Alternative titles; symbols
HGNC Approved Gene Symbol: CFI
SNOMEDCT: 234621005;
Cytogenetic location: 4q25 Genomic coordinates (GRCh38) : 4:109,730,982-109,801,999 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q25 | {Hemolytic uremic syndrome, atypical, susceptibility to, 3} | 612923 | Autosomal dominant | 3 |
| {Macular degeneration, age-related, 13, susceptibility to} | 615439 | Autosomal dominant | 3 | |
| Complement factor I deficiency | 610984 | Autosomal recessive | 3 |
The CFI gene encodes complement factor I ('eye'), a serine proteinase in the complement pathway responsible for cleaving and inactivating the activities of C4b (120820) and C3b (see 120700). Factor I is a plasma glycoprotein composed of 2 polypeptide chains linked by disulfide bonds. Both the light and heavy chains of factor I are encoded by the CFI gene (Catterall et al., 1987). The light chain contains the serine protease domain (Vyse et al., 1994).
Catterall et al. (1987) isolated cDNA clones corresponding to the gene encoding complement factor I from a human liver cDNA library. The deduced 583-amino acid protein comprises both the heavy and light chains of component I, which are sequentially coded from the N terminal. The light chain N terminal is found at residue 322 after 4 basic residues, providing evidence that factor I is synthesized as a single chain polypeptide that is subsequently cleaved. Both the heavy (35.4 kD) and light (27.6 kD) chains contain 3 potential N-glycosylation sites. Northern blot analysis detected a 2.4-kb mRNA transcript.
Goldberger et al. (1987) also cloned the human CFI gene.
Vyse et al. (1994) determined that the CFI gene spans 63 kb and contains 13 exons, the first 8 of which encode the heavy chain and the last 5 the light chain.
By somatic cell hybridization, Goldberger et al. (1987) and Shiang et al. (1987) mapped the CFI gene to chromosome 4q23-q25.
Shiang et al. (1989) mapped the CFI locus to 4q25 by use of somatic cell hybrids, in situ hybridization, and genetic linkage with RFLP markers. They proposed that the order of loci was as follows: cen--GC--INP10--ADH3--EGF--IF--IL2--MNS--qter. By hybridization to fragments generated by low-frequency cutting restriction enzymes and pulsed field electrophoresis, Kolble et al. (1989) showed that the CFI and EGF (131530) genes are located about 40 kb apart. The alcohol dehydrogenase cluster (103720) appeared to be more than 550 kb proximal to EGF, whereas CFI lies distal to EGF.
Nakamura and Abe (1985) described 2 polymorphisms of the C3b inactivator gene, designated FI*A and FI*B, demonstrated by electrophoretic blotting technique. In the course of studying sera from 305 persons, Zhou and Larsen (1989) identified a third variant, designated FI*C. Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988). Ding et al. (1991) provided data on polymorphisms of the CFI gene in Chinese, Korean, and Japanese populations.
Complement Factor I Deficiency
In 2 sibs with complement factor I deficiency (CFID; 610984), Vyse et al. (1996) identified a homozygous mutation in the CFI gene (217030.0001). An unrelated patient was compound heterozygous for 2 mutations in the CFI gene (217030.0001; 217030.0002).
In 2 Brazilian sisters, born of consanguineous parents, with complement factor I deficiency, Baracho et al. (2003) identified a homozygous mutation in the CFI gene (217030.0003). Each parent was heterozygous for the mutation. The older sister had recurrent infections and developed systemic lupus erythematosus (SLE; 152700) with glomerulonephritis and the younger sister died at age 3 years of sepsis.
Servais et al. (2007) described 2 patients with factor I deficiency who developed glomerulonephritis with isolated C3 deposits. The authors called the disorder 'glomerulonephritis C3.' The patients were found to have heterozygous mutations in the CFI gene (see, e.g., 217030.0007).
Susceptibility to Atypical Hemolytic Uremic Syndrome 3
In 3 unrelated patients with atypical hemolytic uremic syndrome (AHUS3; 612923), Fremeaux-Bacchi et al. (2004) identified 3 different heterozygous mutations in the CFI gene (217030.0003-217030.0005). In 2 cases, a nonsense mutation was associated with heterozygous factor I deficiency. In another case, a heterozygous mutation likely led to functional factor I deficiency. In 2 families, an asymptomatic parent also carried the mutation, suggesting incomplete penetrance and that heterozygous pathogenic mutations in the CFI gene confer susceptibility to the development of aHUS.
