Ehlers-Danlos syndromes (EDS) are a group of related disorders that are caused by different genetic defects affecting the structure and function of connective tissue. Most mutations affect the collagen proteins, which are structural proteins that contribute to the strength and flexibility or elasticity of connective tissue. Mutations can affect the strength or amount of collagen protein, which result in joint hypermobility (joints that can stretch beyond normal), skin hyperextensibility (skin that can be stretched beyond normal), and tissue fragility.
Genetic mutations and EDS
Mutations in several genes of the collagen biosynthesis pathway can cause EDS. These include genes that encode different types of collagen proteins found in the connective tissues throughout the body — genes such as COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, and COL12A1.
Other EDS-associated genes encode for proteins that either interact with mature collagen proteins in the connective tissue matrix or are involved in the synthesis or folding of newly-made collagen proteins. These include ADAMTS2, FKBP14, PLOD1, TNXB, ZNF469, PRDM5, SLC39A13, B4GALT6, B4GALT7, CHST14, DSE, C1R, and C1S genes.
Mutations of different EDS types
Classical EDS is caused by mutations in the COL5A1 or COL5A2 gene, which encodes pro-alpha1 or pro-alpha2 proteins that form type 5 collagen.
Classical-like EDS is caused by mutations in the TNXB gene that encodes for a collagen-interacting protein called tenascin-X, which regulates the stability of the body’s elastic fibers.
Cardiac valvular EDS is associated with mutations in the COL1A2 gene, which encodes the pro-apha2 (I) chain that is an important component of type 1 collagen.
Some cases of hypermobile EDS are associated with mutations in the TNXB gene but for many cases, no genetic mutation has been identified.
Vascular EDS is caused by mutations in the COL3A1 gene that encodes for the pro-alpha1 (III) protein, which forms type 3 collagen. Some individuals with vascular EDS also carry mutations in the COL1A1 gene, which is required to form type 1 collagen.
Kyphoscoliotic EDS is caused by mutations in the PLOD1 or FKBP14 gene. PLOD1 encodes for an enzyme called lysyl hydroxylase 1, which converts the amino acid lysine into hydroxylysine in the collagen chain. This helps the cross-linking between individual collagen chains in the connective tissues. The FKBP14 gene encodes for the FK506-binding protein-14 that helps in folding and modifying newly formed proteins, including precursor collagens, so that they attain the three-dimensional form necessary for normal function.
Arthrochalasia EDS is caused by mutations in the COL1A1 or COL1A2 gene that encodes for pro-apha1(I) or pro-apha2(I) chains that form type 1 collagen.
Dermatosparaxis EDS is caused by mutations in the ADAMTS2 gene, which cleaves precursor collagen molecules or pro-collagen chains to form mature functional collagen proteins.
Brittle cornea syndrome (BCS) is caused by mutations in the ZNF469 or PRDM5 gene. The ZNF469 gene encodes for a protein that acts as a transcription factor for the synthesis of collagen proteins or as an extra-nuclear regulator that helps in collagen organization in the extracellular space between adjacent cells. The PRDM5 gene encodes for a transcription factor that regulates the synthesis of new proteins including collagen.
Some cases of spondylodysplastic EDS are caused by mutations in the SLC39A13 gene, which encodes for a protein that is responsible for the transport of zinc ions into the cells. Zinc is essential for the function of connective tissues. Other cases are caused by mutations in the B4GALT6 and B4GALT7 gene, which encodes for proteins that add sugar molecules to proteins, including the proteins that are components of connective tissues.
Musculocontractural EDS is caused by mutations in the CHST14 or DSE gene. CHST14 encodes for an enzyme called carbohydrate sulfotransferase 14, which modifies proteins and carbohydrates by adding sulfate groups that are essential for their function. The DSE gene encodes for an enzyme called dermatan sulfate epimerase, which is essential for the synthesis of a complex sugar molecule called dermatan sulfate that increases the cohesion and stability of connective tissue.
Myopathic EDS is caused in most cases by mutations in the COL12A1 gene, which encodes type 12 collagen. Some patients with myopathic EDS may also have a mutation in the FKBP14 gene.
Last updated: Oct. 12, 2019
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