Collagen structure and function 2 Flashcards
what happens when there is an issue with type I collagen?
osteogenesis imperfecta
mutations in what genes account for 90% of OI cases?
COL1A1 and COL1A2
how is OI inherited?
mostly autosomal dominant
is OI due to quantitative or qualitative abnormalities of collagen I?
both
what is the most common type of OI?
type I
what is type I OI?
- bones predisposed to fracture (most occur before puberty)
- normal stature/blue sclera
- in most cases, “functional null” allele of COL1A1 or COL1A2 genes leads to no (or greatly reduced amounts) protein being produced from one allele
- Other allele unaffected
can patients with type I OI still make normal collagen?
yes- still have one unaffected allele that makes reduced amounts of normal collagen
what trimers are formed in type I OI?
normal (encoded by normal allele)- but only half the amount of normal collagen produced
*quantitative deficiency
what is the most severe type of OI?
type II
what is type II OI?
- Numerous fractures and severe bone deformity
- Short stature
- perinatal lethal
- affects glycine residues that disrupts triple helical structure
can patients with type II OI still make normal collagen?
no
- Abnormal collagen molecules incorporated together with normal collagen into trimers, therefore few or no normal collagen trimers produced
what is type III OI?
progressive deforming type/ bones
fracture easily
-short stature, spinal curvature
-severe bone deformity
-blue sclera
*can be autosomal recessive
what is type IV OI?
severity intermediate
between types I/II
-mutations in COL1A2 and rarely COL1A1
why are many diseases with mutations in ECM proteins inherited in a dominant fashion?
bc mutant alleles mixed into normal ones make it hard to form the correct polymer
what is type V OI?
“mesh-like” bone histology/ calcification
-autosomal dominant but no mutations in collagen genes
what are the autosomal recessive types of OI?
types VI-XVI
*no mutations in type I collagen
mutations in CRTAP causes what?
defective 3-prolyl-hydroxylation which delays collagen folding
what results from a CRTAP null mutation?
severe lethal form of OI (similar to type II)
what are the three components of prolyl-3 hydroxylation complex?
CRTAP
cyclophilin B
prolyl-3-hydroxylase 1 (LEPRE1)
what is caused by mutation in the prolyl-3 hydroxylation complex?
does not allow/delay collagen hydroxylation during biosynthesis
-can cause diseases like OI
different proteins that act in the same pathway can produce diseases with what?
similar phenotypes
what are the two kinds of mutations that can case OI?
-mutations in type 1 collagen genes
-mutations in genes encoding proteins involved in collagen post-translational modifications/regulation of collagen biosynthesis
common orofacial manifestations of OI:
-brown/grey discoloration of teeth
-abnormalities of pulp chamber
orofacial manifestation of severe forms of OI:
-triangular shaped face
-bossing of the forehead
-low set ears
-mid face deficiency/ malocclusions
-may have blue sclera
what is a hereditary disease of dentin?
dentinogenesis imperfecta
symptoms of dentinogenesis imperfecta
-Opalescent/brown teeth that wear easily
-bulbous crowns
-narrow roots
-Small/obliterated pulp chambers or enlarged pulp chambers
-frequent splitting of enamel from dentin under occlusal stress
which type of dentinogenesis imperfecta occurs in families with OI and is due to mutations in COL1A1 or COL1A2?
type I
which type of dentinogensis imperfecta occurs due to mutations in DSPP and is not associated with OI?
type II and type III
implications for dental care for patients with OI
- Teeth in OI patients more susceptible to wear/breakage and/or enamel fracturing from teeth
*teeth can wear down to gingiva - Pulp chamber/root canals may be filled with dentin, so tooth may lose feeling.
- For tooth extractions, extra support of jaw may be needed to avoid
fracturing
Early identification of OI condition/preventative interventions are important for what?
to minimize dental complications
what is the common treatment for OI patients?
bisphosphonates
what disease is associated with abnormal collagen biosynthesis due to nutritional deficiency in Vitamin C?
scurvy
symptoms of scurvy
-lethargy
-bleeding gums/mucous membranes
-fragile blood vessels/petechial hemorrhage of skin
-loss of gingival and periodontal collagen fibers/anchoring fibers-loosening of teeth
-bone pain
why does vitamin C matter in the biosynthesis of collagen?
required as a cofactor for hydroxylation
what happens if hydroxylation of procollagen is prevented or it is unfolded?
retained in ER and/or degraded
-leads to collagen deficiency which causes inability to renew CT matrix
what happens is something with type II collagen goes wrong?
chondrodysplasias
types of chondrodysplasias
achondrogenesis type II/ hypochondrogenesis (ACGII-HCG)
what is thought to cause AGCII-HCG?
involves replacement of glycine by a bulkier amino acid in triple helical region of a1(II) chain
symptoms of ACGII-HCG
-die perinatally or in first weeks of life
-short, barrel-shaped trunk
-very short extremities
-large head, soft cranium
-flat face
-underossification of the axial skeleton.
-hypercellular epiphyseal cartilage
-poorly organized or absent growth plate
-diminished extracellular matrix
-thick, irregular collagen fibrils
characteristics of Ehlers Danlos syndromes:
-Fragility of soft connective tissues
-Manifestations in skin, ligaments, joints, blood vessels, internal organs
-Clinical spectrum varies from mild skin + joint hyperlaxity to severe physical disability/life-threatening complications (ruptured arteries)
-Mild skeletal abnormalities (e.g. osteopenia)
what disease is caused by mutations in genes encoding fibrillar collagens (types III and V)?
Ehlers Danlos syndrome
what can be caused by problems with collagen IV?
kidney problems
what is caused by problems with collagen VII?
epidermolysis bullosa
-can also have enamel defects
what disease is caused by production of autoantibodies against non-collagenous domains of type IV collagen alpha 3 chain?
Goodpasture syndrome
what is Goodpasture syndrome?
anti-glomerular basement antibody disease
rare autoimmune disease
what are issues caused by Goodpasture syndrome?
-kidney filtration
-blood in urine
-burning sensation when urinating
-nephritis
-coughing up blood
-fatigue
-nausea
*can lead to acute renal failure
