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COMPLEMENT FACTOR I; CFI

COMPLEMENT FACTOR I; CFI

Alternative titles; symbolsCOMPLEMENT COMPONENT IFACTOR I; FIC3b INACTIVATORHGNC Approved Gene Symbol: CFICytogenetic location: 4q25 Genomic coordinates (GRC...

Alternative titles; symbols

  • COMPLEMENT COMPONENT I
  • FACTOR I; FI
  • C3b INACTIVATOR

HGNC Approved Gene Symbol: CFI

Cytogenetic location: 4q25 Genomic coordinates (GRCh38): 4:109,730,981-109,802,039 (from NCBI)

▼ Description
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).

▼ Cloning and Expression
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.

▼ Gene Structure
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.

▼ Mapping
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.

▼ Molecular Genetics
Nakamura and Abe (1985) described 2 polymorphisms of the C3b inactivator gene, designated FIA and FIB, 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.

▼ ALLELIC VARIANTS ( 11 Selected Examples):

.0001 COMPLEMENT FACTOR I DEFICIENCY
CFI, HIS400LEU
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).

.0002 COMPLEMENT FACTOR I DEFICIENCY
CFI, IVS5DS G-A, -1
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.

.0003 COMPLEMENT FACTOR I DEFICIENCY
CFI, 2-BP INS, 1205AT
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.

.0004 HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 3
CFI, ARG456TER
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.

.0005 HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 3
CFI, ASP506VAL
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.

.0006 HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 3
CFI, TRP528TER
In a 26-year-old woman with atypical hemolytic uremic syndrome (AHUS3; 612923), Fremeaux-Bacchi et al. (2004) identified a heterozygous G-to-A transversion 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.

.0007 COMPLEMENT FACTOR I DEFICIENCY
CFI, GLY243ASP
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.

.0008 HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 3
CFI, ARG317TRP
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.

.0009 HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 3
CFI, ASP519ASN
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.

.0010 MACULAR DEGENERATION, AGE-RELATED, 13, SUSCEPTIBILITY TO
HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 3, INCLUDED
CFI, GLY119ARG
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.

.0011 MACULAR DEGENERATION, AGE-RELATED, 13, SUSCEPTIBILITY TO
CFI, VAL412MET (rs371432629)
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.

Tags: 4q25

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