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Collagen, type III, alpha 1
Collagen, type III, alpha 1
Collagen, type III, alpha 1
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COL3A1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCOL3A1, EDS4A, collagen type III alpha 1, collagen type III alpha 1 chain, EDSVASC, PMGEDSV
External IDsOMIM: 120180; MGI: 88453; HomoloGene: 55433; GeneCards: COL3A1; OMA:COL3A1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1281

12825

Ensembl

ENSG00000168542

ENSMUSG00000026043

UniProt

P02461

P08121

RefSeq (mRNA)

NM_000090
NM_001376916

NM_009930

RefSeq (protein)

NP_000081

NP_034060

Location (UCSC)Chr 2: 188.97 – 189.01 MbChr 1: 45.35 – 45.39 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Type III Collagen is a homotrimer, or a protein composed of three identical peptide chains (monomers), each called an alpha 1 chain of type III collagen. Formally, the monomers are called collagen type III, alpha-1 chain and in humans are encoded by the COL3A1 gene. Type III collagen is one of the fibrillar collagens whose proteins have a long, inflexible, triple-helical domain.[5]

Gene

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The COL3A1 gene is located on the long (q) arm of chromosome 2 at 2q32.2, between positions 188974372 and 189012745. The gene has 51 exons and is approximately 40 kbp long.[6] The COL3A1 gene is in tail-to-tail orientation with a gene for another fibrillar collagen, namely COL5A2.[6]

Two transcripts are generated from the gene using different polyadenylation sites. [7] Although alternatively spliced transcripts have been detected for this gene, they are the result of mutations; these mutations alter RNA splicing, often leading to the exclusion of an exon or use of cryptic splice sites.[8][9][10] The resulting defective protein is the cause of a severe, rare disease, the vascular type of Ehlers-Danlos syndrome (vEDS). These studies have also provided important information about RNA splicing mechanisms in multi-exon genes.[10][8]

Tissue distribution

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Type III collagen is found as a major structural component in hollow organs such as large blood vessels, uterus and bowel. It is also found in many other tissues together with type I collagen.

Structure

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Type III collagen is synthesized by cells as a pre-procollagen.[11]

The signal peptide is cleaved off producing a procollagen molecule. Three identical type III procollagen chains come together at the carboxy-terminal ends, and the structure is stabilized by the formation of disulphide bonds. Each individual chain folds into a left-handed helix and the three chains are then wrapped together into a right-handed superhelix, the triple helix. 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)-terminal-proteinases 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.

The triple-helical conformation, which is a characteristic feature of all fibrillar collagens, is possible because of the presence of glycine as every third amino acid in the sequence of about 1000 amino acids. When the right-handed super-helix is formed, the glycine residues of each of the monomers are positioned at the center of the super-helix (where the three monomers "touch"). Each left-handed helix is characterized by a complete turn in about 3.3 amino acids. The periodicity induced by the glycines at non-integer spacing results in a super-helix that completes one turn in about 20 amino acids. This (Gly-X-Y)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.

Function

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In addition to being an integral structural component of many organs, type III collagen is also an important regulator of the diameter of type I and II collagen fibrils. Type III collagen is also known to facilitate platelet aggregation through its binding to platelets and therefore, play an important role in blood clotting.

Clinical significance

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Mutations in the COL3A1 gene cause Ehlers-Danlos syndrome, vascular type (vEDS; also known as the EDS type IV; OMIM 130050). It is the most severe form of EDS, since patients often die suddenly due to rupture of large arteries or other hollow organs.[12]

A few patients with arterial aneurysms without clear signs of EDS have also been found to have COL3A1 mutations.[13][14][15]

More recently, mutations in COL3A1 have also been identified in patients with severe brain anomalies suggesting that type III collagen is important for the normal development of the brain during embryogenesis.[16][17][18][19] This disease is similar to that caused by mutations in GRP56 (OMIM 606854). Type III collagen is a known ligand for the receptor GRP56.

The first single base mutation in the COL3A1 gene was reported in 1989 in a patient with vEDS and changed a glycine amino acid to a serine[20] Since then, over 600 different mutations have been characterized in the COL3A1 gene.[21] About 2/3 of these mutations change a glycine amino acid to another amino acid in the triple-helical region of the protein chain.[12] A large number of RNA splicing mutations have also been identified.[10][8] Interestingly, most of these mutations lead to exon skipping, and produce a shorter polypeptide, in which the Gly-Xaa-Yaa triplets stay in frame and there are no premature termination codons.

