Abstract
The complement system is an important effector arm of innate immunity and plays a crucial role in the defense against common pathogens. But effective defense and maintenance of homeostasis requires a careful balance between complement activation and regulation. Factor I (FI) is one of the most important regulators of the complement system. Complete FI deficiency is a rare autosomal recessive disorder typically resulting in severe, recurrent infection by encapsulated bacteria. In the present study, we describe two patients from unrelated families with complete FI deficiency diagnosed at very different ages: Patient 1 is a 60-year-old man who had experienced several severe infections (pneumonia, meningitis, sepsis) since childhood, one of which caused significant and permanent neurologic sequelae. In contrast, patient 2 was diagnosed at the age of 4 years after a single infectious episode (otitis media) and through detection of a flat beta2 peak on serum protein electrophoresis. This early diagnosis of FI deficiency enabled prompt implementation of a therapeutic intervention consisting of vaccination with encapsulated bacteria and prophylactic antibiotics. The two patients had novel homozygous mutations in the CFI gene (p.Gly162Asp and p.His380Arg) that disrupted protein function. Interestingly, p.His380Arg is the first mutation described affecting a residue of the highly conserved FI catalytic triad (His380, Asp429, and Ser525). This study illustrates the importance of early versus late diagnosis of FI deficiency and, in general, highlights the clinical relevance of prompt detection of complement system deficiencies.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Dunkelberger JR, Song WC. Complement and its role in innate and adaptive immune responses. Cell Res. 2010;20(1):34–50.
Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11(9):785–97.
Merle NS, Church SE, Fremeaux-Bacchi V, Roumenina LT. Complement system part I—molecular mechanisms of activation and regulation. Front Immunol. 2015;6:262.
de Paula PF, Barbosa JE, Junior PR, Ferriani VP, Latorre MR, Nudelman V, et al. Ontogeny of complement regulatory proteins—concentrations of factor h, factor I, c4b-binding protein, properdin and vitronectin in healthy children of different ages and in adults. Scand J Immunol. 2003;58(5):572–7.
Nilsson SC, Sim RB, Lea SM, Fremeaux-Bacchi V, Blom AM. Complement factor I in health and disease. Mol Immunol. 2011;48(14):1611–20.
Tsiftsoglou SA, Arnold JN, Roversi P, Crispin MD, Radcliffe C, Lea SM, et al. Human complement factor I glycosylation: structural and functional characterisation of the N-linked oligosaccharides. Biochim Biophys Acta. 2006;1764(11):1757–66.
Goldberger G, Arnaout MA, Aden D, Kay R, Rits M, Colten HR. Biosynthesis and postsynthetic processing of human c3b/c4b inactivator (factor I) in three hepatoma cell lines. J Biol Chem. 1984;259(10):6492–7.
Reis E S, Falcão DA, Isaac L. Clinical aspects and molecular basis of primary deficiencies of complement component C3 and its regulatory proteins factor I and factor H. Scand J Immunol. 2006;63(3):155–68.
Loirat C, Frémeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60.
Kavanagh D, Yu Y, Schramm EC, Triebwasser M, Wagner EK, Raychaudhuri S, et al. Rare genetic variants in the CFI gene are associated with advanced age-related macular degeneration and commonly result in reduced serum factor I levels. Hum Mol Genet. 2015;24(13):3861–70.
Seddon JM, Yu Y, Miller EC, Reynolds R, Tan PL, Gowrisankar S, et al. Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nat Genet. 2013;45(11):1366–70.
Abramson N, Alper CA, Lachmann PJ, Rosen FS, Jandl JH. Deficiency of C3 inactivator in man. J Immunol. 1971;107(1):19–27.
Vyse TJ, Morley BJ, Bartok I, Theodoridis EL, Davies KA, Webster AD, et al. The molecular basis of hereditary complement factor I deficiency. J Clin Invest. 1996;97(4):925–33.
Franco-Jarava C, Colobran R, Mestre-Torres J, Vargas V, Pujol-Borrell R, Hernández-González M. Clinical laboratory standard capillary protein electrophoresis alerted of a low C3 state and lead to the identification of a factor I deficiency due to a novel homozygous mutation. Immunol Lett. 2016;174:19–22.
Bay JT, Katzenstein TL, Kofoed K, Patel D, Skjoedt MO, Garred P, et al. Novel CFI mutation in a patient with leukocytoclastic vasculitis may redefine the clinical spectrum of complement factor I deficiency. Clin Immunol. 2015;160(2):315–8.
