Alternative titles; symbols
HGNC Approved Gene Symbol: CFB
Cytogenetic location: 6p21.33 Genomic coordinates (GRCh38): 6:31,946,095-31,952,084 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.33 | ?Complement factor B deficiency | 615561 | Autosomal recessive | 3 |
| {Hemolytic uremic syndrome, atypical, susceptibility to, 4} | 612924 | Autosomal dominant | 3 | |
| {Macular degeneration, age-related, 14, reduced risk of} | 615489 | Digenic dominant | 3 |
The CFB gene encodes complement factor B, which is part of the alternative complement pathway. Complement factor B is cleaved into a 30-kD N terminal 'Ba' fragment and a 57-kD C-terminal 'Bb' fragment by factor D (CFD; 134350) in the presence of C3b. The C-terminal half of the Bb fragment contains the essential active site residues characteristic of serine proteases, but has a molecular weight twice that of proteinases previously described, suggesting that it is a novel type of serine proteinase. The Bb fragment forms the C3bBb alternative pathway convertase (Christie and Gagnon, 1983).
Complement factor B was originally known as a glycine-rich beta-glycoprotein (GBG).
Christie and Gagnon (1983) determined that the major product of factor B cleavage, Bb, is composed of 505 amino acids and has a molecular mass of 57 kD.
Campbell and Porter (1983) isolated clones corresponding to the complement protein factor B gene from a human liver cDNA library.
Crystal Structure
Forneris et al. (2010) presented crystal structures of the proconvertase C3bB (see 120700) at 4-angstrom resolution and its complex with factor D (134350) at 3.5-angstrom resolution. Their data showed how factor B binding to C3b forms an open 'activation' state of C3bB. Factor D specifically binds the open conformation of factor B through a site distant from the catalytic center and is activated by the substrate, which displaces factor D's self-inhibitory loop. This concerted proteolytic mechanism, which if cofactor-dependent and substrate-induced, restricts complement amplification to C3b-tagged target cells.
Campbell and Porter (1983) determined that the Bb portion of the factor B gene is about 4 kb long. The 3-prime end of the gene codes for amino acids 87-505 of Bb and includes the serine protease domain of the protein.
Campbell (1987) determined that the complete factor B gene spans 6 kb and contains 18 exons, whereas the C2 gene (613927) spans 18 kb.
Allen (1974) showed that GBG and HLA (see, e.g., HLA-A; 142800) are tightly linked on chromosome 6p21. No recombinants were observed among 44 children from 12 informative families. Rittner et al. (1975) found a recombination fraction of 6.1% between HLA and the GBG locus, which they symbolized 'Bf.' They further proposed that Bf is closely linked to the MLC locus with the following order: HLA (first locus)--HLA (second locus)--MLC--Bf--PGM3 (172100). Teisberg et al. (1975) found 90 apparently nonrecombinant offspring from 23 matings.
Raum et al. (1976) concluded that the factor B locus and the C2 deficiency locus (217000) are close together, and that the 2 loci are 3 to 5 cM from the HLA-A and HLA-B loci. Two crossovers out of 57 were observed for C2 versus HLA-B, and 3 out of 72 for factor B versus HLA-B. The order of the genes was taken to be HLA-A, -B, -D, factor B, C2. Albert et al. (1975) presented data they interpreted as suggesting that the Bf locus is between HLA-B and HLA-D. Linkage disequilibrium likewise suggested that Bf is close to HLA-B but not close to HLA-A (Bender et al., 1977). Analysis of what Edwards preferred to call allelic association (because it does not have implications of a disturbance driven by selection or other forces as may 'linkage disequilibrium') led Arnason et al. (1977) to conclude that the HLA-B locus and the Bf locus are very close. For most workers, linkage disequilibrium means merely that the coupling and repulsion phases are not equally frequent.
Raum et al. (1979) found no recombination between C2 and BF in 28 meioses. Furthermore, they found that the C2 and HLA-B loci show a recombination fraction of 0.02 at the maximal lod score, 14.39. This appeared to put C2 outside the MHC and to suggest the order pter, HLA-A, -B, -D, (BF, C2), GLO1 (138750), centromere. On the basis of 4 overlapping cosmid clones, Carroll et al. (1984) aligned 4 human complement genes, which are known to map between HLA-D and HLA-B. The C2 and BF genes are about 30 kb from the two C4 genes, C4A (120810) and C4B (120820), which are separated from each other by about 10 kb. Campbell (1987) reviewed the molecular genetics of C2 and factor B. The 2 genes are closely linked; the 3-prime end of the C2 gene lies only 421 basepairs from the 5-prime end of the factor B gene.