Caprioli et al. (2006) identified 5 different CFI mutations (see, e.g., 217030.0008-217030.0009) in 7 (4.5%) of 156 patients with AHUS. Three of 5 patients had decreased serum C3 levels. Normal renal function was preserved in 33.3% of patients with CFI mutations. Kidney transplant was not effective in preventing recurrence.
Susceptibility to Age-Related Macular Degeneration 13
Van de Ven et al. (2013) identified a missense mutation in the CFI gene (G119R; 217030.0010) in 20 of 3,567 patients with age-related macular degeneration (ARMD13; 615439) and 1 of 3,937 controls, consistent with G119R conferring high risk for developing ARMD (odds ratio, 22.20; p = 3.79 x 10(-6)).
Seddon et al. (2013) sequenced the exons of 681 genes within all reported ARMD loci and related pathways in 2,493 cases. First, each gene was tested for increased or decreased burden of rare variants in cases compared to controls. Seddon et al. (2013) found that 7.8% of ARMD cases compared to 2.3% of controls were carriers of rare missense CFI variants (odds ratio = 3.6; p = 2 x 10(-8)). There was a preponderance of dysfunctional variants in cases compared to controls. Seddon et al. (2013) then tested individual variants for association with disease.
In affected members of 2 Tunisian Jewish families with ARMD, Pras et al. (2015) identified heterozygosity for a missense mutation in the CFI gene (V412M; 217030.0011) that segregated with disease in both families. Analysis of 200 unrelated Tunisian Jewish controls identified 10 heterozygotes, for an estimated carrier frequency of 5% in that population.
In 2 sibs with complement factor I deficiency (CFID; 610984), Vyse et al. (1996) identified a 1282A-T transversion in the CFI gene, resulting in a his400-to-leu (H400L) substitution. A third unrelated patient, who had been previously reported by Thompson and Lachmann (1977) was compound heterozygous for H400L and a splice site mutation (217030.0002).
In a patient with complement factor I deficiency (CFID; 610984) originally reported by Thompson and Lachmann (1977), Vyse et al. (1996) identified compound heterozygosity for 2 mutations in the CFI gene: an 801G-A transition in the last nucleotide of exon 5 and H400L (217030.0001). The 801G-A transition is part of the donor splice site consensus sequence of the fifth intron, which was deleted from the mRNA transcript as a result of the mutation.
In 2 Brazilian sisters, born of consanguineous parents, with complement factor I deficiency (CFID; 610984), Baracho et al. (2003) identified a homozygous 2-bp insertion (1205insAT) in exon 11 of the CFI gene. The insertion resulted in premature termination of the protein. Each parent was heterozygous for the mutation. The older sister had recurrent infections and developed systemic lupus erythematosus (152700) with glomerulonephritis and the younger sister died at age 3 years of sepsis.
In a woman who developed atypical hemolytic uremic syndrome (AHUS3; 612923) after pregnancy, Fremeaux-Bacchi et al. (2004) identified a heterozygous 1366C-T transition in the CFI gene, resulting in an arg456-to-ter (R456X) substitution. The mutation encodes a truncated protein that lacks the serine protease domain. The woman and her unaffected father, who also carried the mutation, showed decreased serum complement factor I. The woman also had decreased serum C3 and factor B, indicating consumptive depletion. The R456X mutation was not identified in 200 control chromosomes.
In a patient with atypical hemolytic uremic syndrome (AHUS3; 612923), Fremeaux-Bacchi et al. (2004) identified a heterozygous A-to-T transversion in exon 13 of the CFI gene, resulting in an asp506-to-val (D506V) substitution close to the serine protease domain. At 17 months of age, the patient had HUS with severe microangiopathic hemolytic anemia, hypertension, and proteinuria. A relapse occurred 6 months later. Two years later, his renal function was normal, but he required antihypertensive treatment. His clinically unaffected mother also carried the mutation. Although serum factor I levels were normal in both the patient and his mother, both showed decreased serum C3 and factor B. The mutation was not identified in 200 control chromosomes.
In a 26-year-old woman with atypical hemolytic uremic syndrome (AHUS3; 612923), Fremeaux-Bacchi et al. (2004) identified a heterozygous G-to-A transition in the CFI gene, resulting in a trp528-to-ter (W528X) substitution predicted to result in a protein lacking the serine protease domain. The patient had recurrence of HUS following a second renal transplantation and thrombotic microangiopathy. Serum factor I levels were 36% of normal controls. The mutation was not identified in 200 control chromosomes.
In a patient with factor I deficiency (CFID; 610984) who developed glomerulonephritis with isolated C3 deposits, Servais et al. (2007) identified a heterozygous mutation in exon 6 of the CFI gene, resulting in a gly243-to-asp (G243D) substitution in a conserved region of the heavy chain possibly involved in ligand binding.
