Loss/Gain of function Flashcards
(33 cards)
Describe loss of function
- function of gene product is lost
- mostly recessive as 1 wt allele is sufficient to provide enough protein product for the specific function
Describe gain of function
- the mutation alters the gene product function but does not abolish its expression
- mostly dominant as the mutated allele prodeuces an altered roduct/function that the normal product does not have
Effects of gain of function
- expression in tissues in abnormal quantities or where it would not be normally expressed
- leads to a constitutively active enzyme
How can we determine is a mutation is a loss or gain of function one?
- Biochemical analysis
- Genetic evidence especially allelic heterogeneity
Allelic heterogeneity
The phenomenon in which different mutations at the same gene/locus lead to similar phenotypic manifestations or same disease
How can biochemical analysis allow us to determine if a mutation is a loss or gain of function one?
if the action of a mutant molecule is increased it is gain of function; otherwise it is a loss of function
What is a recessive loss of function?
The dominant allele can still encode for the 100% production of a protein
What is dominant loss of function?
The recessive allele cannot cover for the mutated allele and therefore produces 50% of the protein
Haploinsufficiency
When a single functional copy of a gene is not sufficient enough product
Describe Haploinsufficiency
- dominant loss of function as a single functional gene is not enough to compensate for the loss of the other copy
- dosage of the gene product is below the level required for normal function
What are dosage-sensitive genes?
- gene products that are part of a quantitative signaling system
- gene products that compete with each other to determine a developmental switch
- gene products that cooperate with each other in interaction with fixed stoichiometry
recessive gain of function
both copies of the gene contains mutations that confer new functions
dominant gain of function
even with one normal gene, the presence of a dominant mutated gene is sufficient to produce the phenotype associated
dominant negative
loss of function that acts in a dominant way because the gene product is part of a multimeric complex
why is dominant negative dominant?
if you have one mutated allele and one wt allele and the protein is part of a complex then the mutant protein is enough to kill the activity of the complex
What is osteogenesis imperfecta an example of?
Dominant negative
Give examples of Dominant negative
Osteogenesis imperfecta
HMGB1: Rage receptor
Describe the condition of osteogenesis imperfecta
In normal conditions: 2 genes for collagen 1A1 and 1A2; they form a trimer [2 1A1 and 1A2]
Mild OI: When collagen 1A1 is mutated, it can be a cause for OI. This means that only 50% of the molecules are produced therefore our trimer will be 50% the physiological level
Sever OI: subtract 25% more of the functioning complexes of the cell
If we have one allele that is mutated and one allele that is wt, you still produce a 2N dosage of collagen 1, but 50% is wt and 50% is mutant. How many trimers will be mutated?
75%
Examples of gain of function mutations
- Charcot Maritou disease
- Huntington’s Disease
- Alpha 1 antitrypsin deficiency
Charcot Maritou disease
Neurodegenerative disease: mutation in PNP22–> 3 copies of a gene: 50% higher expression
Huntington’s Disease
GAIN OF FUNCTION
Protein aggregation: expansion of a triplet CAG, encoding polyglutamine
Normal allele: 6-39 CAG repeats
Intermediate allele: 36-41 repeats
Expanded allele: 36-121 repeats
Alpha 1 antitrypsin deficiency
A new substrate is acquired
Cases where allelic homogeneity is not linked to a gain-of-function
- When mutations are homogenous
- Founder effect
- Selection favouring heterozygotes
