Understanding Genetic Blood Disorders and Mutations

The question asks about a specific genetic disorder that results from a particular change in the haemoglobin protein. Haemoglobin is a vital protein in red blood cells responsible for carrying oxygen throughout the body. It is made up of four protein chains: two alpha ($\alpha$) chains and two beta ($\beta$) chains.

Genetic disorders can occur when there are changes, or mutations, in the genes that code for these protein chains. These mutations can alter the structure or function of the protein, leading to health problems.

Identifying the Disorder: Glutamic Acid to Valine Substitution

The question specifically mentions a substitution of Glutamic acid (Glu) by Valine (Val) at the sixth position of the beta ($\beta$) globin chain of haemoglobin. This is a point mutation in the HBB gene, where a single nucleotide change (A to T) in the codon for the sixth amino acid position in the $\beta$ globin chain gene causes Glutamic acid (which is hydrophilic) to be replaced by Valine (which is hydrophobic).

This specific amino acid substitution is the molecular basis for a well-known genetic blood disorder.

What is Sickle-cell Anaemia?

Sickle-cell Anaemia is an inherited blood disorder characterized by an abnormality in the haemoglobin molecule. The haemoglobin in people with Sickle-cell Anaemia is called haemoglobin S (Hb S). This abnormal haemoglobin molecule tends to aggregate and polymerize when oxygen levels are low.

The aggregation of Hb S distorts the shape of the red blood cells, causing them to become rigid and sickle-shaped, resembling a crescent moon. Normal red blood cells are flexible and disc-shaped, allowing them to flow smoothly through narrow blood vessels. The sickle-shaped cells, however, can block blood flow in small vessels, leading to pain, organ damage, and other serious complications.

The crucial link is that the substitution of Glutamic acid by Valine at the sixth position of the beta globin chain is precisely the mutation that causes haemoglobin S and results in Sickle-cell Anaemia.

Why Other Options are Incorrect

Let's look at the other options provided:

• Phenylketonuria (PKU): This is a metabolic disorder caused by a mutation in the PAH gene, which codes for the enzyme phenylalanine hydroxylase. This enzyme is needed to break down the amino acid phenylalanine. A deficiency in this enzyme leads to a build-up of phenylalanine in the body, causing neurological problems if not treated. It is not related to a mutation in the haemoglobin beta chain or the Glu to Val substitution.
• Haemophilia: This is a group of bleeding disorders in which blood does not clot properly. Haemophilia is typically caused by mutations in genes that code for blood clotting factors, such as Factor VIII (Haemophilia A) or Factor IX (Haemophilia B). These are usually X-linked recessive disorders. It is not related to haemoglobin structure.
• Thalassemia: This is another group of inherited blood disorders affecting haemoglobin production. Thalassemia is caused by mutations or deletions in the genes that control the production of the alpha or beta globin chains of haemoglobin. This leads to reduced production of one or both types of globin chains, resulting in insufficient haemoglobin and smaller, paler red blood cells (anaemia). While it involves globin chains, the specific cause is a reduction in production, not a single amino acid substitution like the one described for Sickle-cell Anaemia.

Therefore, the specific substitution of Glutamic acid by Valine at the sixth position of the beta globin chain is the defining molecular characteristic of Sickle-cell Anaemia among the given options.

Revision Table: Genetic Blood Disorders

Review the key features of the disorders discussed:

Additional Information on Haemoglobin and Mutations

Haemoglobin is a tetrameric protein, meaning it consists of four subunits. In adults, the most common type is Haemoglobin A (Hb A), composed of two $\alpha$ and two $\beta$ globin chains.

A point mutation is a change in a single nucleotide base in the DNA sequence. In the case of Sickle-cell Anaemia, the mutation occurs in the gene for the beta globin chain.

The codon for Glutamic acid (Glu) is typically GAG or GAA. In Sickle-cell Anaemia, the codon for the sixth position of the beta globin chain is changed from GAG to GTG. This single base change (A to T) results in the incorporation of Valine (Val) instead of Glutamic acid at that position. This is a non-polar (hydrophobic) amino acid replacing a polar (hydrophilic) amino acid, which significantly changes the properties of the haemoglobin molecule, especially when oxygen is released.

Understanding the specific amino acid substitution is key to understanding the molecular basis of Sickle-cell Anaemia. This mutation is a classic example used to teach the relationship between a gene mutation, protein structure alteration, and the resulting disease phenotype.