The molecular basis of hereditary complement factor I deficiency.

Abstract

The molecular basis of hereditary complement factor I deficiency is described in two pedigrees. In one pedigree, there were two factor I-deficient siblings, one of whom was asymptomatic and the other suffered from recurrent pyogenic infections. Their factor I mRNA was analyzed by reverse transcription of fibroblast RNA followed by amplification using the polymerase chain reaction. Both siblings were homozygous for the same transversion (adenine to thymine) at nucleotide 1282 in the cDNA. This mutation causes histidine-400 to be replaced by leucine. The altered histidine is a semi-conserved residue within the serine proteinase family, although no function has been ascribed to it. The proband of the second pedigree studied was found to be a compound heterozygote. One allele had the same mutation as the first family, the second allele had a donor splice site mutation that resulted in the deletion of the mRNA encoded in the fifth exon (a low-density lipoprotein receptor domain) from its transcript. ( J. Clin. Invest. 1996. 97:925-933.)

Mutations in Complement Factor I Predispose to Development of Atypical Hemolytic Uremic Syndrome

“…Protein electrophoresis was performed on 12% SDS-PAGE before transfer to nitrocellulose (Hybond ECL; Amersham). The membrane then was stained with a mouse anti-human factor I mAb (MCA507; Serotec, Oxford, UK), which recognizes the 56-kD heavy chain (20). …”

Mutations in complement factor I as found in atypical hemolytic uremic syndrome lead to either altered secretion or altered function of factor I

“…The light chain comprises the SP domain [27]. The concentration of FI in blood is rather low, 35 mg/mL, and it is mainly produced by hepatocytes [28] but also by monocytes [29] and fibroblasts [30].In this report, 14 heterozygous mutations in the FI gene (CFI, complement factor I), previously identified by different groups [4,7,8,31,32], have been studied to determine their effects on protein expression, secretion and function. To date, only the locations of these CFI mutations and the clinical descriptions of patient symptoms have been reported.…”

Molecular characterization of two novel cases of complete complement inhibitor Factor I deficiency

“…Furthermore, in the absence of FI, no iC3b and C3dg can be generated and these are responsible for efficient phagocytosis as well as B--cell memory generation. This explains the predisposition to pyogenic infections in FI deficient patients (Castillo et al, 2009;Vyse et al, 1996;Wahn et al, 1984). Individuals with FI deficiency present with recurrent bacterial infections of the upper and lower respiratory tract, septicaemia and/or meningitis (Floret et al, 1991;Leitao et al, 1997).…”

“…It comprises 13 exons with exons 1--8 encoding the heavy chain and exons 9--13 the serine protease region (Goldberger et al, 1987). Complete FI deficiency is associated with recurrent infections and in some cases also with glomerulonephritis and autoimmune diseases such as systemic lupus erythematosus (Nilsson et al, 2007;Vyse et al, 1996). Heterozygous deficiency of FI predisposes to atypical haemolytic uremic syndrome (Bienaime et al, 2010;Nilsson et al, 2010a;Richards et al, 2001).…”