Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Feb 15;97(4):925–933. doi: 10.1172/JCI118515

The molecular basis of hereditary complement factor I deficiency.

T J Vyse 1, B J Morley 1, I Bartok 1, E L Theodoridis 1, K A Davies 1, A D Webster 1, M J Walport 1
PMCID: PMC507137  PMID: 8613545

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.

Full Text

The Full Text of this article is available as a PDF (324.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abramson N., Alper C. A., Lachmann P. J., Rosen F. S., Jandl J. H. Deficiency of C3 inactivator in man. J Immunol. 1971 Jul;107(1):19–27. [PubMed] [Google Scholar]
  2. Akli S., Chelly J., Mezard C., Gandy S., Kahn A., Poenaru L. A "G" to "A" mutation at position -1 of a 5' splice site in a late infantile form of Tay-Sachs disease. J Biol Chem. 1990 May 5;265(13):7324–7330. [PubMed] [Google Scholar]
  3. Alper C. A., Rosen F. S., Lachmann P. J. Inactivator of the third component of complement as an inhibitor in the properdin pathway. Proc Natl Acad Sci U S A. 1972 Oct;69(10):2910–2913. doi: 10.1073/pnas.69.10.2910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bode W., Meyer E., Jr, Powers J. C. Human leukocyte and porcine pancreatic elastase: X-ray crystal structures, mechanism, substrate specificity, and mechanism-based inhibitors. Biochemistry. 1989 Mar 7;28(5):1951–1963. doi: 10.1021/bi00431a001. [DOI] [PubMed] [Google Scholar]
  5. Catterall C. F., Lyons A., Sim R. B., Day A. J., Harris T. J. Characterization of primary amino acid sequence of human complement control protein factor I from an analysis of cDNA clones. Biochem J. 1987 Mar 15;242(3):849–856. doi: 10.1042/bj2420849. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  7. Engelke D. R., Hoener P. A., Collins F. S. Direct sequencing of enzymatically amplified human genomic DNA. Proc Natl Acad Sci U S A. 1988 Jan;85(2):544–548. doi: 10.1073/pnas.85.2.544. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  9. Goldberger G., Arnaout M. A., Aden D., Kay R., Rits M., Colten H. R. Biosynthesis and postsynthetic processing of human C3b/C4b inactivator (factor I) in three hepatoma cell lines. J Biol Chem. 1984 May 25;259(10):6492–6497. [PubMed] [Google Scholar]
  10. Goldberger G., Bruns G. A., Rits M., Edge M. D., Kwiatkowski D. J. Human complement factor I: analysis of cDNA-derived primary structure and assignment of its gene to chromosome 4. J Biol Chem. 1987 Jul 25;262(21):10065–10071. [PubMed] [Google Scholar]
  11. Grandchamp B., Picat C., de Rooij F., Beaumont C., Wilson P., Deybach J. C., Nordmann Y. A point mutation G----A in exon 12 of the porphobilinogen deaminase gene results in exon skipping and is responsible for acute intermittent porphyria. Nucleic Acids Res. 1989 Aug 25;17(16):6637–6649. doi: 10.1093/nar/17.16.6637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Innis M. A., Myambo K. B., Gelfand D. H., Brow M. A. DNA sequencing with Thermus aquaticus DNA polymerase and direct sequencing of polymerase chain reaction-amplified DNA. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9436–9440. doi: 10.1073/pnas.85.24.9436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Jay E., Bambara R., Padmanabhan R., Wu R. DNA sequence analysis: a general, simple and rapid method for sequencing large oligodeoxyribonucleotide fragments by mapping. Nucleic Acids Res. 1974 Mar;1(3):331–353. doi: 10.1093/nar/1.3.331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Julen N., Dauchel H., Lemercier C., Sim R. B., Fontaine M., Ripoche J. In vitro biosynthesis of complement factor I by human endothelial cells. Eur J Immunol. 1992 Jan;22(1):213–217. doi: 10.1002/eji.1830220131. [DOI] [PubMed] [Google Scholar]
  15. Katz Y., Strunk R. C. Synthesis and regulation of complement protein factor H in human skin fibroblasts. J Immunol. 1988 Jul 15;141(2):559–563. [PubMed] [Google Scholar]
  16. Kraut J. Serine proteases: structure and mechanism of catalysis. Annu Rev Biochem. 1977;46:331–358. doi: 10.1146/annurev.bi.46.070177.001555. [DOI] [PubMed] [Google Scholar]
  17. Krawczak M., Reiss J., Cooper D. N. The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet. 1992 Sep-Oct;90(1-2):41–54. doi: 10.1007/BF00210743. [DOI] [PubMed] [Google Scholar]
  18. Lachmann P. J., Nicol P. Reaction mechanism of the alternative pathway of complement fixation. Lancet. 1973 Mar 3;1(7801):465–467. doi: 10.1016/s0140-6736(73)91886-2. [DOI] [PubMed] [Google Scholar]
  19. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  20. Maillet F., Weiss L., Chibani J., Kazatchkine M. Déficit en facteur I, une protéine régulatrice du complément. Presse Med. 1990 Apr 21;19(16):762–762. [PubMed] [Google Scholar]
  21. Møller Rasmussen J., Teisner B., Jepsen H. H., Svehag S. E., Knudsen F., Kirstein H., Buhl M. Three cases of factor I deficiency: the effect of treatment with plasma. Clin Exp Immunol. 1988 Oct;74(1):131–136. [PMC free article] [PubMed] [Google Scholar]
