Molecular characterization of two novel cases of complete complement inhibitor Factor I deficiency.
Författare
Summary, in English
Factor I (FI) is the major complement inhibitor that degrades activated complement components C3b and C4b in the presence of specific cofactors. Complete FI deficiency results in secondary complement deficiency due to uncontrolled spontaneous alternative pathway activation. In this study we describe two unrelated patients with complete FI deficiency and undetectable alternative complement pathway activity. Both patients had experienced recurrent infections and arthralgia/arthritis. In one patient, analysis of genomic DNA revealed deletion of two adenine nucleotides in exon 2 of the CFI gene (c.133-134delAA), causing a frame shift and premature STOP codon/termination in the FIMAC (FI-membrane attack complex) domain (p.K45SfsX11). The other patient carried an A>T substitution in exon 6 (c.866A>T) encoding the LDLr2 (low density lipoprotein receptor) domain (p.D289V), resulting in an aspartic acid to valine change. Both patients were homozygous for the mutations while their healthy parents were heterozygous carriers. The mutations were introduced into recombinant FI, causing lack of FI expression and secretion upon transient transfection. Mutation p.K45SfsX11 theoretically allows expression of a 55 amino acid fragment of FI that lacks the serine protease domain, preventing proteolytic activity. In contrast, aspartic acid D289 is crucial for folding of FI. This report describes the molecular and functional consequences of two novel mutations of FI, providing a unique insight into the pathogenesis of complete FI deficiency in these patients.
Avdelning/ar
Publiceringsår
2011
Språk
Engelska
Sidor
1068-1072
Publikation/Tidskrift/Serie
Molecular Immunology
Volym
48
Issue
8
Fulltext
Länkar
Dokumenttyp
Artikel i tidskrift
Förlag
Pergamon Press Ltd.
Ämne
- Immunology in the medical area
Status
Published
Forskningsgrupp
- Protein Chemistry, Malmö
- Clinical Chemistry, Malmö
ISBN/ISSN/Övrigt
- ISSN: 1872-9142