Question

A significant number of mutations in the \(H B B\) gene that cause human \(\beta\) -thalassemia occur within introns or in upstream noncoding sequences. Explain why mutations in these regions often lead to severe disease, although they may not directly alter the coding regions of the gene.

Short answer

Answer: Mutations in introns or upstream noncoding sequences of the HBB gene can cause severe β-thalassemia by disrupting normal gene expression or regulation. Introns can contain regulatory elements that affect RNA splicing and mRNA stability, leading to an abnormal or nonfunctional β-globin protein. Upstream noncoding sequences contain regulatory elements controlling gene expression; mutations can alter transcription factor binding and affect β-globin protein levels. Both of these scenarios can lead to the symptoms associated with β-thalassemia.

Step-by-step solution

1. Understanding β-thalassemia and the HBB gene

β-thalassemia is a blood disorder caused by a mutation in the HBB gene, which provides instructions for producing the β-globin protein. This protein is a building block for hemoglobin, the protein responsible for carrying oxygen throughout the body. A mutation in the HBB gene can lead to reduced levels of hemoglobin, which in turn can cause anemia (lack of oxygen in tissues), fatigue, weakness, and more severe health problems.

2. Introns and their role in gene expression

Introns are noncoding sequences found within a gene. Their main role is to be removed during the process of RNA splicing, allowing exons (coding sequences) to be joined together to form the final mature mRNA molecule. Introns can contain critical regulatory elements, such as enhancers and splicing signals, that influence gene expression. Mutations in these regions can disrupt normal gene expression by affecting RNA splicing and the stability of the mRNA molecule, leading to the production of an abnormal or nonfunctional β-globin protein.

3. Upstream noncoding sequences and their role in gene regulation

Upstream noncoding sequences are located before the gene's start codon and are not translated into proteins. These sequences can contain regulatory elements, such as promoters and transcription factor binding sites, which control when and where a gene is expressed. Mutations in these regions can alter the binding of transcription factors, leading to abnormal gene expression or reduced levels of the β-globin protein, causing β-thalassemia.

4. Concluding the explanation

In conclusion, mutations in introns or upstream noncoding sequences of the HBB gene that cause human β-thalassemia often lead to severe disease because they can disrupt normal gene expression or regulation. Even though these mutations may not directly affect the gene's coding region, they can still negatively impact the production, stability, or function of the β-globin protein, ultimately causing the symptoms associated with β-thalassemia.