The functional consequences of COL3A1 mutations can be studied in a cell culture system. A small bunch biopsy of skin is obtained from the patient and used to start the culture of skin fibroblasts which express type III collagen.[13] The type III collagen protein synthesized by these cells can be studied for its thermal stability. In other words, the collagens can be subjected to a short digestion by proteinases called trypsin and chymotrypsin at increasing temperatures. Intact type III collagen molecules, which have formed a stable triple helix, can withstand such treatment till about 41 °C, whereas molecules with mutations that lead to glycine substitutions fall apart at a much lower temperature.

It is difficult to predict the clinical severity based on the type and location of COL3A1 mutations.[22][23] Another important clinical implication is that several studies have reported on mosaicism.[12][24] This refers to a situation where one of the parents carries the mutation in some, but not all of her or his cells, and appears phenotypically healthy, but has more than one affected offspring. In such a situation the risk for another affected child is higher than in a genotypically normal parent.[25]

Type III collagen could also be important in several other human diseases. Increased amounts of type III collagen are found in many fibrotic conditions such as liver and kidney fibrosis, and systemic sclerosis.[26][27][28][29][30][31] This has led to a search for serum biomarkers that could be used for diagnosing these conditions without having to obtain a tissue biopsy. The most widely used biomarker is the N-terminal propeptide of type III procollagen, which is cleaved off during the biosynthesis of type III collagen.[32]

Animal models

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Four different mouse models with COL3A1 defects have been reported.[33][34][35][36] Inactivation of the murine COL3A1 gene using homologous recombination technique led to a shorter life span in homozygous mutant mice. The mice died prematurely from a rupture of major arteries mimicking the human vEDS phenotype. These mice also had a severe malformation of the brain. Another study discovered mice with a naturally occurring large deletion of the COL3A1 gene. These mice died suddenly due to thoracic aortic dissections. The third type of mutant mice were transgenic mice with a Gly182Ser mutation. These mice developed severe skin wounds, demonstrated vascular fragility in the form of reduced tensile strength and died prematurely at the age of 13–14 weeks. The fourth mouse model with defective COL3A1 gene is the tight skin mouse (Tsk2/+), which resembles the human systemic sclerosis.

See also

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Notes

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References

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Further reading

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Collagen, type III, alpha 1

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Collagen, type III, alpha 1, encoded by the COL3A1 , is a critical component of the in vertebrates, forming the alpha-1 chain of , a fibrillar that provides structural support and elasticity to extensible connective tissues such as , blood vessels, lungs, and intestines. This homotrimeric protein consists of three identical pro-alpha1(III) chains that assemble into triple-helical structures, which are subsequently processed into mature collagen fibers through enzymatic cleavage and cross-linking. The COL3A1 is located on 2q32.2 and spans approximately 38 kb, containing 52 exons that encode a precursor protein of 1,466 . is expressed widely during embryonic development and in adult tissues, with particularly high levels in the , , and vascular systems, where it often coexists with to form hybrid that enhance tissue resilience. It plays essential roles in organization, assembly, and integrin-mediated signaling pathways, contributing to tissue integrity and . Mutations in COL3A1 are primarily associated with vascular Ehlers-Danlos syndrome (type IV, EDS IV), an autosomal dominant connective tissue disorder characterized by fragile blood vessels, thin skin, easy bruising, and life-threatening complications such as arterial rupture and organ perforation. Over 500 distinct mutations, including glycine substitutions in the triple-helical domain, exon skipping, and large deletions, have been identified, leading to abnormal collagen secretion, reduced fibril stability, or dominant-negative effects. Additionally, COL3A1 variants are implicated in aortic and arterial aneurysms, as well as rare conditions like polymicrogyria with or without vascular EDS, highlighting its importance in vascular and neural development. Animal models, such as Col3a1-null mice, recapitulate these phenotypes, demonstrating spontaneous vascular ruptures and brain malformations that underscore the gene's conserved role in connective tissue homeostasis.