In 2 members of a family with atypical hemolytic uremic syndrome (AHUS3; 612923), Caprioli et al. (2006) identified a heterozygous 949C-T transition in exon 9 of the CFI gene, resulting in an arg317-to-trp (R317W) substitution.
In 2 members of a family with atypical hemolytic uremic syndrome (AHUS3; 612923), Caprioli et al. (2006) identified a heterozygous 1555G-A transition in exon 13 of the CFI gene, resulting in an asp519-to-asn (D519N) substitution.
In 3 unrelated patients with age-related macular degeneration (ARMD13; 615439), van de Ven et al. (2013) identified heterozygosity for a 355G-A transition in exon 3 of the CFI gene, resulting in a gly119-to-arg (G119R) substitution at a highly conserved residue in the CD5 domain. Genotyping of additional cases resulted in the G119R variant being identified in an overall total of 20 of 3,567 cases versus only 1 of 3,937 controls, consistent with G119R conferring high risk for developing ARMD (odds ratio, 22.20; p = 3.79 x 10(-6)). Van de Ven et al. (2013) noted that most carriers of the G119R variant had stage 4 ARMD. The 1 control carrying the minor allele had numerous hard drusen in all 4 quadrants of the peripheral retina, but had normal macula in both eyes. Van de Ven et al. (2013) also noted that the G119R variant had previously been reported in patients with atypical hemolytic uremic syndrome (AHUS3; 612923) (Maga et al., 2010; Fakhouri et al., 2010); however, there was no significant difference in renal function of ARMD patients with the G119R variant compared to ARMD patients without G119R. Plasma and sera carrying the G119R variant mediated C3b (see 120700) degradation to a lesser extent than that of controls, and the mutant was both expressed and secreted at lower levels in HEK293 cells than wildtype protein. Studies in zebrafish retina demonstrated reduced activity by the G119R mutant in regulating vessel thickness and branching compared to wildtype.
In affected members of 2 unrelated Tunisian Jewish families with age-related macular degeneration (ARMD13; 615439), Pras et al. (2015) identified heterozygosity for a c.1234G-A transition (c.1234G-A, chr4.110,667,573, GRCh37) in the CFI gene, resulting in a val412-to-met (V412M) substitution at a conserved residue within the catalytic serine protease domain. The mutation, which segregated fully with disease in both families, was detected in 2 of 292 in-house exomes (allele frequency, 0.00685) as well as in 1 of 4,600 Caucasian genotypes but in none of 4,406 African American individuals in the 1000 Genomes Project. Analysis of 200 unrelated Tunisian Jewish controls identified 10 heterozygotes, for an estimated carrier frequency of 5% in that population. Pras et al. (2015) noted that in both families, carriers of the V412M variant presented with clinical features of ARMD at a much earlier age than for common ARMD.
Baracho, G. V., Nudelman, V., Isaac, L. Molecular characterization of homozygous hereditary factor I deficiency. Clin. Exp. Immun. 131: 280-286, 2003. [PubMed: 12562389] [Full Text: https://doi.org/10.1046/j.1365-2249.2003.02077.x]
Caprioli, J., Noris, M., Brioschi, S., Pianetti, G., Castelletti, F., Bettinaglio, P., Mele, C., Bresin, E., Cassis, L., Gamba, S., Porrati, F., Bucchioni, S., Monteferrante, F., Fang, C. J., Liszewski, M. K., Kavanagh, D., Atkinson, J. P., Remuzzi, G. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 108: 1267-1279, 2006. [PubMed: 16621965] [Full Text: https://doi.org/10.1182/blood-2005-10-007252]
Catterall, C. F., Lyons, A., Sim, R. B., Day, A. J., Harris, T. J. R. Characterization of the primary amino acid sequence of human complement control protein factor I from an analysis of cDNA clones. Biochem. J. 242: 849-856, 1987. [PubMed: 2954545] [Full Text: https://doi.org/10.1042/bj2420849]
Ding, M., Umetsu, K., Yuasa, I., Nakamura, S., Choi, W. Y., Suzuki, T. Polymorphism of complement component I in mongoloid populations: a new genetic variant IF A2. Hum. Hered. 41: 206-208, 1991. [PubMed: 1937494] [Full Text: https://doi.org/10.1159/000154002]
Fakhouri, F., Roumenina, L., Provot, F., Sallee, M., Caillard, S., Couzi, L., Essig, M., Ribes, D., Dragon-Durey, M.-A., Bridoux, F., Rondeau, E., Fremeaux-Bacci, V. Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J. Am. Soc. Nephrol. 21: 859-867, 2010. [PubMed: 20203157] [Full Text: https://doi.org/10.1681/ASN.2009070706]
Fremeaux-Bacchi, V., Dragon-Durey, M.-A., Blouin, J., Vigneau, C., Kuypers, D., Boudailliez, B., Loirat, C., Rondeau, E., Fridman, W. H. Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome. J. Med. Genet. 41: e84, 2004. Note: Electronic Article. [PubMed: 15173250] [Full Text: https://doi.org/10.1136/jmg.2004.019083]
Goldberger, G., Bruns, G. A. P., 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. 262: 10065-10071, 1987. [PubMed: 2956252]
Kolble, K., Buckle, V. J., Sim, R. A megarestriction map linking the genes for complement component I and epidermal growth factor within band 4q25. (Abstract) Cytogenet. Cell Genet. 51: 1024, 1989.
