As proteins are encoded by DNA sequences (genes), a change in nucleotide sequence can alter protein structure

• Changing the codon sequence of a gene may result in a change in the amino acid sequence of a protein
  

• If this change in protein sequence leads to the abrogation of its normal function, a disease condition may arise
  

An example of a genetic disease caused by a mutation that changes protein structure is sickle cell anaemia

• This disease arises from a point mutation – where a single specific base is changed in the gene sequence
  

Cause of Sickle Cell Anaemia

Sickle cell anaemia results from a base substitution to the 6th codon for the beta chain of haemoglobin

• The DNA sequence changes from CTC → CAC on the template strand (which is transcribed)
  

• The mRNA sequence consequently changes from GAG → GUG at the 6th codon position
  

• In the polypeptide, the sixth amino acid changes from glutamic acid to valine (Glu → Val)
  

The amino acid change alters the structure of haemoglobin, causing it to form insoluble fibrous strands

• The insoluble haemoglobin cannot carry oxygen as effectively, resulting in reduced oxygen supply to tissues
  

Sickle Cell Consequences

The formation of fibrous haemoglobin strands changes the shape of the red blood cell to a sickle shape

• The sickle cells are destroyed more rapidly than normal cells, leading to a low red blood cell count (anaemia)
  

• The sickle cells may form clots within the capillaries, blocking blood supply to vital organs and causing myriad health issues
  

Individuals require two copies of the mutant beta chain gene in order to develop sickle cell anaemia (it is a recessive trait)

• Individuals with only one mutant copy (heterozygous) will be unaffected carriers of the sickle cell trait
  

• These individuals demonstrate increased to malaria, as the parasite cannot effectively replicate within the blood cells
  

• Due to the adaptive advantage of being a carrier, the sickle cell mutation is still prevalent in regions with malaria (e.g. Africa)
  

  Blood Cell Comparison

  

  Normal Cell

  

  Sickle Cell