Genetics

Gene Location and Organization

The is located on the long arm of human at cytogenetic band 2q32.2, with genomic coordinates spanning 188,974,373 to 189,012,746 (GRCh38.p14). This positioning places it within a region associated with connective tissue-related traits, though specific neighboring genes include those involved in diverse cellular processes. The gene encompasses approximately 38 kb of genomic sequence and comprises 51 exons, conventionally numbered 1 through 52 to facilitate comparison with other fibrillar genes such as COL1A1 and COL1A2. Exon sizes range from 45 (e.g., exons 13, 15, 18, and 30) to 1,105 (exon 52, the largest), with all exons except exon 2 initiating with a complete codon; those encoding the triple-helical domain uniformly begin with a codon. Intron lengths vary significantly, from a minimum of 85 bp to a maximum of about 11.5 kb, reflecting the intricate splicing required for pro transcript maturation. The core triple-helical domain, characterized by the repeating Gly-Xaa-Yaa motif essential for fibril formation, is primarily encoded by s 7 through 49, encompassing 43 s that contribute to the ~1,000-amino-acid helical region. The COL3A1 gene exhibits strong evolutionary conservation across mammalian species, underscoring its fundamental role in integrity; for instance, the protein sequence shares approximately 97% identity with the orthologous Col3a1 gene in (Mus musculus). This high similarity extends to bovine and other mammals, with phylogenetic analyses indicating a shared ancestral origin among fibrillar collagens, as evidenced by conserved exon-intron boundaries and functional domains.

Variants and Mutations

The COL3A1 gene, encoding the alpha-1 chain of type III , harbors a variety of pathogenic variants primarily associated with autosomal dominant disorders such as vascular Ehlers-Danlos syndrome (vEDS). The most common variant type consists of substitutions within the triple-helical domain, which disrupt the Gly-X-Y repeat motif essential for fibril formation; these missense mutations account for over 60% of reported cases. Other notable types include mutations that introduce premature stop codons, splice-site alterations leading to aberrant mRNA processing and , and rare structural variants such as in-frame duplications that insert sequences without shifting the . Databases like ClinVar document approximately 600 unique pathogenic variants in COL3A1 as of June 2025, with likely pathogenic variants bringing the total for likely pathogenic or pathogenic to around 700; approximately 90% localized to exons 6 through 47, which encode the triple-helical region crucial for assembly. substitutions predominate in this domain, comprising the majority of missense changes, while variants represent about 5-10% and splice-site variants about 15-20% of the total. These frequencies highlight the gene's mutational hotspot in the helical coding sequence, where even subtle alterations can profoundly affect protein function. At the molecular level, glycine substitutions in the triple-helical domain typically exert dominant-negative effects by incorporating mutant chains into heterotrimers, thereby destabilizing the overall helix structure and impairing fibril cross-linking. In contrast, nonsense mutations and certain splice-site variants often result in haploinsufficiency through nonsense-mediated decay or production of truncated proteins incapable of secretion, reducing functional type III collagen by about 50%. Rare in-frame duplications, such as those recently identified, can locally perturb helix folding and cleavage sites for matrix metalloproteinases, further compromising extracellular matrix integrity without causing complete loss of function. Representative examples include the missense variant c.2476G>A (p.Gly826Ser), a glycine substitution in the helical domain linked to vEDS through helix destabilization. More recently, a 2025 study reported an 18-nucleotide in-frame duplication c.2868_2885dup (p.Leu958_Gly963dup), which inserts a Leu-Ala-Gly-Pro-Pro-Gly sequence and alters collagen turnover near proteolytic sites. These cases underscore the spectrum of mutational mechanisms in COL3A1.

