Collagen Structure and Function Part 2 Flashcards
osteogenesis imperfecta is a — disease
hereditary
osteogenesis imperfecta
bones are extremely brittle and break, often for little or no apparent cause
how many people does OI affect in the US?
20,000-50,000
Mutations in (2) genes account for ~90% of OI cases (>150 different mutations identified)
COL1A1 and COL1A2
COL1A1 and COL1A2 mutations associated with the four types of OI defined classically
types I, II, III, IV
OI is mostly – –
autosomal dominant
Classical Osteogenesis Imperfecta is due to (2) Abnormalities of Type I Collagen
quantitative
qualitative
most common/mild type of OI
type 1
in type 1, bones are predisposed to
fracture (most occur before puberty)
symptoms of type 1 OI
normal stature/blue sclera
type 1 OI is
autosomal dominant
in most cases, “functional null” allele of COL1A1 or COL1A2 genes leads to
no protein being produced from one allele
other allele unaffected therefore patients make
REDUCED amounts of
NORMAL collagen I
mutations can be;
allelic deletion, promoter/enhancer mutations,
splicing mutations, premature termination – i.e. mutations which result
in reduced (or no) production of alpha collagen I chains or production
of alpha collagen I chains that are degraded or incapable of being
assembled into trimers
trimers are formed normally (encoded by normal allele), but
only half the normal amount of collagen produced (quantitative deficiency)
normal protein being made but in reduced amounts is known as
quantitative deficiency
most severe form of OI
type 2 (perinatal lethal)
symptoms of type 2 OI (2)
numerous fractures and severe bone deformity
short stature
type 2 OI is
autosomal dominant (but occurs mainly as spontaneous mutations due to perinatal lethality or parents turn out to be mosaic for mutation) autosomal recessive (rare)
Mutations in COL1A1 or COL1A2 produce — pro-alpha collagen chains,
which become — into collagen trimers (esp. affects glycine residues
of gly-X-Y triplet in triple helical domain)
abnormal
incorporated
Abnormal collagen molecules incorporated together with normal collagen into
trimers, therefore
few or no normal collagen trimers produced
type 3 OI
progressive forming type/bones fracture easily
symptoms of type 3 OI (3)
short stature, spinal curvature
severe bone deformity
blue sclera
type 3 OI is
autosomal dominant
sometimes autosomal recessive
type 3 OI arises from mutations in
COL1A1 and COL1A2
type 4 OI
severity intermediate between types 1 and 2
type 4 is
autosomal dominant
type 4 OI arises from mutations in
COL1A2 and rarely COL1A1
Why are many diseases with mutations in
extracellular matrix proteins inherited in a
dominant fashion?
polymeric molecules incorporate into the fiber, proteins work together in polymers that they can’t fit together
Group of patients identified as type V OI - clinically similar to type IV but specific
clinical features.
Type V - autosomal dominant inheritance pattern but patients had no mutations in
collagen genes
Recessive form(s) of OI long suspected due to cases where unaffected parents had more than one child with severe
bone dysplasia
New — OI types VI and VII proposed
diagnosis based on histology
recessive
Types — OI identified more recently
autosomal recessive
VIII-XVI
None of these forms of OI had mutations in type — collagen genes
1
Now up to – genes known to cause different forms of OI
15
CRTAP (cartilage associated protein) forms a complex with (2)
cyclophilin
B (encoded by PPIB gene) and prolyl 3-hydroxylase 1 (encoded by
LEPRE1 gene
It is the prolyl-3 hydroxylase 1 that actually
— collagen alpha1(I) chain at one specific residue (Pro986)
hydroxylates
Mutations in CRTAP cause defective 3-prolyl-hydroxylation which delays
collagen folding
Type 7 OI is caused by a
hypomorphic CRTAP defect (severely reduced amounts of normal CRTAP protein).
CRTAP null mutations result in a
severe lethal form OI (similar to type II)
Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone
disorder resembling
lethal/severe osteogenesis imperfecta
For patients with inherited diseases, you should first look for mutations
in genes already known to cause
similar phenotypes
For patients with inherited diseases, you should first look for mutations
in genes already known to cause
similar phenotypes
Then it is often worthwhile to look for mutations in genes of proteins that interact with the known gene or that may be working in the same
biochemical pathway
What if you have two diseases with phenotypes that are very similar, but which have been associated with completely different genes?