Abbal et al. (1987) studied 3 independent families with the same new BF variant. Assuming that these rare variants derived from single mutations and that the differences in haplotypes bearing said variants must be the result of a minimum of 'historic' crossovers, the order is probably HLA-B, C2, BF, C4A, 21-OHA, C4B, 21-OHB, DR.
Alper et al. (1972) found evidence of extensive polymorphism of serum glycine-rich beta-glycoprotein (GBG) in humans. At least 5 components were demonstrated on electrophoresis. It was concluded that 4 alleles exist at a locus then designated GB. GB(S) and GB(F) were found in all populations but in different proportions. The common alleles, GB(S) and GB(F), have a frequency of about 0.73 and 0.25, respectively (Allen, 1974).
Raum et al. (1979) found a rare genetic type of properdin factor B (F1) in 22.6% of patients with insulin-dependent diabetes but in only 1.9% of the general population. If this is an indication of linkage disequilibrium, not association, as the authors suggested, only some populations should show the relationship.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Complement Factor B Deficiency
In a woman with complement factor B deficiency (CFBD; 615561), Slade et al. (2013) identified compound heterozygous truncating mutations in the CFB gene (138470.0007 and 138470.0008). The patient had recurrent systemic infections with encapsulated bacteria since early childhood. Laboratory studies showed normal immunoglobulins and lymphocytes, but functional ELISA showed that the alternative complement pathway was inactive. The defect was not complemented by factor B-depleted serum, and factor B was undetectable by radial immunodiffusion. The mutations were found by genome sequencing of the CFB gene and segregated with the disorder in the family. Complement studies in the parents showed normal activity of the alternative complement pathway. The findings illustrated the role of complement factor B in the protection against infection with encapsulated organisms.
Age-Related Macular Degeneration
Because CFH (134370) haplotypes are associated with age-related macular degeneration (ARMD; see 603075), Gold et al. (2006) hypothesized that the same may be true for activators of the same pathway, such as complement factor B. Gold et al. (2006) screened the BF and C2 genes for genetic variation in 2 independent cohorts comprising approximately 900 individuals with ARMD and approximately 400 matched controls. Haplotype analyses identified a statistically significant common risk haplotype and 2 protective haplotypes. Haplotype H10, consisting of the L9H variant (138470.0003) of BF and the E318D variant (613927.0004) of C2, and haplotype H7, consisting of the variant in intron 10 (613927.0005) of C2 and the R32Q variant (138470.0004) of BF, conferred a significantly reduced risk of ARMD (OR = 0.36 and 0.45, respectively). Combined analysis of the C2/BF haplotypes and CFH variants showed that variation in the 2 loci can predict the clinical outcome in 74% of affected individuals and 56% of controls.
Thakkinstian et al. (2012) reviewed the association of C2/CFB gene polymorphisms with ARMD by pooling data from 19 studies published between 2006 and 2011 for 4 polymorphisms: rs9332739 (613927.0004) and rs547154 (613927.0005) in the C2 gene and rs4151667 (138470.0003) and rs641153 (138470.0004) in the CFB gene. Pooled minor allele frequencies for all 4 SNPs were between 4.7% and 9.6%, except for an Indian population in which the C allele at rs9332739 was the major allele. For the C2 polymorphisms, the minor C allele at rs9332739 and the minor T allele at rs547154 carried estimated relative risks (odds ratios) of 0.55 (95% confidence interval (CI) 0.46, 0.65) and 0.47 (95% CI 0.39, 0.57), respectively. For the CFB polymorphisms, the minor A alleles at rs4151667 and rs614153 carried estimated risks of 0.54 (95% CI 0.45, 0.64) and 0.41 (95% CI 0.34, 0.51), respectively. These allele effects contributed to an absolute lowering of the risk of all AMD in Caucasian populations by 2.0-6.0%.
