Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: CFH
SNOMEDCT: 234622003, 312926005;
Cytogenetic location: 1q31.3 Genomic coordinates (GRCh38): 1:196,652,043-196,747,504 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q31.3 | {Hemolytic uremic syndrome, atypical, susceptibility to, 1} | 235400 | Autosomal dominant; Autosomal recessive | 3 |
| {Macular degeneration, age-related, 4} | 610698 | Autosomal dominant | 3 | |
| Basal laminar drusen | 126700 | Autosomal dominant | 3 | |
| Complement factor H deficiency | 609814 | Autosomal dominant; Autosomal recessive | 3 |
Complement factor H (CFH), originally known as beta-1H globulin, is a serum glycoprotein that regulates the function of the alternative complement pathway in fluid phase and on cellular surfaces. It binds to C3b (see C3, 120700), accelerates the decay of the alternative pathway convertase C3bBb, and also acts as a cofactor for complement factor I (CFI; 217030), another C3b inhibitor (Ault, 2000; Perez-Caballero et al., 2001).
Ripoche et al. (1988) deduced the amino acid sequence of human factor H from 3 overlapping cDNA clones. The 1,213-residue protein is arranged in 20 homologous units of approximately 60-residues each, referred to as 'short consensus repeats' (SCR) or 'complement control protein' (CCP) modules (Perez-Caballero et al., 2001). In addition to the 150-kD factor H protein, Misasi et al. (1989) identified a second gene product, a 43-kD factor H molecule (FHL1), present in human plasma.
Estaller et al. (1991) isolated a full-length cDNA corresponding to the human CFH gene. They found that alternative splicing yields 2 products: a 4.3-kb mRNA transcript encoding the full-length 150-kD protein and a 1.8-kb transcript encoding the 43-kD protein.
Schwaeble et al. (1987), Estaller et al. (1991), and others described the alternatively spliced FHL1 isoform. It was characterized in human plasma and found to have factor H complement regulatory activity and cell adhesion activity. The FHL1 protein represents 2 to 10% of the factor H concentration in plasma.
Three different mRNA species (4.3 kb, 1.8 kb, and 1.4 kb) for complement factor H are expressed constitutively in human liver. Schwaeble et al. (1991) presented evidence that the expression of the 3 different mRNA species is regulated by tissue-specific control mechanisms.
By immunoprecipitation and immunoblot analyses, Kunert et al. (2007) found that factor H, via SCR domains 6 to 7 and 19 to 20, and CFHR1 (134371), via SCR domains 3 to 5, bound to surface-expressed Pseudomonas aeruginosa elongation factor Tuf and also to recombinant Tuf. Factor H and plasminogen (PLG; 173350) bound simultaneously to Tuf, and PLG was proteolytically activated. Plasma without factor H did not support P. aeruginosa survival, and survival increased in a factor H dose-dependent manner. Kunert et al. (2007) proposed that Tuf acts as a virulence factor by acquiring host proteins to the pathogen surface, controlling complement, and possibly facilitating tissue invasion.
Using DNA arrays and Northern blot analysis, Lukiw et al. (2008) found that the expression of MIR146A (610566) was significantly upregulated in Alzheimer disease (AD; 104300) neocortex and hippocampus compared with normal control tissue. They identified a putative MIR146A-binding site in the 3-prime untranslated region (UTR) of CFH, and confirmed that the expression of CFH was downregulated in AD brain compared with controls. Upregulation of MIR146A and downregulation of CFH was also found in stressed primary human neuronal/glial cell cocultures, which is a model of AD. They further found that MIR146A was upregulated by NF-kappa-B (see 164011) and concluded that NF-kappa-B-sensitive MIR146A modulates the expression of CFH as part of the inflammatory response in AD brain.
Malondialdehyde (MDA) is a common lipid peroxidation product that accumulates in many pathophysiologic processes, including age-related macular degeneration (ARMD; see 603075). Weismann et al. (2011) identified CFH as a major MDA binding protein that can block both the uptake of MDA-modified proteins by macrophages and MDA-induced proinflammatory effects in vivo in mice. The CFH polymorphism tyr402 to his (Y402H; 134370.0008), which is strongly associated with ARMD, markedly reduces the ability of CFH to bind MDA, indicating a causal link to disease etiology. Weismann et al. (2011) concluded that their findings provided important mechanistic insights into innate immune responses to oxidative stress.