Molecular Biology

Protein Structure

The pro-α1(III) chain, encoded by the COL3A1 gene, is a 1,466-amino-acid polypeptide that serves as the precursor to the mature α1(III) chain of type III collagen. This primary structure is organized into three distinct regions: an N-terminal propeptide encompassing residues 1–257, a central collagenous domain spanning residues 258–1243, and a C-terminal propeptide. The N- and C-terminal propeptides are non-collagenous globular domains that facilitate intracellular folding and assembly, while the central domain defines the characteristic fibrillar nature of the protein. The central region consists of approximately 329 repeating Gly-X-Y triplets, where glycine occupies every third position to enable tight packing in the helical core, X is predominantly proline (about 20–25% of residues), and Y is frequently hydroxyproline, contributing to structural stability through stereoelectronic effects. In terms of secondary and tertiary structure, the collagenous domain adopts a left-handed polyproline II-type , with each chain twisting at approximately 3 residues per turn and a rise of 0.29 nm per residue along the axis. Three pro-α1(III) chains associate in register via interchain hydrogen bonds involving the NH groups and the backbone carbonyls of X positions in adjacent chains, forming a right-handed supercoiled with a diameter of about 1.5 nm and a length of roughly 300 nm in the mature form. This homotrimeric [α1(III)]₃ assembly is the predominant quaternary structure for type III collagen, though heterotrimers incorporating α1(III) and α1(I)/α2(I) chains from can occur in certain tissues, influencing diameter and elasticity. The exhibits periodic variations in symmetry, such as 7/2 or 10/3 helical repeats over short segments, which arise from ( and ) distribution and affect local flexibility.60441-0/fulltext) Post-translational modifications are essential for stabilizing the triple-helical structure and enabling higher-order assembly. residues in the Y position are hydroxylated to 4-hydroxyproline by prolyl 4-hydroxylase (P4H), and residues are hydroxylated to hydroxylysine by lysyl hydroxylase (LH), both enzymes requiring (vitamin C) as a cofactor to maintain iron in the ; deficiencies in these modifications lead to unstable helices prone to overmodification or degradation. Approximately 10% of hydroxylysines in the central domain are further glycosylated with or glucosylgalactose, adding bulk and potentially modulating interchain interactions. Additionally, lysyl oxidase catalyzes the oxidative deamination of specific and hydroxylysine residues near the N- and C-termini to form aldehydes, which spontaneously condense into covalent cross-links such as aldimines or aldols, enhancing tensile strength during extracellular maturation.82649-7/fulltext) Structural insights into the triple-helical domain have been derived from crystallographic studies of synthetic peptides mimicking COL3A1 sequences. For instance, the PDB entry 1BKV represents a 21-residue peptide from human type III collagen (corresponding to a Gly-X-Y segment), revealing how sequence variations induce local bends and imino-poor regions that propagate flexibility along the helix, with interchain hydrogen bonding patterns confirming the canonical triple-helical geometry. These models highlight the rod-like rigidity of the domain while underscoring its capacity for subtle conformational adaptations essential for fibril packing.

Biosynthesis and Assembly

The biosynthesis of collagen type III alpha 1 (COL3A1) begins with transcription of the COL3A1 gene, located on chromosome 2q32.2, into a 5.5 kb mRNA that encodes a 1466-amino-acid pre-pro-alpha1(III) chain. This mRNA is translated by ribosomes on the rough (ER), where the nascent polypeptide is translocated into the ER lumen, and the 24-amino-acid is cleaved to yield the pro-alpha1(III) chain. In the ER, the pro-alpha1(III) chains undergo essential post-translational modifications, including hydroxylation of proline and lysine residues by prolyl 4-hydroxylase and lysyl hydroxylase enzymes, respectively, which require ascorbic acid () as a cofactor; approximately 145 of 239 proline residues are converted to 4-hydroxyproline to stabilize the subsequent . Selected hydroxylysine residues are further glycosylated with and glucose, contributing to chain and assembly fidelity. Three pro-alpha1(III) chains then associate via their C-terminal propeptides, initiating trimer formation through interchain bonds that stabilize the complex; this stepwise association starts with folding of the C-propeptides, followed by disulfide linkage at the carboxyl end before progression to the amino end. The forms through a zipper-like folding mechanism from the to the , where each chain adopts a left-handed polyproline II that coils into a right-handed superhelix, facilitated by the repeating Gly-Xaa-Yaa motif and hydrogen bonding between chains; heat shock protein 47 (HSP47) acts as a chaperone to prevent premature aggregation during this process. The completed procollagen trimer, comprising three identical alpha1(III) chains, is transported through the Golgi apparatus and secreted into the via secretory vesicles. Extracellularly, N- and C-terminal propeptides are cleaved by ADAMTS proteinases and , respectively, yielding mature tropocollagen molecules that spontaneously self-assemble in a staggered array into with a characteristic D-period of approximately 67 nm, as observed in electron . Lysyl oxidase then catalyzes oxidative deamination of and hydroxylysine residues in the telopeptides, enabling covalent cross-links such as aldimine bonds that enhance fibril tensile strength. Quality control during biosynthesis occurs primarily in the ER, where misfolded trimers—often due to COL3A1 mutations like Gly619Arg that reduce thermal stability from 41°C to 20–36°C—trigger the unfolded protein response, leading to ER stress, intracellular retention, and potential degradation via ER-associated degradation pathways.