Susceptibility to Atypical Hemolytic Uremic Syndrome 4
In affected members of a large Spanish kindred with atypical hemolytic uremic syndrome-4 (AHUS4; 612924), Goicoechea de Jorge et al. (2007) identified a heterozygous mutation in the CFB gene (F286L; 138470.0005). Functional expression studies showed that the mutant CFB resulted in increased formation of the C3bBb complex, indicating a gain-of-function effect that enhanced the generation of C3b. Goicoechea de Jorge et al. (2007) noted that the family showed incomplete penetrance for the F286L mutation. Further genetic analysis showed that all members with the F286L mutation who developed aHUS also carried the at-risk MCP (120920) haplotype described by Esparza-Gordillo et al. (2005). Goicoechea de Jorge et al. (2007) identified a second heterozygous mutation in the CFB gene (K323E; 138470.0006) in another unrelated patient with aHUS; this patient also carried the MCP haplotype. These findings indicated that the aHUS phenotype results from multiple different genetic hits in the complement pathway, and that persistent activation of the alternative pathway can also result in aHUS.
Alper et al. (1973) showed that the glycine-rich beta-glycoprotein (GBG) in humans is the same as factor B in the properdin system, also known as C3 proaccelerator. Because of the tight linkage of GBG and HLA and the general characteristics of GBG, homology to the mouse S gene was considered possible. The mouse S gene determines a polymorphic serum protein that lies in the midst of the H-2 region. In 1974, at the Second International Congress of Immunology, the WHO nomenclature committee on complement proposed that this be called factor B. Other names have included properdin factor B and C3 proactivator.
The WHO-IUIS Nomenclature Sub-committee (1993) made recommendations on nomenclature for complement factor B.
Taube et al. (2006) studied mice deficient in C4, a critical component of the classical complement pathway, or in Cfb, an essential protein in the alternative complement pathway. Following ovalbumin sensitization and allergen challenge, Cfb-deficient mice, but not C4-deficient mice, showed significantly lower airway hyperresponsiveness (AHR) and less airway inflammation than wildtype mice. Goblet cell hyperplasia and Il4 (147780), Il5 (147850), and Il13 (147683) levels in bronchoalveolar lavage fluid were significantly reduced in Cfb-deficient mice compared with C4-deficient and wildtype mice. Development of AHR and airway inflammation could be restored in Cfb-deficient mice with prior intranasal administration of Cfb. Administration of anti-Cfb to sensitized mice reduced AHR development and airway inflammation. Taube et al. (2006) concluded that complement activation through the alternative pathway after allergen exposure in sensitized hosts is critical to development of AHR and airway inflammation.
Bullous pemphigoid (BP) is a subepidermal blistering skin disorder of the elderly associated with autoantibodies directed against the hemidesmosomal proteins BP180 (COL17A1; 113811) and BP230 (DST; 113810). Nelson et al. (2006) found that mice deficient in the alternative pathway complement factor B had delayed and less intense subepidermal blisters following challenge with anti-BP180. Mice lacking the classical complement component C4 were resistant to experimental BP and had significantly reduced mast cell degranulation and neutrophil skin infiltration. BP disease in C4-deficient mice could be restored by treatment with a mast cell degranulating agent or by injection of the neutrophil chemoattractant IL8 (146930). Nelson et al. (2006) concluded that complement activation via the alternative and classical pathways is necessary for blister formation in experimental BP.
The molecular basis for allelic variation at the factor B locus, i.e., the 2 common alleles F and S, has been defined; a G-to-A transition in codon 8 changes the amino acid from arginine in the S allele to glutamine in the F allele (Campbell, 1987). This fits with the difference in electrophoretic mobility of the 2 variants, with the F allele carrying a less positive charge and thus moving more toward the anode. Mejia et al. (1994) presented the complete cDNA sequence of the BF*S allele. BF*S is the most common allele. The BF*S, BF*FA, and BF*FB have a combined frequency in excess of 0.95. Davrinche et al. (1990) showed that these differ from one another at the codon for the seventh amino acid: CAG (gln) in BF*FA, TGG (trp) in BF*FB, and CGG (arg) in BF*S. The changes involve nucleotides 94 and 95 (see fig. 1 of Mejia et al., 1994). (Codon 8 in the cDNA corresponds to amino acid 7 in the protein.)