Lauer et al. (2011) showed that the Y402H polymorphism of factor H affected surface recruitment by monomeric CRP (123260) to specific patches on necrotic retinal pigment epithelial (RPE) cells. Enhanced attachment of the protective Y402 variants of both factor H and FHL1 by monomeric CRP resulted in more efficient complement control and provided an antiinflammatory environment. Monomeric CRP was generated on the surface of necrotic RPE cells, and this newly formed monomeric CRP colocalized with the cell damage marker ANXA5 (131230). Once bound to the cell surface, the factor H-monomeric CRP complexes allowed complement inactivation and reduced the release of TNF (191160). Lauer et al. (2011) concluded that the Y402 variants of factor H and FHL1 allow better and more efficient clearance and removal of cellular debris and reduce inflammation and pathology.
Nan et al. (2013) noted that the subretinal pigment epithelial deposits that are a hallmark of age-related macular degeneration contain both C3b and millimolar levels of zinc. By ultracentrifugation and x-ray scattering, they showed that of C3, C3u, and C3b associated strongly with a zinc concentration over 100 micromol, whereas C3c and C3d associated only weakly. In the presence of zinc, C3 formed soluble oligomers, whereas C3u and C3b precipitated. CFH formed large oligomers with a zinc concentration over 10 micromol. The complex of CFH and C3b lost solubility and was precipitated by zinc in a concentration-dependent manner, thereby inhibiting complement activation. Nan et al. (2013) concluded that zinc-induced precipitation may contribute to the initial development of subretinal pigment epithelial deposits in retina and reduce progression to advanced age-related macular degeneration in higher risk patients.
By NMR analysis, Hocking et al. (2008) determined that module-3 of factor H resembled module-3 of factor B (CFB; 138470), consistent with factor H competing with factor B for binding C3b.
Using x-ray crystallography, Jokiranta et al. (2006) solved the structure of recombinant C-terminal domains 19 and 20 of CFH at 1.8-angstrom resolution. The structure revealed that short consensus repeat domain-20 contains a short alpha-helix, as well as a patch of basic residues at its base. Most aHUS-associated mutations either destabilize the structure or cluster in a unique region on the surface of domain-20. Mutation analysis indicated that the region is involved in C3b binding. Jokiranta et al. (2006) concluded that the majority of aHUS-associated mutations on the surface of CFH domains 19 and 20 interfere with the interaction of CFH and C3b.
Schneider et al. (2009) presented the structure of factor H in complex with its pathogen surface-protein ligand in Neisseria meningitidis. This revealed how the important human pathogen N. meningitidis subverts immune responses by mimicking the host, using protein instead of charged-carbohydrate chemistry to recruit the host complement regulator, factor H. The structure also indicated the molecular basis of the host specificity of the interaction between factor H and the meningococcus.
The CFH gene is located on chromosome 1q32-q32.1 within a cluster of genes encoding the regulatory complement components of the activation of C3 (RCA for 'regulators of complement activation'). This gene cluster includes decay-accelerating factor (DAF; 125240), C4-binding protein (C4BPA; 120830 and C4BPB; 120831), and the factor H-related genes CFHR1, CFHR2 (600889), CFHR3 (605336), CFHR4 (605337), and CFHR5 (608593), among others. The gene family has arisen by multiple duplication events (Richards et al., 2001; Diaz-Guillen et al., 1999; Jozsi et al., 2005)
Rodriguez de Cordoba et al. (1985) concluded that CFH, C4BP, C3b receptor (C3BR; 120620), and C3d receptor (C3DR; 120650) represented a cluster of genes that segregated independently of HLA, the C2, Bf, C4 cluster (on 6p), and C3 (on 19p). Reid et al. (1986) noted that there is a superfamily of structurally related proteins that interact with C3b or C4b. Rodriguez de Cordoba and Rubinstein (1987) found close linkage of CFH and alleles at the C4BP and C3BR loci. Weis et al. (1987) assigned C3BR and C3DR to 1q32; the factor H gene was presumably located there as well. By use of cDNA probes for HF and C4BP on a panel of somatic cell hybrids, Hing et al. (1988) assigned these genes to 1q.
