|MadSci Network: Genetics|
Hi Laura, Cystic fibrosis is a good example of how a single amino acid change can lead to disastrous outcomes. Just to remind ourselves, cystic fibrosis is an autosomal recessive multisystem disease characterised by the production of abnormally thick mucus. Affected organs include the lung, the pancreas, the reproductive tract, etc. It has been estimated that 1 in 25 Caucasians are heterozygous carriers of the defected CF gene. The mutated gene is located on chromosome 7 and it encodes for the cystic fibrosis transmembrane regulator (CFTR) which is a modulator of a membrane chloride channel. As your have pointed out, the defect CFTR peptide is just 1 amino acid shorter than normal, then how does it lead to such profound effect? The reason can be understood if we re-visit some basic biochemical concepts. Peptide chains have 4 degrees of conformation:- 1. primary conformation concerns about the sequence of amino acid in the peptide chain; 2. secondary conformation concerns about the hudrogen bonding that gives rise to basic structure like alpha-helices and beta-pleated sheets, etc.; 3. tertiary conformation concerns about the actual folding of the protein into its functional shape; 4. whereas quaternary conformation concerns about how individual folded protein are linked together in a functional unit (e.g. 4 folded globin chains linked as a single haemoglobin molecule). It turns out that the most important functional determinant of protein structure lies in its higher degree conformation i.e. tertiary and quaternary. This is to say that the most important functional feature of a protein is its 3-D shape. Individual amino acid can be changed, or even inserted/deleted, but as long as the crucial amino acids that hold the protein together and determine the folding of the peptide remained, the shape of the resulting protein would be the same, so as its function. However, in cystic fibrosis, the missing amino acid is in a crucial position that contribute to the structural folding of the resulting peptide. Therefore, the folding of the CFTR becomes defective, and a non- functional CFTR is produced. AS a result, chloride ion transport is disrupted across the cell surface leading to the production of abnormally thick mucus. Perhaps an even more impressive example is sickle-cell anaemia. The genetic abnormality is a single nucleotide change in the DNA leading to an amino acid substitution in the gene coding for the beta- globin chain (Glu -> Val at position 6). This single amino acid substitution (due to its crucial posision), with exactly the same resultant peptide length, is enough to disrupt the tertiary conformation of the beta-globin chain leading to all clinical manifestation of sickle- cell anaemia. Genetics is a fascinating subject and I hope the above information helps:- ) Joshua Chai Student DOctor School of Clinical Medicine University of Cambridge, UK
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