Expression and Distribution

Tissue and Cellular Localization

Type III collagen, encoded by the COL3A1 gene, is predominantly expressed in extensible connective tissues that require flexibility and resilience. It is a major structural component in the dermis of the skin, where it contributes to the suppleness of this layer, as well as in the media of large blood vessels, providing elasticity to arterial walls. High levels are also observed in the alveolar septa of the lungs, the muscularis of the intestines, and the myometrium of the uterus, supporting distensibility in these hollow organs. In contrast, expression is notably lower in rigid tissues such as bone and cartilage, where type I collagen predominates. At the cellular level, COL3A1 is primarily synthesized by fibroblasts, which are the main producers of components in connective tissues. Smooth muscle cells in vascular and visceral structures also express significant amounts, contributing to the matrix surrounding these cells. Myofibroblasts, differentiated fibroblasts involved in tissue repair and , show elevated COL3A1 expression, particularly during processes. Immunohistochemical studies confirm this distribution, with staining prominent in fibroblast-rich regions of the skin and vascular media. Subcellularly, the type III collagen protein is secreted into the , where it assembles into fine reticular fibers that form a supportive network in soft tissues. These fibers often co-localize with , incorporating into heterotypic that enhance overall matrix organization and tensile properties. analyses of and vascular tissues reveal that type III collagen constitutes approximately 20-30% of the total content in these locations, underscoring its quantitative importance in maintaining tissue compliance.

Regulation of Expression

The expression of the COL3A1 gene, encoding the alpha-1 chain of type III collagen, is tightly regulated at the transcriptional level by multiple signaling pathways. signaling plays a central role in upregulating COL3A1 through the activation of Smad proteins, particularly Smad3, which bind to specific sites in the gene's promoter to enhance transcription in fibroblasts. Additionally, the promoter region of COL3A1 contains binding sites for transcription factors AP-1 and Sp1, which collaborate with Smad3 to form regulatory complexes that further modulate expression in response to extracellular cues. During development, COL3A1 exhibits dynamic expression patterns, with high levels in fetal tissues such as and blood vessels to support tissue elasticity and remodeling, followed by a progressive postnatal decrease as predominates in mature extracellular matrices. This temporal regulation is evident in embryonic and neonatal stages, where COL3A1 contributes to early formation, and its downregulation postnatally aligns with tissue maturation and reduced proliferative demands. In processes like , COL3A1 expression is transiently upregulated to facilitate formation and scar resolution, while in fibrotic conditions, sustained elevation promotes excessive matrix deposition. Environmental factors also influence COL3A1 expression. Mechanical stress, such as that experienced by fibroblasts in stretched tissues, engages the /TAZ pathway, which translocates to the nucleus to support remodeling under biomechanical load. Pathological dysregulation often involves COL3A1 overexpression in fibrotic disorders, such as liver and , where elevated levels contribute to accumulation and organ stiffness. In tumors, including non-small cell , COL3A1 upregulation correlates with stromal remodeling that aids tumor progression and invasion. MicroRNAs, notably miR-29 family members, act as suppressors by directly targeting the 3' of COL3A1 mRNA, reducing its expression and thereby mitigating in conditions like .

