Learning Objectives

• Describe the two-step transesterification process that removes introns.
• Identify the roles of snRNPs and the spliceosome.
• Recognize the GT-AG rule for splice site identification.
• Correlate splicing defects with clinical conditions like Spinal Muscular Atrophy (SMA) and SLE.

1. The Splicing Mechanism

Pre-mRNA (hnRNA) is transformed into mature mRNA through the precise removal of introns. This process is mediated by the spliceosome.

• The GT-AG Rule: Introns typically start with GU (at the 5′ splice site) and end with AG (at the 3′ splice site).
• The Spliceosome: Composed of snRNPs (small nuclear ribonucleoproteins), which consist of snRNA bound to proteins like the Smith (Sm) protein.

Step-by-Step Breakdown:

1. The primary transcript combines with U1 snRNP and other snRNPs to form the spliceosome.
2. First Cleavage: Occurs at the 5′ splice site. The 5′ end of the intron attaches to the Branch Point (Adenine).
3. Lariat Formation: A loop-shaped intermediate (lariat) is generated.
4. Second Cleavage: Occurs at the 3′ splice site. The lariat is released, and the two exons are joined together.

2. Clinical Correlations: Autoimmunity

The components of the spliceosome are frequent targets of the immune system in rheumatic diseases:

• Anti-Smith (Anti-Sm) Antibodies: Highly specific for Systemic Lupus Erythematosus (SLE). These target the proteins associated with snRNPs.
• Anti-U1 RNP Antibodies: Associated with Mixed Connective Tissue Disease (MCTD), SLE, and other rheumatic conditions.

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3. Clinical Correlations: Spinal Muscular Atrophy (SMA)

SMA is a devastating genetic disorder caused by defective snRNP assembly.

• Pathophysiology: Mutation in the SMN1 gene $\rightarrow$ $\downarrow$ SMN protein $\rightarrow$ Impaired snRNP assembly.
• Consequence: Congenital degeneration of the Anterior Horns of the spinal cord.
• Presentation: Symmetric weakness and hypotonia, commonly referred to as “Floppy Baby Syndrome.”

4. High-Yield Summary Table

Activity