A 2-year-old boy is evaluated for easy bruising. His parents report that he develops marked bruising and open wounds following minor trauma. The skin is difficult to suture due to its extreme fragility. Physical examination reveals hyperextensible skin, multiple ecchymoses over the forearms and pretibial regions, and an umbilical hernia. A skin biopsy is performed, and histochemical evaluation of the biopsy reveals a defect in extracellular processing of collagen. Which of the following steps of collagen synthesis is most likely impaired in this patient?
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This child likely has Ehlers-Danlos syndrome, a group of rare hereditary disorders characterized by defective collagen synthesis. The condition can be caused by a deficiency in procollagen peptidase, the enzyme that cleaves terminal propeptides from procollagen in the extracellular space. Impaired propeptide removal results in the formation of soluble collagen that does not properly crosslink. Consequently, patients often have joint laxity, hyperextensible skin, fragile tissue with easy bruising, and poor wound healing.
Each collagen molecule consists of 3 polypeptide α-chains held together by hydrogen bonds, forming a triple helix. Collagen assumes this conformation because each of the α-chains has a simple, repetitive amino acid sequence represented as (Gly-X-Y)n. The smallest amino acid, glycine (Gly), is necessary at every third position to ensure compact coiling of the helix. Many of the amino acids represented by X and Y are proline residues, which kink the polypeptide chain and enhance the rigidity of the helical structure due to their ring configuration.
Mature collagen is synthesized by fibroblasts, osteoblasts, and chondroblasts through the following steps:
As translation begins in the cytoplasm, an amino acid signal sequence at the N-terminus of the α-chain facilitates ribosomal binding to the rough endoplasmic reticulum (RER) and passage of the growing polypeptide chain (pre-pro-α-chain) into the RER.
Inside the RER, the hydrophobic signal sequence is cleaved to yield the pro-α-chain. Proline and lysine at the Y positions of the pro-α-chain are hydroxylated to hydroxyproline and hydroxylysine, respectively (Choice D). Glycosylation of select hydroxylysine residues also occurs within the RER (Choice A).
The central helical region of the pro-α-chain is flanked by N- and C-terminal propeptides. Disulfide bond formation between the C-terminal propeptide region of 3 α-chains brings the chains into an alignment favorable for assembly into a triple helix (procollagen molecule) (Choices B and E).
Procollagen molecules are then transported through the Golgi apparatus into the extracellular space. The N- and C-terminal propeptides are cleaved by procollagen peptidases, converting procollagen into less soluble tropocollagen.
Tropocollagen monomers self-assemble into collagen fibrils. Finally, lysyl oxidase helps create covalent crosslinks between collagen fibrils to form strong collagen fibers.
Educational objective:
Ehlers-Danlos syndrome is a group of rare hereditary disorders characterized by defective collagen synthesis. It can be caused by procollagen peptidase deficiency, which results in impaired cleavage of terminal propeptides in the extracellular space. Patients often have joint laxity, hyperextensible skin, and tissue fragility due to the formation of soluble collagen that does not properly crosslink.