Dominant Negative Mutations Flashcards
What is a dominant negative mutation?
mutant gene product interferes w/ function of normal gene product
what kinds of proteins are usually affected by dominant negative mutations
structural proteins like collagen
What does OI stand for
osteogenesis imperfecta
What is mode of inheritance for OI
AD
A more severe mutations leads to what kind of phenotype vs. less severe in OI
more severe mutation is less severe phenotype
OI has significant clinical ______
heterogenity
What protein is affected in OI
Type I Collagen
What two genes are involved in OI
proalpha 1 (COL1A1) and proalpha2 (COL1A2)
presentation: weak bones, increased frequency of fractures, possible bone deformities, short stature, blue sclera, significant clinical heterogeneity is what disease
OI
What type of treatments are there for OI
supportive
What is structure of collagen
triple helix
What aa are in alpha chain of collagen
Gly-X-Y
X is usually proline
Y is usually hydroxyproline or hydroxylysine
What kind of mutations cause type I OI?
null mutations
haploinsufficiency
What is mildest form of OI
type I
What kind of mutations cause Type III-IV
missense
dominant negative
What is most severe form of OI
type II
what is phenotype of type II OI
fetus dies :(
AKA perinatal lethal
Why is OI unique in regards to mutations and phenotype
null mutation causes milder phenotype: type I
missense mutation cuases more severe phenotype like Type II
Severe forms of OI are almost always due to _____ missense mutations
sporadic
What is intermediate form of OI
Type III & IV
Where are missense mutations in Type II OI?
glycine resides of collagen
COL1A1 produces what
alpha 1 chain of collagen
COl1A2 produces what
alpha 2 chain of collagen
What happens if there is a missense mutation on one locus of COL1A1
if glycine is mutated to some other aa it will cause a bend or kink in structure of colagen
How is OI dominant negative
one missense mutation causes a negative affect on the other two collagen strands and the collagen as a whole, so it is dominant and creates a negative affect on the other two alpha chains, producing a bad structure
If there is a missense mutation and produces OI, how much collagen produced is normal?
1/4 is normal 3/4 is abnormal
How does collagen winding proceed?
C to N terminus
closer mutation is to C terminus, what happens
winding stops
when collagen hits kink what happens to its winding
it stops
In OI how much collagen is excreted from cell
only 1/4
3/4 is trapped in cell
The closer the mutation is to C terminus, the more ___ the OI disease
severe
What types of mutations cause type I OI
null mutation
What happens if there is an entire gene deletion of COL1A1?
1/2 as much alpha 1 is produced, but all that is produced is normal
Is there dominant negative affect in type I OI?
No
how much triple helical collagen is produced in type I OI?
1/2 as much
What is the structure of the collagen produced in Type I OI?
normal
If OI is AR what will mtuation be
abnormal collagen modification but no COL1A1 o COL1A2 mutation
clinical severity in AR OI is what
highly varibale
AR OI is deficient for enzymes involved in what
post-translational modification
What mutation causes stickler syndrome
Null mutation of type II collagen
Dominant negative missense mutations result in more ____ chondroplasias
severe
Severe myopia, brother short born with cleft palate, father short, bilateral hip replacements, reintal detachment is what disease
stickler syndrome