  22. Nagasawa S., Stroud R. M. Mechanism of action of the C3b inactivator: requirement for a high molecular weight cofactor (C3b-C4bINA cofactor) and production of a new C3b derivative (C3b'). Immunochemistry. 1977 Nov-Dec;14(11-12):749–756. doi: 10.1016/0019-2791(77)90345-7. [DOI] [PubMed] [Google Scholar]
  23. Neurath H. Proteolytic enzymes, past and present. Fed Proc. 1985 Nov;44(14):2907–2913. [PubMed] [Google Scholar]
  24. Pangburn M. K., Schreiber R. D., Müller-Eberhard H. J. Human complement C3b inactivator: isolation, characterization, and demonstration of an absolute requirement for the serum protein beta1H for cleavage of C3b and C4b in solution. J Exp Med. 1977 Jul 1;146(1):257–270. doi: 10.1084/jem.146.1.257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Patthy L. Modular design of proteases of coagulation, fibrinolysis, and complement activation: implications for protein engineering and structure-function studies. Methods Enzymol. 1993;222:10–21. doi: 10.1016/0076-6879(93)22004-y. [DOI] [PubMed] [Google Scholar]
  26. Perkins S. J., Smith K. F. Identity of the putative serine-proteinase fold in proteins of the complement system with nine relevant crystal structures. Biochem J. 1993 Oct 1;295(Pt 1):109–114. doi: 10.1042/bj2950109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Robberson B. L., Cote G. J., Berget S. M. Exon definition may facilitate splice site selection in RNAs with multiple exons. Mol Cell Biol. 1990 Jan;10(1):84–94. doi: 10.1128/mcb.10.1.84. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Shapiro M. B., Senapathy P. RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res. 1987 Sep 11;15(17):7155–7174. doi: 10.1093/nar/15.17.7155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Shiang R., Murray J. C., Morton C. C., Buetow K. H., Wasmuth J. J., Olney A. H., Sanger W. G., Goldberger G. Mapping of the human complement factor I gene to 4q25. Genomics. 1989 Jan;4(1):82–86. doi: 10.1016/0888-7543(89)90318-2. [DOI] [PubMed] [Google Scholar]
  30. Sim R. B., Day A. J., Moffatt B. E., Fontaine M. Complement factor I and cofactors in control of complement system convertase enzymes. Methods Enzymol. 1993;223:13–35. doi: 10.1016/0076-6879(93)23035-l. [DOI] [PubMed] [Google Scholar]
  31. Solal-Celigny P., Laviolette M., Hebert J., Atkins P. C., Sirois M., Brun G., Lehner-Netsch G., Delâge J. M. C3b inactivator deficiency with immune complex manifestations. Clin Exp Immunol. 1982 Jan;47(1):197–205. [PMC free article] [PubMed] [Google Scholar]
  32. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  33. Thompson R. A., Lachmann P. J. A second case of human C3b inhibitor (KAF) deficiency. Clin Exp Immunol. 1977 Jan;27(1):23–29. [PMC free article] [PubMed] [Google Scholar]
  34. Towbin H., Staehelin T., Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. doi: 10.1073/pnas.76.9.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Vetvicka V., Reed W., Hoover M. L., Ross G. D. Complement factors H and I synthesized by B cell lines function to generate a growth factor activity from C3. J Immunol. 1993 May 1;150(9):4052–4060. [PubMed] [Google Scholar]
  36. Vyse T. J., Bates G. P., Walport M. J., Morley B. J. The organization of the human complement factor I gene (IF): a member of the serine protease gene family. Genomics. 1994 Nov 1;24(1):90–98. doi: 10.1006/geno.1994.1585. [DOI] [PubMed] [Google Scholar]
  37. Vyse T. J., Späth P. J., Davies K. A., Morley B. J., Philippe P., Athanassiou P., Giles C. M., Walport M. J. Hereditary complement factor I deficiency. QJM. 1994 Jul;87(7):385–401. [PubMed] [Google Scholar]
  38. Weil D., D'Alessio M., Ramirez F., Steinmann B., Wirtz M. K., Glanville R. W., Hollister D. W. Temperature-dependent expression of a collagen splicing defect in the fibroblasts of a patient with Ehlers-Danlos syndrome type VII. J Biol Chem. 1989 Oct 5;264(28):16804–16809. [PubMed] [Google Scholar]
  39. Whaley K. Biosynthesis of the complement components and the regulatory proteins of the alternative complement pathway by human peripheral blood monocytes. J Exp Med. 1980 Mar 1;151(3):501–516. doi: 10.1084/jem.151.3.501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Whitehead T. P., Kricka L. J., Carter T. J., Thorpe G. H. Analytical luminescence: its potential in the clinical laboratory. Clin Chem. 1979 Sep;25(9):1531–1546. [PubMed] [Google Scholar]
  41. Ziegler J. B., Alper C. A., Rosen R. S., Lachmann P. J., Sherington L. Restoration by purified C3b inactivator of complement-mediated function in vivo in a patient with C3b inactivator deficiency. J Clin Invest. 1975 Mar;55(3):668–672. doi: 10.1172/JCI107975. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES