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.

Verified step by step guidance

1. Understand that the HBB gene encodes the beta-globin subunit of hemoglobin, and proper expression of this gene is crucial for normal hemoglobin function.
2. Recognize that introns and upstream noncoding sequences contain important regulatory elements such as splice sites, promoters, enhancers, and silencers that control gene expression and mRNA processing.
3. Explain that mutations in introns can disrupt normal splicing by altering splice donor or acceptor sites, leading to incorrect removal of introns and potentially producing abnormal or nonfunctional mRNA transcripts.
4. Note that mutations in upstream noncoding regions can affect promoter or enhancer sequences, reducing or abolishing transcription initiation and thus decreasing the amount of beta-globin mRNA produced.
5. Conclude that although these mutations do not change the protein-coding sequence directly, they can severely impair gene expression or mRNA processing, resulting in little or no functional beta-globin protein and causing severe β-thalassemia.

Key Concepts

Role of Introns and Noncoding Sequences in Gene Expression

Introns and upstream noncoding regions contain regulatory elements essential for proper gene expression, such as splice sites and promoters. Mutations here can disrupt normal RNA processing or transcription initiation, leading to faulty or reduced production of the β-globin protein, even though the coding sequence remains unchanged.

Splicing Mechanism and Its Impact on mRNA

Splicing removes introns from pre-mRNA to produce mature mRNA. Mutations in intronic splice sites can cause incorrect splicing, resulting in abnormal mRNA that may be degraded or translated into dysfunctional proteins, contributing to severe β-thalassemia symptoms.

Regulatory Elements and Their Influence on Gene Expression Levels

Upstream noncoding sequences often contain promoters and enhancers that regulate gene transcription. Mutations in these regions can reduce or abolish gene expression, decreasing β-globin production and causing severe disease phenotypes despite an intact coding region.