See 138470.0001.
Gold et al. (2006) identified a 26T-A transversion in the CFB gene, resulting in a leu9-to-his variant (L9H; rs4151667). In approximately 900 individuals with ARMD (ARMD14; 615489) and approximately 400 controls, they found a significant association between haplotype H10, consisting of the L9H variant and the E318D variant (613927.0004) of the C2 gene, and a reduced risk of ARMD.
Maller et al. (2006) replicated the association of the L9H variant of CFB and the E318D variant of C2 with risk of ARMD, noting that although this pair of SNPs has minor alleles that confer an equivalent protective effect, they found these effects to be independent and distinct.
Gold et al. (2006) identified a 95G-A transition in the CFB gene, resulting in an arg32-to-gln variant (R32Q; rs641153). In approximately 900 individuals with ARMD (ARMD14; 615489) and approximately 400 controls, they found a significant association between haplotype H7, consisting of the R32Q variant and the intron 10 variant (613927.0005) of the C2 gene, and a reduced risk of ARMD.
Maller et al. (2006) replicated the association of the R32Q variant of CFB and the intron 10 variant of C2 with risk of ARMD, noting that although this pair of SNPs has minor alleles that confer an equivalent protective effect, they found these effects to be independent and distinct.
In affected members of a large Spanish kindred with atypical hemolytic uremic syndrome-4 (AHUS4; 612924), Goicoechea de Jorge et al. (2007) identified a heterozygous 858C-G transversion in exon 6 of the CFB gene, resulting in a phe286-to-leu (F286L) substitution in the von Willebrand type A domain. The family had originally been reported by Carreras et al. (1981). The mutation segregated with low levels of C3 (120700) in all individuals with AHUS. The mutation was not found in 100 control individuals. Functional expression studies showed that the mutant CFB resulted in increased formation of the C3bBb complex, indicating a gain-of-function effect that enhanced the generation of C3b. This explains the increased levels of CFB cleavage and C3 consumption found in mutation carriers. However, the mutant protein also showed increased decay, suggesting that the gain-of-function effect occurs only when the supply of CFB is unlimited. Goicoechea de Jorge et al. (2007) noted that the family showed incomplete penetrance for the F286L mutation. Further genetic analysis showed that all members with the F286L mutation who developed aHUS also carried the at-risk MCP (120920) haplotype described by Esparza-Gordillo et al. (2005). These findings again indicated that the aHUS phenotype can result from multiple hits in the complement pathway.
In a patient with AHUS4 (612924), Goicoechea de Jorge et al. (2007) identified a de novo heterozygous 967A-G transition in exon 7 of the CFB gene, resulting in a lys323-to-glu (K323E) substitution in the von Willebrand type A domain. The mutation was not found in 100 control individuals. Functional expression studies showed that the mutant protein was less resistant to accelerated decay by DAF (125240) and factor H (CFH; 134370). The patient was also found to carry the at-risk MCP (120920) haplotype described by Esparza-Gordillo et al. (2005). These findings again indicated that the aHUS phenotype can result from multiple hits in the complement pathway.
In a 32-year-old woman, born of unrelated parents of English and Scottish origin, with complement factor B deficiency (CFBD; 615561) manifest as recurrent systemic infections with encapsulated bacteria since early childhood, Slade et al. (2013) identified compound heterozygous mutations in the CFB gene: a c.766C-T transition in exon 6, resulting in a gln256-to-ter (Q256X) substitution, and a 4-bp deletion (c.1894_1987delTTTG; 138470.0008) in exon 15, resulting in a frameshift and premature termination (Phe632CysfsTer8). Laboratory studies showed normal immunoglobulins and lymphocytes, but functional ELISA showed that the alternative complement pathway was inactive. The defect was not complemented by factor B-depleted serum, and factor B was undetectable by radial immunodiffusion. The mutations were found by genome sequencing of the CFB gene and segregated with the disorder in the family. Complement studies in the parents showed normal activity of the alternative complement pathway.
For discussion of the 4-bp deletion (c.1894_1987delTTTG) in exon 15 of the CFB gene that was found in compound heterozygous state in a patient with complement factor B deficiency by Slade et al. (2013), see 138470.0007.
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