Rey-Campos et al. (1988) found that an HF probe did not hybridize to 800-kb fragments in which 4 other components of the RCA gene cluster were located: CR1--CR2--DAF--C4BP (in this order); however, the RCA gene cluster may be more than 1 to 7 megabases long. Kompf et al. (1988) reported linkage between HF and peptidase A, which maps to chromosome 18, but Kompf et al. (1989) withdrew this claim.
Kompf et al. (1989) confirmed the linkage of CFH and clotting factor XIIIB (F13B; 134580) and found evidence for linkage of PEPC (170000) and HF, and of PEPC and F13B. The linkage of PEPC and HF favored the assignment of PEPC to 1q32. By pulsed field gel electrophoresis, Rey-Campos et al. (1990) concluded that the HF and F13B genes are physically linked; the smallest DNA segment found to hybridize with both probes was 650 kb long.
By linkage studies in interspecific backcrosses of Mus spretus and Mus musculus domesticus, Seldin (1989) demonstrated that the Cfh locus in the mouse is situated on chromosome 1.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988). By isoelectric focusing under completely denaturing conditions, Rodriguez de Cordoba and Rubinstein (1984) identified 3 allelic variants of factor H. Using polyacrylamide gel isoelectric focusing, Nakamura et al. (1990) demonstrated extensive polymorphism of the CFH gene in Japanese.
Susceptibility to Atypical Hemolytic Uremic Syndrome 1
In affected members of a large family with autosomal dominant atypical hemolytic uremic syndrome (AHUS1; 235400) originally reported by Edelsten and Tuck (1978), Goodship et al. (1997) and Warwicker et al. (1998) identified a heterozygous mutation in the CFH gene (134370.0001). Although none of the patients had decreased levels of plasma factor H, Warwicker et al. (1998) postulated that the mutation disrupted the structure and function of the protein. A sporadic patient was found to have a heterozygous deletion in the CFH gene (134370.0011).
Rougier et al. (1998) reported 6 cases of complement factor H deficiency in children with acute glomerular disease. Five of the 6 children presented with atypical hemolytic uremic syndrome. Two of the 6 children, who were first cousins, exhibited a homozygous deficiency characterized by the absence of the 150-kD form of factor H; Dragon-Durey et al. (2004) identified a homozygous mutation in the CFH gene (134370.0012) in these 2 children. Dragon-Durey et al. (2004) identified 9 different heterozygous mutations in the CFH gene in 9 unrelated patients with atypical HUS; 2 of the patients had been reported by Rougier et al. (1998). The findings indicated that both homozygous and heterozygous CFH mutations predispose to the development of aHUS.
Perez-Caballero et al. (2001) identified 5 mutations in the CFH gene (see, e.g., 134370.0007) in 4 of 13 Spanish patients with aHUS who presented normal complement profiles and whose plasma levels of factor H were, with 1 exception, within the normal range. Four mutations were missense mutations that altered amino acid residues in the C-terminal portion of factor H within a region that is involved in the binding to solid-phase C3b and to negatively charged cellular structures. This clustering of mutations in HF1 suggested that a specific dysfunction in the protection of cellular surfaces by factor H is a major pathogenic condition underlying aHUS.
Richards et al. (2001) performed a mutation screening of the HF1 gene in 19 familial and 31 sporadic patients with HUS. Mutations were found in 2 familial and 3 sporadic patients, and these clustered in exons 18-20, a domain important for host recognition.
Sanchez-Corral et al. (2002) reported the structural and functional characterization of 3 different mutant factor H proteins purified from the plasma of patients with aHUS. Studies showed a high molecular mass factor H protein that resulted from the covalent interaction between factor H and serum albumin. The mutant CFH proteins showed a normal cofactor activity in the proteolysis of fluid-phase C3b by factor I, but demonstrated very low binding to surface-bound C3b. This functional impairment was also demonstrated in recombinant mutant factor H proteins expressed in COS-7 cells. The data supported the hypothesis that patients with aHUS and complement H defect have a specific dysfunction in the protection of cellular surfaces from alternative complement activation.
Pangburn (2002) found that recombinant CFH proteins with C-terminal deletions affecting polyanion- and C3b-binding sites were unable to control spontaneous activation of the alternative complement pathway on host-like surfaces. They concluded that mutations in the C-terminal domain of CFH prevent host polyanion recognition, resulting in uncontrolled activation of complement on susceptible host tissues that leads to renal failure in familial HUS patients.
