Module 9: Effects of DNA mutations

• point mutation = one base pair is replaced with another

  -->Transition= purine ro purine (A --> G)

  pyrimidine ro pyrimidine (T --> C)

  -->Transversion= purine to pyrimidine vice versa (A or G --> T or C)
• insertion mutation = one or more base pairs are inserted
• deletion mutation = one or more base pairs are deleted
• inversion mutation = two or more base pairs are excised and reinserted in the opposite orientation
• Non-synonymous/ missense mutation = changes the amino acid sequence
• synonymous/ silent mutation = no effect on the amino acid sequence
• nonsense mutation = changes a codon for an amino acid into a stop codon
• read through mutation = changes a stop codon to a codon for an amino acid
• frameshift mutation = changes the reading frame (all codons downstream of the mutation are changed)
• reversing the effect of a mutation (suppressive mutations):

  *in second site reversion, a second mutation restores the correct amino acid sequence, through the nucleotide sequence is still altered
• monogenic disorders = inherited diseases caused by defects in individual genes (about 6000 known, 10,000 estimated in total)
• Effects of mutations on the cystic fibrosis gene:

  *the cystic fibrosis transmembrane regulator (CFTR) gene directs synthesis of the CFTR protein

  *the CFTR protein is a chloride channel on the cell surface and is responsible for proper balance of salt and water within and outside a cell

  *mutation in CFTR causes a dysfunction of the salt and water balance, leading to thick mucous and excessive loss of salt in the sweat
• loss of function (recessive disorder) = need mutations in both copies/ alleles of the gene
• carriers = mutation in only one copy/ allele of the gene
• commonest mutation in UK patients is called ΔF508 or ΔF508del (68% of cases)

  *Δ = three nucleotides

  *removes a codon for phenyl amine (F)

  -->508th amino acid in the polypeptide (1480 amino acids in total)

  *The CFTR protein is still made but does not get to the cell surface/ membrane
• 2nd commonest mutation is G542X (2.5% OF cases)

  *nonsense mutation

  *changes a glycine (G) at position 542 to a stop codon (X)

  *The CFTR protein is not made the abnormal position of the stop codon causes the mRNA to be degraded
• 3rd commonest mutation is G551D (1.5% of cases)

  *non-synonymous point mutation (missense mutation)

  *changes a glycine (G) at position 551 to an aspartic acid (D)

  *The CFTR protein is made and gets to the cell surface, but works at 4% of the normal rate
• Treatment for Cystic Fibrosis

  *Orkambi is made up of both Ivacaftor and Lumacaftor

  *Ivacaftor is a CTFR potentiator that facilitates increased chloride ion transport by potentiating the channel-open probability (or gating) of the CTFR protein at the cell surface

  *Lumacaftor improves the conformational stability of F508del- CTFR, resulting in increased processing and trafficking of mature CTFR protein to the cell surface
• mutations may not affect the phenotype as many organisms are diploids (two copies of each chromosome) so the unaffected chromosome can function normally

  *some people carry mutant alleles that do not affect them
• some human genes need both copies to be functional

  HAPLOINSUFFICIENCY = a mutation in just one will cause disease

  e.g. mandibulofacial dysostosis groin almeida type (MFDGA)

  -->craniofacial disorder caused by haploinsufficiency of RNA splicing

  factor EFTUD2

  -->part of U5- defective RNA splicing of pre-mRNAs required for

  development
• some diseases result from large deletion mutations
• unusual numbers of chromosomes might also lead to disease:

  -->trisomy = three copies of a chromosome

  -->Down syndrome caused by 3 copies of chromosome 21

  *monosomy = one chromosome missing

  -->monosomy of chromosome 7 leads ro bone marrow failure (high risk

  of leukaemia)
• chromosome translocation occurs when part of one chromosome becomes attached to another chromosome