Ehlers-Danlos Syndrome (EDS) is a group of inherited disorders that primarily affect connective tissues throughout the body. These disorders arise from changes to the genes that instruct the body on how to produce collagen, the main protein component of connective tissue. The resulting molecular defects lead to tissue fragility, hypermobility, and other systemic problems. This article explores the relationship between the structure of collagen and the varied manifestations of Ehlers-Danlos Syndrome.
The Foundation: What Is Collagen?
Collagen is the most plentiful protein found in mammals, making up about one-third of the total protein content in the human body. It provides structural support and organization to tissues, functioning as the body’s internal scaffolding. Collagen is a principal component of skin, tendons, ligaments, bones, and blood vessels, providing them with tensile strength and elasticity.
The defining feature of a collagen molecule is its triple helix structure, often referred to as tropocollagen. This rod-like structure is formed by three parallel polypeptide chains that coil tightly around one another. The tight packing requires that every third amino acid must be glycine, leading to a repeating sequence pattern. Modified amino acids, such as hydroxyproline, contribute significantly to the stability of this helix.
Once synthesized, multiple triple-helical collagen molecules self-assemble into larger structures known as fibrils. These fibrils then bundle together to create the macroscopic fibers and networks that provide the necessary strength to connective tissues. Collagen is a family of at least 28 different types, with types I, II, III, and V being the most abundant.
Ehlers-Danlos Syndrome: An Overview
Ehlers-Danlos Syndrome is currently categorized into 13 distinct subtypes based on clinical features and underlying genetic causes. All forms of EDS share a fundamental problem with connective tissue strength, resulting in highly flexible joints and fragile skin. The condition’s severity ranges from mild joint hypermobility to life-threatening complications involving organ and vessel rupture.
The common clinical signs of EDS include joint hypermobility, where joints extend beyond the normal range of motion, and skin hyperextensibility, meaning the skin is unusually stretchy. Affected individuals often experience chronic joint pain, frequent joint dislocations, and develop thin, atrophic scars. EDS can also impact the vascular system, eyes, and internal organs.
The most prevalent type is Hypermobile EDS (hEDS), characterized by generalized joint laxity and chronic pain. Classical EDS (cEDS) is distinguished by pronounced skin fragility, extensive atrophic scarring, and velvety, stretchy skin. Vascular EDS (vEDS) is the most severe form, due to the extreme fragility of blood vessels and hollow organs, which puts individuals at high risk for spontaneous rupture.
The Molecular Defect: How Collagen Fails in EDS
The root cause of tissue weakness in EDS lies in inherited genetic mutations that interfere with the normal life cycle of collagen molecules. These mutations can disrupt any stage of the complex process, from the initial synthesis of the polypeptide chains to the final assembly of the strong collagen fibers. The resulting defective collagen molecules are unable to provide the necessary tensile strength.
Faulty Chain Production
One common mechanism involves the production of faulty procollagen chains, which are precursors to the mature collagen molecule. If a mutation causes an incorrect amino acid substitution, particularly replacing a necessary glycine residue within the triple helix, the chain cannot fold correctly. The presence of a bulkier amino acid prevents the tight coiling of the three chains, leading to a structurally unstable triple helix.
A single defective chain can destabilize the entire three-chain structure, a phenomenon known as a dominant-negative effect. Since the three chains combine randomly, the presence of one mutant chain means that the majority of the resulting triple helices will be unstable. These unstable molecules are often degraded by the cell or secreted outside the cell in a structurally flawed state.
Processing Errors
In other cases, the defect may involve the enzymes that modify or process the collagen chains after they are made. Some mutations prevent the proper removal of propeptides, which must be cleaved before final fiber assembly. If these propeptides remain attached, the collagen molecules cannot align correctly or form the necessary cross-links to build strong, mature fibers. This structural weakness is what makes the skin hyperextensible, the joints unstable, and the blood vessels prone to rupture.
Linking Specific Collagen Genes to EDS Types
The distinct clinical presentation of each EDS type is directly tied to the mutated collagen gene and the resulting defect in the specific collagen protein. The classification of EDS is increasingly reliant on identifying the precise genetic variant. This molecular link explains why different types of EDS carry different risks, as the various collagen types are concentrated in specific body structures.
Classical EDS (cEDS)
cEDS is most frequently caused by mutations in the COL5A1 and COL5A2 genes, which encode the alpha chains of type V collagen. Type V collagen is a minor fibrillar collagen that plays a significant role in regulating the diameter and structure of the larger type I collagen fibrils. A common mechanism in cEDS is COL5A1 haploinsufficiency, where one copy of the gene is non-functional, resulting in a reduced amount of type V collagen available for fiber assembly. This reduction or defect leads to disorganized collagen bundles, which causes the characteristic skin hyperextensibility and abnormal scarring seen in cEDS.
Vascular EDS (vEDS)
vEDS is caused by pathogenic variants in the COL3A1 gene, which provides instructions for making the alpha chain of type III collagen. Type III collagen is primarily found in the walls of blood vessels and hollow organs like the intestines, providing them with elasticity and strength. Mutations in COL3A1 result in defective type III collagen, making these tissues extremely fragile and susceptible to rupture or dissection, which is the high-risk feature of vEDS.
Arthrochalasia EDS (aEDS)
Another rare form, Arthrochalasia EDS (aEDS), is associated with mutations in the COL1A1 or COL1A2 genes, which encode the chains of type I collagen. Type I collagen is the most abundant collagen in the body, prominent in bone and skin. The defect often involves a specific mutation that prevents the proper cleavage of the N-terminal propeptide. This failure in processing disrupts the formation of mature type I collagen fibrils, resulting in severe generalized joint hypermobility and congenital hip dislocation, the hallmark features of aEDS.