In a registry of atypical HUS in German-speaking countries, Neumann et al. (2003) identified HF1 germline mutations in 16 of 111 patients (14%), including 2 of 8 patients with familial atypical HUS. Hypocomplementemia was not regularly associated with germline mutations, and serum factor H levels were sometimes elevated. Normal C3 levels were found in 10 of 16 mutation-positive patients and elevated serum factor H in 6 of the 16.
Caprioli et al. (2003) analyzed the complete HF1 gene in 101 patients with aHUS, 32 patients with thrombotic thrombocytopenic purpura (TTP; 274150), and 106 controls. They found 17 different HF1 mutations (16 heterozygous and 1 homozygous) in 33 HUS patients. Thirteen mutations were located in exons 22 and 23. No TTP patient carried HF1 mutations. HUS manifested earlier and the mortality rate was higher in HF1 mutation carriers than in noncarriers. Kidney transplants invariably failed for disease recurrences in patients with HF1 mutations, while in nonmutated patients half of the grafts were functioning after 1 year. In addition, Caprioli et al. (2003) found that 3 HF1 polymorphisms were strongly associated with aHUS: a -257T promoter allele, a 2089G allele in exon 14, and a 2881T allele in exon 19. Two or 3 disease-associated variants led to a higher risk of HUS than 1 alone.
Saunders et al. (2006) described an interactive internet database of factor H-associated aHUS mutations. Two new insights were obtained from this collection of data. First, phenotypic data on factor H clarified their classification of type I and type II disorders that both lead to HUS, where type I affects secretion and folding of factor H, and type II leads to expressed protein in plasma that is functionally defective. Second, new mutations showed more clearly that SCR domains from SCR16 to SCR20 are important for the ligand-binding activities of factor H.
Complement Factor H Deficiency With C3 Glomerulopathy
In a Native American boy with factor H deficiency (CFHD; 609814) who developed membranoproliferative glomerulonephritis associated with C3 glomerulopathy, originally reported by Vogt et al. (1995), Ault et al. (1997) identified compound heterozygosity for 2 mutations in the CFH gene (134370.0002; 134370.0003).
In 4 patients with membranoproliferative glomerulonephritis and factor H deficiency, Dragon-Durey et al. (2004) identified 3 different homozygous mutations in the CFH gene (see, e.g., 134370.0010; 134370.0013).
Among 22 patients with biopsy-proven membranoproliferative glomerulonephritis, Abrera-Abeleda et al. (2006) found an association between 4 SNPs in the CFH gene and 3 SNPs in the CFHR5 gene. The findings strengthened the hypothesis that complement control plays a role in the pathogenesis of the disease.
Servais et al. (2007) found that 2 patients with factor H deficiency who developed glomerulonephritis with isolated mesangial C3 deposits had heterozygous mutations in the CFH gene (see, e.g., 134370.0017). The authors termed the disorder 'glomerulonephritis C3.' In addition, they found that 1 of 13 unrelated patients with membranoproliferative glomerulonephritis had a heterozygous CFH mutation.
Age-Related Macular Degeneration 4
Age-related macular degeneration-4 (ARMD4; 610698) is strongly associated with the Y402H variant (134370.0008) in the CFH gene.
Li et al. (2006) found strong association (p less than 10(-30)) between ARMD4 and a SNP in exon 10 of CFH, rs2274700 (134370.0015).
In a case-control study of 1,238 unrelated affected individuals with advanced ARMD and 934 controls, Maller et al. (2006) observed the strongest association (p = 2.65 x 10(-61)) with a SNP in intron 14 of the CFH gene, rs1410996 (134370.0016), and the association was independent of Y402H.
Raychaudhuri et al. (2011) identified a rare high-risk haplotype ('H5') that lacked both the Y402H and rs10737680-rs1410996 risk alleles, but contained the R1210C substitution (134370.0017). Genotyping R1210C in 2,423 ARMD cases and 1,122 controls demonstrated high penetrance (present in 40 cases vs 1 control; p = 7.0 x 10(-6)) and an association with a 6-year-earlier onset of disease (p = 2.3 x 10(-6)). Raychaudhuri et al. (2011) suggested that loss-of-function alleles at CFH are likely to drive ARMD risk.
Hoffman et al. (2014) identified a missense variant in the CFH gene (P503A; 134370.0023) in 3 Amish sibs with ARMD. Case-control analysis showed strong association with ARMD in an Amish population, but the P503A variant was not found in non-Amish cases or controls.
