A large number of hereditary diseases are due to defects in what genes?
ECM component genes
Where are most defects found?
In collagen genes
What does neutrophil elastase do?
Degrades elastin
To which class of enzymes does elastase belong?
Serine proteases
How is elastase inactivated?
By alpha1-antitrypsin (alpha1-antiprotease)
What type of inhibitor is alpha1-antitrypsin?
Suicide inhibitor
What is a serpin?
A sering protease inhibitor
From what does alpha1-antitrypsin protect the tissues?
Released serine proteases
Emphysema results from a deficiency in what?
Alpha1-antitrypsin
What is seen histologically in alpha-1 antitrypsin deficiency?
Advanced panacinar destruction of the lung parenchyma
Accumulation of macrophages
Sever acute and chronic bronchiolitis
Marfan syndrome results in what?
Very long limbs Heart defects Vascular problems Retinal detachment AD with variable expressivity
What causes Marfan syndrome?
Fibrillin mutations
What are some of the changes that cause Marfan syndrome?
Ca++ binding interactions
Disulfide sites
Hydrophobic packing regions
Ehlers-Danlos sydrome (EDS) is a group of how many diseases?
At least 10
What are common symptoms of Ehlers-Danlos syndrome?
Structural weaknesses in connective tissues:
- Fragile/hyperextensible skin
- Hypermobile joints
Most forms of EDS result from defects in which fibrillar collagens?
I, II, III
What is the most severe EDS mutation?
EDS type IV
How is EDS passed genetically?
It is autosomal dominant
What is the characteristic symptom of EDS type IV?
Overextensible connective tissue
Overextensible connective tissue from EDS type IV leads to what?
Arterial rupture (sudden death)
Intestinal perforation
Rupture of uterus during pregnancy or labor
Easily bruised, thin, translucent skin
EDS type IV results from what defect?
Mutation in collagen alpha-1 (III) gene
How does EDS type IV cause problems?
Causes slow synthesis/defective secretion of collagen
Entire fibril is defective
What is the major symptom of EDS types VIIA, B and C?
Dislocation of major joints (hips, knees)
What other symptoms are found in EDS types VIIA, B and C?
Hyperextensible, easily bruised skin
EDS types VII A and B result from what mutation?
Collagen alpha1 (I) or alpha1 (I) gene
What does the alpha1 (I) or alpha2 (II) mutation do?
Eliminates the cleavage site for collagen N-proteinase, so incomplete collagens assemble, forming defective fibrils
EDS type VII C is called what?
Dermatosparaxis
How is EDS type VII C passed hereditarily?
Autosomal recessive
Type C EDS results from what?
Deficiency of collagen N-proteinase, causing skin fragility
Osteogenesis imperfecta is a group of how many diseases?
8
What characterizes osteogenesis imperfecta?
Ready occurrence of multiple fractures, leading to bone deformities
What does defective type I collagen lead to in the eye?
Blue sclera
What is type I osteogenesis imperfecta?
Type I collagen is normal, but there isn’t enough of it
What does type I osteogenesis cause?
Easily fractured bones
Loose joints
Blue sclera
Which type of Type I oseogenetsis imperfecta causes dentinogenesis imperfecta?
Type IB
What causes type IB osteogenesis imperfecta?
Mutation in collagen alpha2 (I) gene
What does Ehlers-Danlos syndrome type IV cause in the mouth?
Excessive bleeding of soft tissues, reduced healing
*Doesn’t affect the teeth (usually)
What does EDS type VIII cause in the mouth?
Periodontal defects
Severe bleeding on brushing
What do deficiencies in cross linking cause?
Weak blood vessels
Incorrect bone formation
Demineralization
What are the most common cross-link deficiency diseases?
Lathyrism
Copper deficiency
Lathyrism can come from regular consumption of what?
pea seeds
What characterizes lathyrism?
Spine deformities
Demineralization of bone
Dislocation of joints
Aortic aneurysms
What causes lathyrism?
Beta-aminopropionitrile - a potent irreversibel inhibitor of lysyl oxidase
Inhibition of lysyl oxidase by beta-aminopropionitrile causes what?
Blockage of cross-linking causing reduced fibril stability
Why does copper deficiency affect cross-linking?
Lysyl oxidase required copper as a co-factor
A copper deficiency primarily affects what?
Skin - becomes loose and wrinkled
Other than lack of dietary copper, what else can cause copper deficiency?
Two rare X-linked diseases causing defects in copper metabolism
What is implicated as the defective gene causing dentinogenesis imperfecta type II?
Dentin sialoprotein
What are symptomes of dentinogenesis imperfecta type II?
Irregular dentin formation
Blue, gray or violet teeth
-may be opalescent
Easily chipped enamel due to defective dentinoenamel junction
Inherited defects in basement membranes are caused by what collagens?
VII
XVII
Laminin5
Integrins
What is epidermolysis bullosa (EB)?
Hereditary blistering disease
How is the severity of EB determined?
By the depth of layer separation that occurs
What causes dystrophic EB?
Defects in anchoring fibrils that help attach basement membrane to underlying stromal connective tissue (collagen VII)
What does dystrophic EB lead to?
Mutilating scarring
What causes recessive junctional EB?
Defects in collagen alpha1 (XVII) gene
What does recessive junctional EB lead to?
Separation within skin basement membrane
Blistering
Cavities due to enamel hypoplasia and tooth pitting
Failure of teeth to erupt
What is caused by recessive EB junctional Herlitz?
Extensive blistering of skin and mucous membranes
Neonatal death
What causes recessive EB junction Herlitz?
Defects in laminin 5 genes