Function

Role in Extracellular Matrix

Type III collagen, encoded by the COL3A1 gene, plays a pivotal role in the composition and organization of the extracellular matrix (ECM) by forming thin reticular fibers with diameters typically ranging from 10 to 30 nm. These fibers arise from the self-assembly of type III collagen homotrimers and integrate seamlessly with type I collagen fibrils, creating hybrid networks that enhance the overall architecture of the ECM in soft connective tissues. Type III collagen also regulates the diameter and organization of heterotypic fibrils formed with type I collagen, preventing excessive thickening and maintaining tissue flexibility. This interweaving supports the structural integrity of tissues requiring both rigidity and adaptability, such as skin and blood vessels, by preventing excessive bundling of thicker type I fibrils. The biomechanical properties imparted by type III collagen to the ECM include contributions to elasticity and tensile strength, which are modulated by its relative abundance alongside . In tissues like , where type III collagen constitutes approximately 15-20% of the total collagen content, this ratio ensures appropriate compliance and flexibility, allowing the tissue to withstand deformation without fracturing. Higher proportions of type III collagen promote a more elastic network capable of storing , contrasting with the stiffer, load-bearing characteristics dominated by . Type III collagen engages in key interactions with other ECM constituents, binding to to facilitate matrix assembly and , while associating with such as α1β1 and α2β1 to mediate cell-ECM . It also interacts with proteoglycans like , which regulate diameter and spacing during assembly. Furthermore, type III collagen modulates (MMP) activity, serving as a substrate for enzymes like MMP-1 and MMP-8, thereby influencing ECM remodeling and turnover rates. During assembly, type III molecules arrange in a quarter-staggered with adjacent molecules offset by approximately 67 nm (the D-period), leading to overlap and gap zones of roughly 40 nm and 27 nm in the periodic banding pattern. This organization results in a D-banding pattern, with a periodicity of approximately 67 nm, that is prominently visible under (TEM) and reflects the quarter-staggered alignment essential for stability.

Physiological and Pathophysiological Roles

Type III collagen, encoded by the COL3A1 gene, plays essential roles in maintaining tissue integrity and supporting physiological processes across multiple organ systems. In vascular tissues, it provides tensile strength and elasticity to walls, facilitating their ability to withstand hemodynamic stress and contributing to overall vascular . During , type III collagen is a primary component of early , where it forms a provisional matrix that supports migration, , and re-epithelialization; its synthesis predominates in the initial proliferative phase before being gradually replaced by for scar maturation. In organ development, it is critical for the structural formation of tissues such as the lungs, heart valves, and , ensuring proper and functional maturity during embryogenesis. Pathophysiologically, dysregulation of type III collagen contributes to tissue dysfunction through both excess deposition and deficiency. Excessive deposition occurs in fibrotic conditions, such as , where elevated turnover of type III collagen correlates with disease progression and excessive remodeling, leading to stiffening and impaired organ function. Conversely, reduced levels result in tissue fragility; in Col3a1 heterozygous mice, approximately 50% reduction in type III collagen content leads to diminished mechanical properties and increased susceptibility to rupture in vascular and dermal structures. Full models demonstrate severe impacts, with 95% perinatal due to cardiovascular and , underscoring its indispensable role in tissue resilience. Emerging evidence highlights type III collagen's involvement in cancer stroma, where its remodeling facilitates alterations that promote tumor cell invasion and in malignancies such as and cancers. In vascular pathology independent of genetic syndromes, altered type III collagen deposition contributes to formation by compromising arterial wall stability and elasticity. Additionally, it interacts with immune cells during ; for instance, neutrophils degrade type III collagen in inflamed tissues, modulating the inflammatory response and matrix turnover. These roles emphasize type III collagen's dynamic influence on tissue repair and progression.

Clinical Significance

Associated Diseases

Vascular Ehlers-Danlos syndrome (vEDS, OMIM 130050) is the primary disorder associated with pathogenic variants in the COL3A1 gene, an autosomal dominant disorder characterized by fragility of arterial, intestinal, and uterine walls. Key clinical features include arterial rupture or , intestinal , thin translucent with visible veins, easy bruising, and characteristic facial features such as thin lips, prominent eyes, and a pinched . The estimated of vEDS ranges from 1 in 50,000 to 1 in 200,000 individuals, with complications often manifesting in the third or fourth decade of life, though pediatric cases can occur. is reduced, with median survival around 48-51 years, primarily due to vascular events. Beyond vEDS, COL3A1 dysfunction has been linked to familial thoracic aortic aneurysms and dissections, where reduced type III collagen contributes to vessel wall weakening without the full vEDS phenotype. Spontaneous pneumothorax, resulting from lung tissue fragility, affects up to 10-20% of individuals with COL3A1 variants, often as an early presenting feature. Pelvic vessel fragility predisposes to complications such as uterine rupture during pregnancy or obstetric hemorrhage, occurring in approximately 2-5% of pregnancies in affected women. Rare associations include contributions to organ fibrosis, such as in pulmonary or cardiac tissues, where altered COL3A1 expression promotes excessive extracellular matrix deposition. Additionally, emerging evidence implicates COL3A1 dysregulation in cancer progression, particularly in non-small cell lung cancer and breast cancer, where it facilitates tumor invasion and metastasis through matrix remodeling. Genotype-phenotype correlations in COL3A1 variants reveal that missense substitutions affecting residues in the triple helical domain (Gly-X-Y repeats) are the most common and typically cause severe vascular phenotypes, including early arterial ruptures, due to dominant-negative effects on fibril assembly. In contrast, C-terminal mutations, such as nonsense or frameshift variants leading to , often result in milder manifestations with later onset and reduced risk of catastrophic events. Splice-site variants can produce variable severity depending on the degree of abnormal protein incorporation into . The association between COL3A1 and vEDS was first established in the 1970s through clinical descriptions of the vascular subtype (then termed EDS type IV), with molecular confirmation of causative mutations in the late 1970s and 1980s via biochemical and genetic analyses. , often musculoskeletal or neuropathic, and non-rupture gastrointestinal issues such as dysmotility and , are common in vEDS, affecting quality of life in a significant proportion of patients (e.g., chronic pain reported in ~79% in surveys). These findings underscore the need for broader clinical surveillance in COL3A1-related disorders.

