in the C-propeptide of COL3A1

7.1.4. RNA splicing mutations in COL3A1

Fig. 7.

7.1.5. Germline and somatic cell mosaicism in the relatives of patients with COL3A1 mutations

7.1.6. Biochemical and cellular effects of COL3A1 mutations

7.1.7. Genotype-phenotype correlations among vEDS patients

7.2. Genetic studies for other human diseases

7.2.1. COL3A1 mutations in patients with brain disorders

7.2.2. Studies for other human diseases using COL3A1 genetic variants

7.3. Altered COL3A1 mRNA and protein levels, or degradation in human diseases

Table 2.

7.3.1. Cardiac diseases

7.3.2. Other diseases

8. Col3a1 mutant mice

Table 3.

8.1. Inactivation by knockout of the murine Col3a1 gene

8.2. A large deletion of the murine Col3a1 gene

8.3. Transgenic mice overexpressing a mutated form of Col3a1

8.4. Tsk2/+ mice with a missense mutation

9. Conclusions

Supplementary Material

Highlights.

Acknowledgments

List of abbreviations

Footnotes

References

Associated Data

Supplementary Materials

ACTIONS

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