Basal Laminar Drusen
Drusen are hallmark lesions of ARMD and consist of focal-inflammatory and/or immune-mediated depositions of extracellular material at the interface of the retinal pigment epithelium (RPE) and the Bruch membrane. Boon et al. (2008) evaluated the role of CFH in 30 probands with early-onset drusen (126700) and identified heterozygous nonsense, missense, and splice variants in 5 families. The affected individuals all carried the tyr402-to-his ARMD4 risk variant (Y402H; 134370.0008) on the other allele. This supported an autosomal recessive disease model in which individuals who carry a CFH mutation on 1 allele and the Y402H variant on the other allele develop drusen. Their findings strongly suggested that monogenic inheritance of CFH variants can result in basal laminar drusen in young adults, and this can progress to maculopathy and severe vision loss later in life.
Associations Pending Confirmation
Davila et al. (2010) performed a genomewide association study for susceptibility to meningococcal disease using 475 patients and 4,703 controls from the UK, followed by 2 replication studies for the most significant SNPs in western and southern European cohorts consisting of 968 patients and 1,376 controls. They identified SNPs within CFH (rs1065489; P = 2.2 x 10(-11)) and CFHR3 (rs426736; P = 4.6 x 10(-13)) that replicated independently in both cohorts. The SNP in CFH, rs1065489, is nonsynonymous and results in an asp936-to-glu substitution. Davila et al. (2010) noted that the causative agent of meningococcal disease, Neisseria meningitidis, evades complement-mediated killing by binding to host CFH. They proposed that genetic variation in these regulators of complement activation plays a role in determining the occurrence of invasive versus asymptomatic colonization by this organism.
Hogasen et al. (1995) reported hereditary membranoproliferative glomerulonephritis type II caused by factor H deficiency in the Norwegian Yorkshire pig. Affected animals had excessive complement activation, massive deposits of complement in the renal glomeruli, and died of renal failure within 11 weeks birth. Hegasy et al. (2002) identified mutations in the factor H gene as the basis for porcine factor H deficiency and membranoproliferative glomerulonephritis. Studies showed that the mutant factor H was not properly secreted from cells.
Pickering et al. (2002) showed that mice deficient in factor H (Cfh -/- mice) develop membranoproliferative glomerulonephritis spontaneously and are hypersensitive to developing renal injury caused by immune complexes. Introducing a second mutation in the gene encoding complement factor B (CFB; 138470), which prevents C3 turnover in vivo, prevented development of the phenotype of Cfh -/- mice. The authors concluded that uncontrolled C3 activation in vivo is essential for the development of membranoproliferative glomerulonephritis associated with deficiency of factor H.
Pickering et al. (2006) found that mice deficient in both Cfh and C5 (120900) developed membranoproliferative glomerulonephritis, but they showed reduced mortality and glomerular cellularity compared with mice deficient in Cfh alone. In a model of heterologous nephrotoxic nephritis, Cfh-deficient mice showed increased susceptibility to renal inflammation that was critically dependent on C5. Inhibition of C5 by administration of a monoclonal anti-C5 antibody protected Cfh-deficient mice during nephrotoxic nephritis.
Coffey et al. (2007) found that 2-year-old Cfh -/- mice exhibited significantly reduced visual acuity and rod response amplitudes on electroretinography compared with age-matched controls. Retinal imaging by confocal scanning laser ophthalmoscopy revealed an increase in autofluorescent subretinal deposits in Cfh -/- mice, whereas fundus and vasculature appeared normal. Examination of tissue sections showed an accumulation of complement C3 (120700) in neural retina of mutant mice, together with a decrease in electron-dense material, thinning of the Bruch membrane, changes in the cellular distribution of retinal pigment epithelial cell organelles, and disorganization of rod photoreceptor outer segments. Coffey et al. (2007) concluded that CFH is required for the long-term functional health of the retina.
Laskowski et al. (2020) found that Cfh -/- mice, especially Cfh -/- males, were more prone to spontaneous liver tumor development than wildtype. Cfh -/- liver showed unregulated alternative pathway activation, widespread deposition of complement-activation fragments throughout sinusoids, elevated transaminase levels, increased hepatic Cd8 (see 186910)-positive and F4/80 (ADGRE1; 600493)-positive cells, overexpression of hepatic mRNA associated with inflammatory signaling pathways, steatosis, and increased collagen deposition. Likewise, biopsy study showed extensive deposition of complement fragments within human liver tumors, and database analysis revealed that increased CFH expression was associated with improved survival in patients with hepatocellular carcinoma (HCC; 114550), whereas CFH mutations were associated with worse survival.
