Module 9 - Effects of DNA mutation Flashcards
Point mutations
One base is replaced by another: can be either transition (purine-purine or pyrimidine-pyrimidine) or transversion (purine-pyrimidine)
This can occur due to base analogues or tautomers
Insertion mutation
Occurs as nucleotdies are inseted into the nucleotide sequences
This can occur due to intercalating agents (ethidium bromide)
Deletion mutations
The deletion of a base pair
Inversion mutations
Two or more base pairs are excised and reinserted in the opposite direction
Synonymous mutations
Have no effect on the amino acid sequence (UUA and UUG both produce leucine)
Also called a silent mutation
Non-synonymous mutations
Changes the amino acid sequence
Also called a missense mutation
Nonsense mutations
Changes a codon for an amino acid into a stop sequence
Readthrough mutations
Changes a stop sequence into an amino acid sequence
Frameshift mutations
Shifts the reading frame which causes multiple changes to successive amino acids
Suppressive mutations
In second site reversion, a second mutation restores the correct amino acid sequence, though the nucleotide sequence is still altered
Monogenic disorders
Caused by defects in a single gene, roughly 6,000 of them
Most common - inherited breast cancer
Second most common - cystic fibrosis (~1/2500 born with CF each year in the UK)
CFTR gene
Cystic fibrosis transmembrane regulator genes
CFTR protein is a chloride channel on the cell surface and is responsible for the proper balance of salt and water within a cell and outside the cell
If this gene is mutated and dysfunctional, the water and salt balance is messed up and thick mucous is produced and excessive salt is lost during perspiration
The most common form of cystic fibrosis mutation
Due to the deletion of three nucleotides which removes a codon for phenylalanine (F), the 508th/1480 amino acid in the polypeptide.
This causes the polypeptide to be made but not into the surface of the membrane.
Called ΔF508 or F508del, causes 68% of cases
The second most common form of cystic fibrosis mutation
Changes a glycine (G) at position 542 into a stop codon (X)
Nonsense mutation, forming G542X
2.5% of cases
The third most common form of cystic fibrosis mutation
Changes a glycine (G) at position 551 to an aspartic acid (D)
Non-synonymous point mutation (Missense mutation), forming G551D
1.5% of cases
Orkambi
Made up of Ivacaftor and Lumacaftor.
Has been shown to be effective in people with cystic fibrosis with the F508del mutation.
Lumacaftor
Improves the conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature CFTR protein to the cell surface
Ivacaftor
CFTR potentiator that facilitates increased chloride ion transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface
haploinsufficiency
Occurs when only one copy of a gene is functional, causing too little protein to be produced
Alagille syndrome
An example of haploinsufficiency
It results in heart abnormalities and liver problems from abnormal bile ducts
the gene codes for the CD339 (JAG1) protein which is involved in cell-to-cell signaling during embryo development
How being a carrier may affect the possible effect of a disease?
With some human genes, being a carrier gives a predisposition to disease:
Retinoblastoma, retinal cancer, is an example:
Sporadic retinoblastoma is rare and randomly occurs throughout the population; however, familial retinoblastoma is more common in affected families
If someone in the family has only one functional copy of the retinal tumour-resistant gene
Trisomy
Caused by having three copies of a chromosome
Monosomy
Caused by having one copy of a chromosome
Trisomy 7 - bone marrow underdeveloped: high chance of leukaemia
Chromosome translocation
Occurs as part of one chromosome moves to another chromosome
A common form - chromosome 22 and chromosome 9 exchange segments (this can cause leukaemia)