Diagnosis, Variants, and Management

Diagnosis of conditions associated with pathogenic variants in the COL3A1 gene, such as vascular Ehlers-Danlos syndrome (vEDS), typically begins with clinical evaluation of suggestive features including arterial fragility, thin translucent , easy bruising, and family history. Confirmation relies on molecular , with next-generation sequencing (NGS) panels targeting collagen genes or single-gene sequencing of COL3A1 detecting over 95% of pathogenic variants, including missense, , splice site changes, and small insertions/deletions. Biochemical analysis in cultured fibroblasts can support by assessing type III procollagen synthesis and ; pulse-chase assays reveal reduced or abnormal of procollagen III in affected individuals. For vascular manifestations, imaging modalities such as , MRI, or CT are used to detect arterial aneurysms, dissections, or ectasias, guiding surveillance and risk assessment. Pathogenic variants in COL3A1 are classified according to the American College of and (ACMG) guidelines, which categorize them as pathogenic or likely pathogenic based on criteria including null variants (e.g., or frameshift) from the last 50 of the penultimate , segregation data, and functional from biochemical assays showing abnormal III production. Over 600 unique COL3A1 variants have been reported, with glycine substitutions in the triple-helical domain often deemed pathogenic due to their disruptive effect on structure. Fibroblast-based III assays provide additional for variant pathogenicity by quantifying reduced levels, complementing genetic findings. Management of COL3A1-related disorders emphasizes multidisciplinary supportive care to mitigate complications from tissue fragility. control is prioritized using beta-blockers like celiprolol, which a demonstrated reduces the rate of arterial events from 7.2 to 2.2 per 100 patient-years ( 0.30, 95% CI 0.09-0.97). As of 2025, phase 3 trials such as DiSCOVER are evaluating celiprolol's efficacy in reducing vascular events in vEDS patients in the . Patients should avoid high-risk activities and invasive procedures, with elective surgeries deferred unless life-threatening; when necessary, interventions require specialized vascular expertise and preoperative imaging. Regular surveillance imaging, including annual MRI or CT of the head, , chest, and , is recommended to monitor for asymptomatic vascular changes. Genetic counseling is essential for families with COL3A1 pathogenic variants, given the autosomal dominant inheritance pattern conferring a 50% recurrence risk to offspring of affected individuals, though up to 50% of cases may arise de novo. Options for prenatal diagnosis via chorionic villus sampling or amniocentesis, and preimplantation genetic testing, are available for at-risk pregnancies following identification of the familial variant. Counseling also addresses variable expressivity and the importance of cascade screening for first-degree relatives.