Haerynck F, Stordeur P, Vandewalle J, Van Coster R, Bordon V, De Baets F, et al. Complete factor I deficiency due to dysfunctional factor I with recurrent aseptic meningo-encephalitis. J Clin Immunol. 2013;33(8):1293–301.
Alba-Domínguez M, López-Lera A, Garrido S, Nozal P, González-Granado I, Melero J, et al. Complement factor I deficiency: a not so rare immune defect: characterization of new mutations and the first large gene deletion. Orphanet J Rare Dis. 2012;7:42.
Nita IM, Genel F, Nilsson SC, Smart J, Truedsson L, Choo S, et al. Molecular characterization of two novel cases of complete complement inhibitor factor I deficiency. Mol Immunol. 2011;48(8):1068–72.
Nilsson SC, Trouw LA, Renault N, Miteva MA, Genel F, Zelazko M, et al. Genetic, molecular and functional analyses of complement factor I deficiency. Eur J Immunol. 2009;39(1):310–23.
Ponce-Castro IM, González-Rubio C, Delgado-Cerviño EM, Abarrategui-Garrido C, Fontán G, Sánchez-Corral P, et al. Molecular characterization of complement factor I deficiency in two Spanish families. Mol Immunol. 2008;45(10):2764–71.
Baracho GV, Nudelman V, Isaac L. Molecular characterization of homozygous hereditary factor I deficiency. Clin Exp Immunol. 2003;131(2):280–6.
Riera C, Lois S, de la Cruz X. Prediction of pathological mutations in proteins: the challenge of integrating sequence conservation and structure stability principles. Wiley Interdiscip Rev Comput Mol Sci. 2014;4(3):249–68.
Capriotti E, Fariselli P, Casadio R. I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure. Nucleic Acids Res. 2005;33(Web Server issue):W306–10.
Bromberg Y, Rost B. Correlating protein function and stability through the analysis of single amino acid substitutions. BMC Bioinformatics. 2009;10(Suppl 8):S8.
Le Quintrec M, Lionet A, Kamar N, Karras A, Barbier S, Buchler M, et al. Complement mutation-associated de novo thrombotic microangiopathy following kidney transplantation. Am J Transplant. 2008;8(8):1694–701.
Roversi P, Johnson S, Caesar JJ, McLean F, Leath KJ, Tsiftsoglou SA, et al. Structural basis for complement factor I control and its disease-associated sequence polymorphisms. Proc Natl Acad Sci U S A. 2011;108(31):12839–44.
Martínez VG, Moestrup SK, Holmskov U, Mollenhauer J, Lozano F. The conserved scavenger receptor cysteine-rich superfamily in therapy and diagnosis. Pharmacol Rev. 2011;63(4):967–1000.
Tsiftsoglou SA, Willis AC, Li P, Chen X, Mitchell DA, Rao Z, et al. The catalytically active serine protease domain of human complement factor I. Biochemistry. 2005;44(16):6239–49.
Gabutti G, Stefanati A, Kuhdari P. Epidemiology of Neisseria meningitidis infections: case distribution by age and relevance of carriage. J Prev Med Hyg. 2015;56(3):E116–20.
Grumach AS, Kirschfink M. Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. Mol Immunol. 2014;61(2):110–7.
Acknowledgements
We are deeply grateful to the affected individuals and their families who participated in this study. We also acknowledge Celine Cavallo for English language assistance.
Funding
This study was funded by Instituto de Salud Carlos III, grant PI14/00405, co-financed by the European Regional Development Fund (ERDF).
Author information
Authors and Affiliations
Contributions
Clinical data and management of the patients: XSM, FMR, VMB, AMN, PSP.
Immunological laboratory analysis: CFJ, MHG, MGP.
Genetic, molecular and bioinformatics analysis: RC, EAC, XdC, CFJ.
Writing the manuscript and critical revision: CFJ, RC, PSP, EAC, XdC.
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
ESM 1
(PDF 466 kb)
Rights and permissions
About this article
Cite this article
Franco-Jarava, C., Álvarez de la Campa, E., Solanich, X. et al. Early Versus Late Diagnosis of Complement Factor I Deficiency: Clinical Consequences Illustrated in Two Families with Novel Homozygous CFI Mutations. J Clin Immunol 37, 781–789 (2017). https://doi.org/10.1007/s10875-017-0447-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10875-017-0447-x