It may be worthwhile to do experiments to determine whether these genes interact in a
common biochemical pathway
OI can be caused by mutations in (2)
type I collagen genes or in genes encoding proteins involved in collagen post-translational
modifications/ regulation of collagen biosynthesis
dentinogenesis imperfecta is a hereditory disease of dentin with (5)
- Opalescent/brown teeth that wear easily
- bulbous crowns
- narrow roots
- Small/obliterated pulp chambers
- frequent splitting of enamel from dentin under occlusal stress
type 1 occurs in families with
osteogenesis imperfecta (especially type 3, 4) due to mutations in COL1A1 or COL1A2
shields type 2
not associated with OI (due to mutations in DSPP)
shields type 3
brandywine type
occurs in racial segregate in maryland, USA (due to mutations in DSPP)
brandywine
opalescent/brown teeth in patient with osteogenesis imperfecta
Teeth in OI patients are more susceptible to
wear/breakage and/or enamel fracturing from teeth
If untreated – teeth can wear down to
gingiva
Pulp chamber/root canals may be filled with dentin, so tooth may
lose feeling
Early identification of OI condition/preventative interventions is important to
minimize dental complications
Meticulous oral hygiene / regular periodic examinations to identify
teeth needing care
For tooth extractions, extra support of jaw may be needed to avoid
fracturing
OI patients increasingly being treated with
bisphosphonates
consequences of long term bisphosphonate use starting in childhood
not known, but some association with
Osteonecrosis of the Jaw in
cancer patients on high dose BPs
scurvy is associated with abnormal collagen biosynthesis due to
nutritional deficiency in vitamin C (ascorbic acid)
dietary vitamin c (ascorbic acid) deficiency leads to
scurvy
symptoms of scurvy (5)
• Lethargy
•Bleeding gums/mucous membranes
•Fragile blood vessels/petechial hemorrage of skin
•Loss of gingival and periodontal collagen fibers/anchoring
fibers - loosening of teeth
•Bone pain
— = important co-factor for prolyl and lysyl hydroxylases that
hydroxylate proline/lysine residues
Vitamin C
If hydroxylation is prevented, unfolded procollagen is (2)
retained in ER
and/or degraded
Leads to deficient collagen assembly – inability to renew
connective
tissue matrix
oral manifestations of scurvy (2)
gum recession
wobbly teeth bc they’re not attached to the alveolar bone
mutations in type 2 collagen is linked to
chondrodyplasias
Achondrogenesis type II / hypochondrogenesis (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
over – mutations causing ACGII-HCG reported
10
Over ten mutations causing ACGII-HCG reported. All involve replacement of — by a bulkier amino acid in triple helical region of α1(II) chain
glycine
Ehlers danlos syndrome is a heterogeneous group of diseases characterized by (4)
• 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)
how many subtypes of ED?
7
ED subtypes are mostly linked to mutations in genes encoding for (2)
fibrillar collagens (types 3, 5) or enzymes involved in post translational modifications of collagens
glomerulonephritis, endstage kidney
disease, hearing loss (due to disruption of
function of basement membrane)
Alport Syndrome
Congenital form of muscular dystrophy
Bethlem
Myopathy
Inherited connective tissue disorder chracterized by blistering of the skin and mucosal membranes due to defect in anchoring between dermis and epidermis. (1:50,000). Defects in enamel/caries
Epidermolysis
bullosa (EB)
Developmental disorder with eye
abnormalities including retinal detachment
Knobloch
Syndrome
good pasture syndrome is an — disease
autoimmune, rare
in good pasture syndrome, autoantibodies produced against non collagenous domains of
type 4 collagen alpha 3 chain
type 4 (alpha 3) is important in
golmerular basement membrane
good pasture syndrome leads to problems with (7)
kidney filtration blood in urine burning sensation when urinating nephritis coughing up blood fatigue nausea
good pasture syndrome can lead to
acute renal failure
