Collagen

  • Most abundant protein in the human body.
  • Extensively modified by posttranslational

Modification.

  • Organizes and strengthens extracellular matrix.
  • Be (So Totally) Cool, Read Books.
  • Type I Most common (90%)—Bone (made by osteoblasts), dermis, Tendon, dentin, fascia, cornea, late wound repair (scar tissue). Type I: bone.

    ↓ production in osteogenesis imperfecta type I.

    Type II Cartilage (including hyaline), vitreous body,

    nucleus pulposus.

    Type II: cartwolage.
    Type III Reticulin—skin, blood vessels, lungs, intestines, bone marrow, lymphatics, uterus, fetal tissue, granulation tissue.

    Pliable, stretchy stuff.

    Type III: deficient in the uncommon, vascular

    type of Ehlers-Danlos syndrome (ThreE D).

     Type IV Basement membrane, basal lamina, lens. Type IV: under the floor (basement membrane).

    Defective in Alport syndrome; targeted by

    autoantibodies in Goodpasture syndrome.

  • Collagen synthesis and structure
    1. Synthesis—translation of collagen α chains (preprocollagen)—usually Gly-X-Y (X and Y are proline or lysine). Glycine content best reflects collagen synthesis (collagen is 1⁄3 glycine).
    2. Hydroxylation—hydroxylation of specific proline and lysine residues. Requires vitamin C; deficiency → scurvy.
    3. Glycosylation—glycosylation of pro-α-chain hydroxylysine residues and formation of procollagen via hydrogen and disulfide bonds (triple helix of 3 collagen α chains). Problems forming triple helix → osteogenesis imperfecta.
    4. Exocytosis—exocytosis of procollagen into extracellular space.
    5. Proteolytic processing—cleavage of disulfide-rich terminal regions of procollagen → insoluble tropocollagen. Problems with cleavage → Ehlers-Danlos syndrome.
    6. Cross-linking—reinforcement of many staggered tropocollagen molecules by covalent lysine-hydroxylysine cross-linkage (by copper-containing lysyl oxidase) to make collagen fibrils. Problems with N-terminal propeptide removal → Ehlers-Danlos syndrome. Problems with lysyl oxidase → Menkes disease.
  • Osteogenesis imperfecta
    • Genetic bone disorder (brittle bone disease) caused by a variety of gene defects (most commonly COL1A1 and COL1A2).
    • Most common form is autosomal dominant with ↓ production of otherwise normal type I collagen. Manifestations can include:
      • Multiple fractures with minimal trauma (A,B); may occur during the birth process
      • Blue sclerae (C) due to the translucent connective tissue over choroidal veins
      • Some forms have tooth abnormalities, including opalescent teeth that wear easily due to lack of dentin (dentinogenesis imperfecta)
      • Hearing loss (abnormal ossicles)
    • May be confused with child abuse.
    • Treat with bisphosphonates to ↓ fracture risk.
    • Patients can’t BITE:
      • Bones = multiple fractures
      • I (eye) = blue sclerae
      • Teeth = dental imperfections
      • Ear = hearing loss
  • Ehlers-Danlos syndrome
    • Faulty collagen synthesis causing hyperextensible skin (A), hypermobile joints (B), and tendency to bleed (easy bruising).
    • Multiple types. Inheritance and severity vary. Can be autosomal dominant or recessive. May be associated with joint dislocation, berry and aortic aneurysms, organ rupture.
    • Hypermobility type (joint instability): most common type.
    • Classical type (Type I & II) (joint and skin symptoms): caused by a mutation in type V collagen (eg, COL5A1, COL5A2).
    • Vascular type (fragile tissues including vessels [eg, aorta], muscles, and organs that are prone to rupture): deficient type III procollagen.
  • Menkes disease
    • X-linked recessive connective tissue disease caused by impaired copper absorption and transport due to defective Menkes protein (ATP7A). Leads to ↓ activity of lysyl oxidase (copper is a necessary cofactor) ↓ defective collagen.
    • Results in brittle, “kinky” hair, growth retardation, and hypotonia.

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