Loss/Gain of function

Question 1

Describe loss of function

Answer 1

1. function of gene product is lost
2. mostly recessive as 1 wt allele is sufficient to provide enough protein product for the specific function

Question 2

Describe gain of function

Answer 2

1. the mutation alters the gene product function but does not abolish its expression
2. mostly dominant as the mutated allele prodeuces an altered roduct/function that the normal product does not have

Question 3

Effects of gain of function

Answer 3

1. expression in tissues in abnormal quantities or where it would not be normally expressed
2. leads to a constitutively active enzyme

Question 4

How can we determine is a mutation is a loss or gain of function one?

Answer 4

1. Biochemical analysis
2. Genetic evidence especially allelic heterogeneity

Question 5

Allelic heterogeneity

Answer 5

The phenomenon in which different mutations at the same gene/locus lead to similar phenotypic manifestations or same disease

Question 6

How can biochemical analysis allow us to determine if a mutation is a loss or gain of function one?

Answer 6

if the action of a mutant molecule is increased it is gain of function; otherwise it is a loss of function

Question 7

What is a recessive loss of function?

Answer 7

The dominant allele can still encode for the 100% production of a protein

Question 8

What is dominant loss of function?

Answer 8

The recessive allele cannot cover for the mutated allele and therefore produces 50% of the protein

Question 9

Haploinsufficiency

Answer 9

When a single functional copy of a gene is not sufficient enough product

Question 10

Describe Haploinsufficiency

Answer 10

• 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

Question 11

What are dosage-sensitive genes?

Answer 11

• 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

Question 12

recessive gain of function

Answer 12

both copies of the gene contains mutations that confer new functions

Question 13

dominant gain of function

Answer 13

even with one normal gene, the presence of a dominant mutated gene is sufficient to produce the phenotype associated

Question 14

dominant negative

Answer 14

loss of function that acts in a dominant way because the gene product is part of a multimeric complex

Question 15

why is dominant negative dominant?

Answer 15

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

Question 16

What is osteogenesis imperfecta an example of?

Answer 16

Dominant negative

Question 17

Give examples of Dominant negative

Answer 17

Osteogenesis imperfecta
HMGB1: Rage receptor

Question 18

Describe the condition of osteogenesis imperfecta

Answer 18

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

Question 19

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?

Answer 19

75%

Question 20

Examples of gain of function mutations

Answer 20

1. Charcot Maritou disease
2. Huntington’s Disease
3. Alpha 1 antitrypsin deficiency

Question 21

Charcot Maritou disease

Answer 21

Neurodegenerative disease: mutation in PNP22–> 3 copies of a gene: 50% higher expression

Question 22

Huntington’s Disease

Answer 22

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

Question 23

Alpha 1 antitrypsin deficiency

Answer 23

A new substrate is acquired

Question 24

Cases where allelic homogeneity is not linked to a gain-of-function

Answer 24

1. When mutations are homogenous
2. Founder effect
3. Selection favouring heterozygotes

Question 25

What is trinucleotide repeat expansion?

Answer 25

Regions within some genes that contain stretches of 3 nucleotides are repeated

Question 26

What happens when we have trinucleotide repeat expansion in non-coding regions of genes?

Answer 26

Transcriptional suppression/abnormal RNA processing

Question 27

What happens when we have trinucleotide repeat expansion in coding exons?

Answer 27

Repeats have modest expansions: longer polyGln tracts

Question 28

Anticipation

Answer 28

Disease becomes more severe throughout the generation and the earlier the onset

Question 29

Why does anticipation occur?

Answer 29

It is related to the stability of the expansion

Question 30

What are features of HD mutation transmission?

Answer 30

1. In paternal transmission there is a propensity toward larger repeat expansion than maternal
2. Positive correlation between expansion size and earlier onset and increased severity

Question 31

Fragile X syndrome

Answer 31

LOSS OF FUNCTION
- Caused by changes in the gene FMR1 on the X chromosome which is an expansion of the CGG triplet repeat: associated with hyper-methylation of the cytosine residues of the CGG repeats
- repeats can be above 200
- the FMR1 gene codes for a FMRP protein responsible for the development of connections between neurons

Question 32

Which is a gene that can be involved in both gain and loss of function?

Answer 32

PMP22 gene

Question 33

Describe PMP22 gene

Answer 33

1. alterations in PMP-22 conc causes CMT1A resulting from over expression of the PMP22 protein–> gain of function
2. Deletion of the same chromosome region that was duplicated in CMT1A–> loss of function