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Linking C5 deficiency to an exonic splicing enhancer mutation
Nicole Pfarr1, Dirk Prawitt, Michael Kirschfink
1Children's Hospital of Johannes Gutenberg-University of Mainz, Mainz, Germany.
Journal of Immunology (Baltimore, Md. : 1950)
|March 22, 2005
Summary
A rare genetic mutation in complement component 5 (C5) exon 10 causes C5 deficiency, leading to severe recurrent infections. This study identifies a noncanonical splicing mutation altering an exonic splicing enhancer, impacting C5 production.
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- The complement system, a key part of innate immunity, protects against infections.
- Complement component 5 (C5) dysfunction is linked to severe, recurrent infections.
- C5 deficiency leads to a significant increase in susceptibility to pathogenic microorganisms.
Observation:
- A patient with C5 deficiency exhibited immunochemical and functional deficits.
- Genetic analysis revealed an A-to-G transition in C5 exon 10, changing lysine to arginine.
- This mutation was heterozygous in family members with reduced C5 and homozygous in the patient with near-complete deficiency.
Findings:
- The A-to-G transition in exon 10 disrupted an exonic splicing enhancer (ESE).
- This ESE alteration led to exon 10 skipping during mRNA splicing.
- Exon skipping resulted in a premature STOP codon, causing C5 deficiency.
Implications:
- Identifies a novel noncanonical splicing mutation affecting an ESE in C5.
- Demonstrates how seemingly silent mutations can cause significant disease phenotypes.
- Highlights the critical role of ESEs in maintaining proper gene expression and function.