Linking C5 Deficiency to an Exonic Splicing Enhancer Mutation

As an important component of the innate immune system, complement provides the initial response to prevent infections by pathogenic microorganisms. Patients with dysfunction of C5 display a propensity for severe recurrent infections. In this study, we present a patient with C5 deficiency demonstrate...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of immunology (1950) 2005-04, Vol.174 (7), p.4172-4177
Main Authors: Pfarr, Nicole, Prawitt, Dirk, Kirschfink, Michael, Schroff, Claudia, Knuf, Markus, Habermehl, Pirmin, Mannhardt, Wilma, Zepp, Fred, Fairbrother, William, Loos, Michael, Burge, Christopher B, Pohlenz, Joachim
Format: Article
Language:English
Subjects:
Alternative Splicing
Child, Preschool
Complement C5 - deficiency
Complement C5 - genetics
DNA Mutational Analysis
Exons
Family Health
Humans
Male
Mutation
Phenotype
Sequence Analysis, DNA
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:As an important component of the innate immune system, complement provides the initial response to prevent infections by pathogenic microorganisms. Patients with dysfunction of C5 display a propensity for severe recurrent infections. In this study, we present a patient with C5 deficiency demonstrated by immunochemical and functional analyses. Direct sequencing of all C5 exons displayed no mutation of obvious functional significance, except for an A to G transition in exon 10 predicting an exchange from lysine to arginine. This sequence alteration was present in only one allele of family members with a reduced serum C5 concentration and in both alleles of the patient with almost complete C5 deficiency, suggesting that this alteration may be producing the phenotype. Recent findings indicate that distinct nucleotide sequences, termed exonic splicing enhancers (ESEs), influence the splicing process. cDNA from all family members harboring the mutated allele showed skipping of exon 10, which resulted in a premature STOP codon, explaining the lack of C5 in the propositus. Sequence analysis of the mutated region revealed the substitution to be located within an ESE, as predicted by the RESCUE-ESE program. The altered ESE sequence is located close to the 5' splicing site and also lowers the predicted strength of the splice site itself. This apparently inconsequential sequence alteration represents a noncanonical splicing mutation altering an ESE. Our finding sheds a new light on the role of putative silent/conservative mutations in disease-associated genes.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.174.7.4172