Question

Difficulty: MediumGene Mutations and Chromosomal Aberrations

Sickle cell anaemia is a well-known inherited disease caused by a point mutation in the gene encoding the β\beta-globin chain of human haemoglobin. Which of the following alterations at the primary protein structure level directly causes the formation of abnormal haemoglobin S (HbS)?

  1. Replacement of glutamic acid with valine at the sixth position of the β\beta-globin polypeptide chainAnswer
  2. B
    Deletion of a nucleotide triplet resulting in the total absence of the β\beta-globin chain
  3. C
    Nondisjunction resulting in an extra copy of the chromosome bearing the globin gene family
  4. D
    Inversion of a chromosome segment containing the genes responsible for ABO blood grouping

Answer

The formation of abnormal haemoglobin S (HbS) in sickle cell anaemia is caused by the replacement of glutamic acid with valine at the sixth position of the β\beta-globin polypeptide chain.
Sickle cell anaemia is caused by a single nucleotide substitution in the β\beta-globin gene located on chromosome 11, where adenine is substituted by thymine. This alters the mRNA codon from GAG to GUG, causing valine to replace glutamic acid at the 6th position of the β\beta-chain, leading to polymerisation of haemoglobin molecules under low oxygen tension.

Step-by-Step Solution

1
Identify the genetic nature of sickle cell anaemia
It is a gene (point) mutation caused by a single base pair substitution in the DNA sequence of the β\beta-globin gene.
Understanding whether a trait is caused by a point mutation or structural/numerical chromosomal aberration narrows down the biological mechanisms.
2
Determine the molecular consequence at the protein level
The codon GAG (coding for glutamic acid) is mutated to GUG (coding for valine) at codon position 6 of the β\beta-globin polypeptide.
Replacing a hydrophilic amino acid (glutamic acid) with a hydrophobic amino acid (valine) alters the solubility and structural properties of haemoglobin under low oxygen conditions.

Key Concept

Gene Point Mutation and Molecular Consequences in Sickle Cell Anaemia
Estimated Time:1m 0s
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