Connective tissue disease Flashcards
What are the 3 key components of connective tissue?
- Collagen
- Elastin
- Fibrillin
What is the basic structure of collagen?
Triple helix
- 3 long alpha chains
What specific amino acids are highly abundant in collagen?
- Proline
- Lysine
- Glycine (mainly)
What disease has defective production of type 1 collagen?
Osteogenesis imperfecta
What tissues contain type 1 collagen?
- Bone
- Skin
- Tendons, ligaments
- Cornea
- Internal organs
What tissues contain type 2 collagen?
- Cartilage
- Intervertebral discs
- Vitreous humor (eye)
What tissues contain type 3 collagen?
- Skin
- Blood vessels
Collagen (type 1, 2, 3) molecules that assemble into polymers are known as what?
Fibrils
What tissues contain type 4 collagen?
- Basement membrane
- Basal lamina (beneath epithelial layer)
- Lens
- Cochlea
What is ALport’s syndrome?
X-linked recessive type 4 collagen defect
- Mutations to alpha-3,4,5 chains
What is the calssic triad of symptoms in Alport syndrome?
Male with:
- Hematuria
- Hearing loss
- Occular disturbances
Where are the alpha chains of collagen synthesized?
Rough ER
- Contains signal molecules
- Pre-procollagen
What are the alpha chains referred to once signal molecules are added and they enter to ER lumen?
Pro-alpha chains
What occurs in the Endoplasmic reticulum lumen to pro-alpha chains?
- Proline and lysines hydroxylated
- Hydroxylysines glycosylated (sugar added to hydroxylysine)
- Propeptides (extra amino acids), disulfide bonds
- 3 pro alpha chains combine -> procallagen
What does hydroxylation of proline and lysine require?
Vit C
- (Hydroxy)lysine or proline
What cannot form in vit c deficiency (scurvy)?
Defective pro-alpha chains
- Do not form triple helix
What are propeptides?
Extra amino acids added to N and C ends of pro-alpha chains
What do the 3 pro-alpha chains combine to form?
Procollagen
After propeptides (from N and C terminal) cleaved what is formed?
Tropocollagen
What are the extracellular modifications that occur to tropocollagen?
Collagen fibrils form - self assemble as less soluble
- Strenthened thru lysine crosslinking
-
What are collagen fibers?
Bundels of triple helixes
What extracellular enzyme crosslinks lysine to form collagen fibrils?
Lysyl oxidase
What does lysyl oxidase require as a cofactor?
Copper
What are wrinkles due to?
- Decreased production of elastin and collagen in dermis
- Collagen/elastin fibers also thicken and clump
What is sclroderma caused by?
Fibroblast activation
- Excess collagen deposition
- Stiff hardened tissues (skin, organ systems)
What kind of disorder is scleroderma
Autoimmune
Mutation in what genes causes type 1 osteogenesis imperfecta?
COL1A1 or COL1A2 genes
- Code for alpha chains for type 1 collagen
Rank the types of osteogenesis imperfecta in terms of severity?
II, III, IV, I
- II is lethal in utero
What are the symptoms of osteogenesis imperfecta?
- Fractures with minimal trauma (beware of child abuse)
- Blue sclera
- Hearing loss (abnormal malleus, incus, stapes)
Dentinogenesis imperfecta (discoloured, translucent or shiny teeth), fall out easily)
This condition is most commonly associated with what disease?
- Type III, IV osteogenesis imperfecta
- Rarely type 1
What are ehlers danlos syndromes generally all due to?
Defective collagen synthesis
What genes cause classic Ehlers Danlos syndrome?
COL5A1 and COL5A2
How is ehlers danlos syndrome inherited?
Aut Dominant
What type of collagen is defective in Ehlers danlos syndrome?
Type V (interacts with other collagens)
What genes cause vascular Ehlers danlos syndrome?
COL3A1
What type of collagen is defective in vascular ehlers danlos syndrome?
Type 3
What are the clinical features of classic type (type V collagen) ehlers danlos syndrome?
- Hypermobile joints
- Hyperextensible (velvity) skin
- Easy bruising
- Think wide ‘cigarette paper’ scars
- Mitral valve prolapse
Ehlers danlos syndrome (vascular type, type 3 collagen) classically has what features?
- Thin skin, easy bruising
- Aneurysms - berry
- Intestinal perforation
- Uterus rupture during pregnancy
What percentage of those with Ehlers danlos syndrome (vascular type, type 3 collagen) have a vascular event / rupture by 40?
80%
- Median age of death is 48 years old
Menkes disease is inherited how?
X linked recessive
Menkes disease is a disease of what gene and what does it code for?
ATP7A
- ATPase which uptakes/transports copper
Impaired copper absorption (Menkes disease) causes a deficiency in what enzyme?
Lysyl oxidase
- Involved in collagen synthesis
Gene which causes Wilsons disease?
ATP7B
Clinical features of Menkes disease?
- Sparse, brittle (kinky) hair
- Low body temp
- Hypotonia, seizures
- Poor growth
- Developmental delay
- Osteoperosis / fractures
- Fatal usually in childhood
Elastin is found where?
Main component of elastic fibres (allows stretching/recoil)
- Arteries (50% of aortic tissue)
- Skin
- Lungs
- Ligaments
- Vocal cords
- Ligamentum flava
What amino acids are contained in elastin?
- Glycine
- Lysine
- Proline
Since elastin contains the same amino acids as collagen what differentiates it?
Most are non-hydroxylated
- No hydroxylysine
- Some hydroxyproline
Also not glycosylated
what is elastin excreted as?
Tropoelastin (assembled into elastin fibers with crosslinking)
Alpha 1 antitrypsin inhibits what enzyme?
Elastase
Emphysema is caused by an inbalance between what?
Neutrophil elastase (destroys elastase) and elastase inhibitor (AAT) protects elastin
- Incr elastase decr AAT
Williams syndrome is due to a chromosomal abnormality in what chr?
Partial deletion on long arm of chr 7
What protein is not present in Williams syndrome?
Elastin
What are the clinical features of Williams syndrome?
- Elfin appearence, IQ impaired
- Supravalvular aortic stenosis (constriction of ascending aorta above aortic valve)
What is the major component of microfibrils?
Fibrillin
What kind of protein is fibrillin?
Glycoprotein
What are microfibrils?
Sheath that surrounds elastin core
What are elastic fibres composed of?
- Elastin
- Microfibrils (made of fibrillin)
- Other molecules
A deficiency in fibrillin (component of microfibrils) causes what syndrome?
Marfan
What gene causes Marfans?
Where is it located?
FBN1 gene (codes for fibrillin-1)
- Chr 15
What is the wrist and thumb sign? (Marfans)
Wrist sign
- Tip of thumb covers entire fingernail of fifth finger
Thumb sign
- Thumb protrudes beyond ulnar border
What eye signs can be seen in Marfans?
- Cataracts (early age)
- Dislocation of lens (commonly due to trauma)
- Lens classically dislocated in upward/outward direction
What are the CV associations with Marfan?
Mitral valve prolapse
Thoracic aortic aneurysm and dissection
- Cystic medial necrosis
- Cysts and necrosis pf medial layer
What other conditions may have a Marfinoid habitus?
- Homocystinuria
- MEN 2B
- Rare forms of Ehlers Danlos
