Type of mutation seen in sickle cell anaemia:

Ans. (c) Point mutationRef: Harpers Biochemistry 30th Ed; Page No- 416* Mutations in DNA are transcribed into mRNA, and thus can cause changes in the encoded protein.* Severity of damage in mutation: Silent << Missense < Nonsense < Frameshift.* Basic point about mutation:* Transition# Pyrimidine to pyrimidine (eg, C to T) or Purine to purine (eg, A to C).* Transversion# Pyrimidine to purine (eg, C to C) or Purine to pyrimidine (eg, A to T).* Types of Mutation:Point mutation:* It occurs when one base in DNA is replaced by another, altering the codon in mRNA.* Types of Point mutation:# Silent mutation: Substitution of nucleotide occurs but codes for same amino acid. Example: CGA to CGG causes no change, since both codons specify arginine. Base changes most commonly occur in 3rd position of codon (tRNA wobble).# Missense mutation: Mutations result in one amino acid being replaced by another. Conservative missense mutation: If the new amino acid is similar in chemical structure. Example: - Sickle cell disease (substitution of glutamic acid with valine at position 6 in the b-globin chain).# Nonsense mutation: Mutations result in a premature termination of the growing polypeptide chain Nucleotide substitution resulting in early stop codon (UAC, UAA, UCA). Ex: CGA to UGA causes arginine to be replaced by a stop codon.Extra MilePoint mutationSilent mutationFlemoglobin (Sickle cell Anemia)Substitution of glutamic acid with valine at position 6 in the b-globin chainHb MilwaukeeGlutamateHb BristolAspartateHb SydneyAlanineMissense mutationAcceptable mutationPartially acceptable mutationUnacceptable mutationHb - hikari (b chain)Hb -S (b chain)Hb - M Boston (a chain)Non sense mutationCoding codon - Stop cdodonStop codon - Coding codonb-thalassemiaa-thalassemiaInsertions* Addition of base (when a base or a number of bases are added to DNA).* They can result in a protein with more amino acids than normal.Deletions* Removal of Base (when a base or a number of bases are removed from the DNA).Frameshift mutations:* Due to insertion or deletion of nucleotides that are not a multiple of three results in Frameshift mutation.* The reading frame is shifted so that completely different sets of codons are read beyond the point where the mutation starts.* Protein may be shorter or longer, and its function may be disrupted or altered.* Example: Duchenne muscular dystrophy, Tay-Sachs diseaseCystic fibrosis* Cystic fibrosis is most commonly caused by deletion of three nucleotides from the coding region of CFTR gene.* Deletion of phenylamine at the 508th position (dF508) in the protein encoded by that gene.* This dF508 mutation prevents normal folding of the CF trans- membrane conductance regulator (CFTR) protein, leading to its destruction by the proteasome.* Oligonucleotide probe is used to test for cystic fibrosis.Splice site mutation* Mutation at a splice site - retained intron in the mRNA - protein with impaired or altered function.* Example: Mutations that cause the incorrect splicing of b-globin mRNA are responsible for some b-thalassemia.* Others example: Rare causes of cancers, dementia, epilepsy