Maga, T. K., Nishimura, C. J., Weaver, A. E., Frees, K. L., Smith, R. J. H. Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum. Mutat. 31: E1445-E1460, 2010. Note: Electronic Article. [PubMed: 20513133] [Full Text: https://doi.org/10.1002/humu.21256]
Nakamura, S., Abe, K. Genetic polymorphism of human factor I (C3b inactivator). Hum. Genet. 71: 45-48, 1985. [PubMed: 3897024] [Full Text: https://doi.org/10.1007/BF00295667]
Pras, E., Kristal, D., Shoshany, N., Volodarsky, D., Vulih, I., Celniker, G., Isakov, O., Shomron, N., Pras, E. Rare genetic variants in Tunisian Jewish patients suffering from age-related macular degeneration. J. Med. Genet. 52: 484-492, 2015. [PubMed: 25986072] [Full Text: https://doi.org/10.1136/jmedgenet-2015-103130]
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
Seddon, J. M., Yu, Y., Miller, E. C., Reynolds, R., Tan, P. L., Gowrisankar, S., Goldstein, J. I., Triebwasser, M., Anderson, H. E., Zerbib, J., Kavanagh, D., Souied, E., Katsanis, N., Daly, M. J., Atkinson, J. P., Raychaudhuri, S. Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nature Genet. 45: 1366-1370, 2013. [PubMed: 24036952] [Full Text: https://doi.org/10.1038/ng.2741]
Servais, A., Fremeaux-Bacchi, V., Lequintrec, M., Salomon, R., Blouin, J., Knebelmann, B., Grunfeld, J.-P., Lesavre, P., Noel, L.-H., Fakhouri, F. Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uremic syndrome. J. Med. Genet. 44: 193-199, 2007. [PubMed: 17018561] [Full Text: https://doi.org/10.1136/jmg.2006.045328]
Shiang, R., Murray, J. C., Divelbiss, J. E., Patil, S., Overhauser, J., Wasmuth, J. J., Buetow, K. H. A physical map for the long arm of chromosome 4 using D4S35, D4S1, MT2P1, ALB, AFP, GC, INP10, ADH3, EGF, IL2, FGG, FGB, and MNS, IF, FGFB. (Abstract) Cytogenet. Cell Genet. 46: 691, 1987.
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 4: 82-86, 1989. [PubMed: 2563353] [Full Text: https://doi.org/10.1016/0888-7543(89)90318-2]
Thompson, R. A., Lachmann, P. J. A second case of human C3b inhibitor (KAF) deficiency. Clin. Exp. Immun. 27: 23-29, 1977. [PubMed: 849647]
van de Ven, J. P. H., Nilsson, S. C., Tan, P. L., Buitendijk, G. H. S., Ristau, T., Mohlin, F. C., Nabuurs, S. B., Schoenmaker-Koller, F. E., Smailhodzic, D., Campochiaro, P. A., Zack, D. J., Duvvari, M. R., and 13 others. A functional variant in the CFI gene confers a high risk of age-related macular degeneration. Nature Genet. 45: 813-817, 2013. [PubMed: 23685748] [Full Text: https://doi.org/10.1038/ng.2640]
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 24: 90-98, 1994. [PubMed: 7896293] [Full Text: https://doi.org/10.1006/geno.1994.1585]
Vyse, T. J., Morley, B. J., Bartok, I., Theodoridis, E. L., Davies, K. A., Webster, A. D. B., Walport, M. J. The molecular basis of hereditary complement factor I deficiency. J. Clin. Invest. 97: 925-933, 1996. [PubMed: 8613545] [Full Text: https://doi.org/10.1172/JCI118515]
Zhou, M., Larsen, B. A new polymorphic variant of human complement factor I. Hum. Genet. 82: 393, 1989. [PubMed: 2525517] [Full Text: https://doi.org/10.1007/BF00274006]