Splicing is a critical post-transcriptional modification that converts precursor mRNA (pre-mRNA) into mature mRNA by removing noncoding regions (introns) and joining coding sequences (exons). This ensures that mRNA can be properly translated into a functional protein.
Mechanism of Splicing
- Recognition of Splice Sites
- Introns typically begin with GU at the 5′ splice site and end with AG at the 3′ splice site.
- snRNPs (small nuclear ribonucleoproteins) recognize these consensus sequences and mediate splicing.
- snRNPs + other proteins form the spliceosome complex.
- Spliceosome Formation
- U1 snRNP binds to the 5′ splice site (GU): U1 snRNP
- U2 snRNP binds near the branch point adenine: U2 snRNP
- Spliceosome assembles: U1, U2, U4, U5, U6 snRNPs
- Intron loop (lariat) forms: Branch point A nucleotide
- Cleavage and joining of exons: RNA ligase activity
- Splicing Result
- Introns are removed as lariat structures
- Exons precisely joined → Mature mRNA ready for translation
Key Clinical Correlations
| Condition | Molecular Defect | Pathophysiology | Clinical Presentation |
|---|---|---|---|
| Spinal Muscular Atrophy (SMA) | Defective SMN protein → abnormal snRNP assembly | Loss of anterior horn cells | Floppy baby syndrome, symmetric weakness |
| Systemic Lupus Erythematosus (SLE) | Anti-U1 snRNP antibodies | Interferes with normal splicing | Multi-system autoimmune disease |
| Mixed Connective Tissue Disease (MCTD) | Anti-U1 RNP antibodies | Similar to SLE features | Arthritis, Raynaud phenomenon, myositis |
Key Points to Remember
- Introns: noncoding; removed
- Exons: coding; joined
- Spliceosome: made of snRNA + proteins (snRNPs)
- 5′ GU – 3′ AG rule defines intron boundaries
- Clinical link: snRNP dysfunction → neurodegenerative or autoimmune disease
Learning Objective
Explain the mechanism of pre-mRNA splicing and its clinical implications, including diseases caused by defective snRNP function (e.g., spinal muscular atrophy and SLE).
