A significant number of mutations in the HBB gene that cause human β-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.

Key Concepts

Introns and Noncoding Sequences

Introns are noncoding segments of a gene that are transcribed into precursor mRNA but are removed during RNA splicing. Noncoding sequences upstream of a gene can regulate gene expression. Mutations in these regions can disrupt splicing or regulatory elements, leading to improper gene expression or protein production, which can result in severe diseases like β-thalassemia.

Gene Regulation

Gene regulation involves mechanisms that control the timing, location, and amount of gene expression. Regulatory elements, such as enhancers and silencers, can be located in noncoding regions. Mutations in these areas can alter the binding of transcription factors, leading to insufficient or excessive production of the gene product, contributing to disease pathology.

Splicing Mechanism

Splicing is the process by which introns are removed from precursor mRNA and exons are joined together to form mature mRNA. Mutations affecting splicing signals can lead to the inclusion of introns or exclusion of exons in the final mRNA. This can produce dysfunctional proteins or lead to nonsense-mediated decay, both of which can severely impact cellular function and contribute to conditions like β-thalassemia.