Research Models and Advances

Animal and In Vitro Models

Animal models have been instrumental in elucidating the role of COL3A1 in integrity, particularly through targeted disruptions in mice. Homozygous Col3a1 null mice exhibit perinatal lethality, with approximately 95% mortality by weaning age and most deaths occurring within 48 hours of birth due to rupture of major blood vessels such as the . Surviving homozygous mutants display thin and fragile with spontaneous lesions in about 60% of cases, as well as disorganized and irregularly sized fibrils in the and vascular walls, closely mimicking the vascular fragility seen in vascular Ehlers-Danlos syndrome (vEDS). Heterozygous Col3a1 null mice, modeling , are viable but develop age-dependent aortic lesions, including dilation and susceptibility, with reduced collagen III content in the contributing to mechanical weakness. These models, first established in the , demonstrated the essential function of type III in fibrillogenesis and cardiovascular development. Conditional knockout models of Col3a1 in mice have been developed to investigate tissue-specific effects, allowing temporal and spatial control of inactivation to bypass embryonic lethality and focus on adult phenotypes in targeted organs like the vasculature or skin. For instance, floxed Col3a1 alleles crossed with tissue-specific lines enable studies of III loss in cells, revealing localized disruptions in assembly and vessel stability without systemic failure. Although models predominate, exploratory work in other species supports vascular studies of Col3a1 function; for example, ongoing efforts to generate mutants in closely related genes (such as col1a2) aim to model vEDS-like phenotypes in a high-throughput system for embryonic vascular development. Rat models have been used in complementary vascular injury studies, where modulation of Col3a1 expression highlights its role in arterial repair and , though dedicated knockouts remain limited. In vitro models complement animal studies by providing insights into cellular mechanisms of COL3A1 dysfunction. Dermal cultures derived from vEDS patients with COL3A1 show significantly reduced of type III collagen, often to 10-20% of normal levels, accompanied by intracellular retention and stress. These cultures exhibit altered deposition, with thinner and disorganized collagen fibrils, enabling direct assessment of effects on protein and . Advanced three-dimensional (3D) systems, such as patient-derived (ECM) scaffolds, have further refined modeling of COL3A1's biomechanical roles. Fibroblasts from individuals with COL3A1 (e.g., G939D) produce ECM with increased compliance, elevated content, and prolonged , leading to impaired endothelial and altered vascular mechanics in vEDS. These 2023 findings underscore how mutant COL3A1 alters ECM stiffness and cellular responses in vascular fragility, offering a platform to test therapeutic interventions without relying on animal systems.

Emerging Research and Therapeutics

Recent studies from 2023 to 2025 have identified COL3A1 as a prognostic biomarker in , where its overexpression correlates with (ECM) stiffening that promotes tumor invasion and immune cell infiltration. In , COL3A1 expression in cancer-associated fibroblasts within the has been linked to aggressive disease progression and poor outcomes, highlighting its role in ECM remodeling driven by obesity-related factors. Additionally, patient-derived ECM models demonstrate that COL3A1 variants alter mechanics, increasing rupture risk in metastatic contexts. In the context of , post-2020 research has revealed upregulated COL3A1 expression in samples from severe cases, contributing to through enhanced fibrotic gene signatures dominated by collagens. This hyper-expression persists in non-resolving infections, exacerbating tissue scarring via pro-fibrotic pathways. Bioinformatics analyses post-2020 have implicated COL3A1 in key ECM-receptor interactions and signaling, particularly in aging tissues where it drives mesenchymal drift and loss of cellular identity. In neurodegeneration, transcriptomic studies using show COL3A1 deregulation in ECM-related pathways, associating it with altered stiffness and progression in models like . Therapeutic strategies targeting COL3A1 include CRISPR-Cas9 gene editing for correcting pathogenic variants in collagen disorders, with applications demonstrated in patient-derived models to restore ECM integrity, though specific COL3A1 corrections remain in preclinical stages for vascular Ehlers-Danlos syndrome. Anti-fibrotic drugs like inhibit the TGF-β/COL3A1 axis by reducing COL3A1 expression in fibroblasts, with ongoing trials exploring its efficacy in post-COVID-19 and other fibrotic conditions. Similarly, novel compounds such as AK3280 suppress TGF-β-induced COL3A1 upregulation in multiple fibrotic models. Additionally, the chemical chaperone 4-phenylbutyric acid has been demonstrated in 2025 studies to rescue molecular defects in patient-derived cells with COL3A1 mutations, offering potential for vEDS treatment. Nanotherapies for vessel reinforcement are emerging, with nanoparticle delivery systems designed to modulate ECM components like COL3A1 in vascular diseases, enhancing mechanical stability without direct COL3A1 targeting yet reported. Future directions emphasize approaches based on variant-specific mechanics, where patient-derived ECM analyses predict rupture risks from COL3A1 mutations to guide tailored interventions. AI-predicted structures, such as those generated by for COL3A1 variants, are facilitating by modeling mutant protein conformations for targeted therapies in and cancer.

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