In affected members of a large family with autosomal dominant atypical hemolytic uremic syndrome (AHUS1; 235400) originally reported by Edelsten and Tuck (1978), Goodship et al. (1997) and Warwicker et al. (1998) identified a heterozygous C-to-G transversion in exon 20 of the CFH gene, predicted to result in an arg1197-to-gly (ARG1197GLY) substitution in SCR20. Although none of the patients had decreased levels of plasma factor H, Warwicker et al. (1998) postulated that the mutation disrupted the structure and function of the protein. Richards et al. (2001) subsequently referred to this mutation as arg1215 to gly (R1215G) based on numbering that includes the initiation codon and signal peptide.
Manuelian et al. (2003) identified the R1215G mutation in another patient with AHUS1. In vitro functional expression studies showed that the mutant protein had decreased binding to C3b/C3d, heparin, and human endothelial cells.
In a Native American boy with complement factor H deficiency (CFHD; 609814) and membranoproliferative glomerulonephritis originally reported by Vogt et al. (1995), Ault et al. (1997) identified compound heterozygosity for 2 mutations in the CFH gene: a 1679T-C transition resulting in a cys518-to-arg (CYS518ARG) substitution in short consensus repeat (SCR) number 9, and a 2949G-A transition resulting in a cys991-to-tyr (CYS991TYR; 134370.0003) substitution in SCR16. Both mutations affected conserved cysteine residues characteristic of SCR modules and predicted profound changes in the higher order structure of the 155-kD factor H protein. These mutations are referred to as cys536 to arg (C536R) and cys959 to tyr (C959Y) based on numbering that includes the initiation codon and signal peptide.
Using in vitro functional expression studies, Schmidt et al. (1999) demonstrated that the mutant CFH proteins identified by Ault et al. (1997) were not properly secreted due to disruption of specific disulfide bonds.
For discussion of the cys959-to-tyr (C959Y) mutation in the CFH gene that was found in compound heterozygous state in a patient with complement factor H deficiency (CFHD; 609814) by Ault et al. (1997), see 134370.0002.
In affected members of a Bedouin kindred with atypical hemolytic uremic syndrome (AHUS1; 235400), originally reported by Ohali et al. (1998), Ying et al. (1999) identified a homozygous C-to-T transition in exon 20 of the CFH gene, resulting in a ser1191-to-leu (S1191L) substitution. Although Western blot analysis detected low levels of the normal-sized factor H protein, fibroblast studies indicated that factor H was not properly secreted.
See also 134370.0005 and Buddles et al. (2000).
In 2 affected individuals from a Bedouin kindred with atypical hemolytic uremic syndrome (AHUS1; 235400), originally reported reported by Ohali et al. (1998) and Ying et al. (1999) (see 134370.0004), Buddles et al. (2000) found a different homozygous mutation in the CFH gene: an A-to-T transversion followed by a 24-bp deletion. The effect of this was to replace the last 7 amino acids of the protein with 3 different amino acids. Crucially, this deleted the final cysteine residue that forms a disulfide bridge essential for protein folding.
In 3 affected sibs of a consanguineous Italian family with complement factor H deficiency (CFHD; 609814) reported by Brai et al. (1988) and Misiano et al. (1993), Sanchez-Corral et al. (2000) identified a homozygous 638G-T transversion in the CFH gene, resulting in a glu171-to-ter (GLU171TER) substitution and premature termination of the protein. The proband was a woman with chronic renal failure; her 2 affected brothers had recurrent meningococcal infections. Western blot analysis showed the absence of both factor H and its spliced isoform FHL1 in the affected sibs. This mutation is referred to as glu189 to ter (E189X) based on numbering that includes the initiation codon and signal peptide.
In a patient with atypical hemolytic uremic syndrome (AHUS1; 235400), Perez-Caballero et al. (2001) found heterozygosity for a 3639T-G transversion in exon 23 of the HF1 gene, resulting in a leu1189-to-arg (L1189R) missense mutation. The mutation was not found in the father of the patient; the mother had died of postpartum HUS. Chronic renal failure was present. There was a normal complement profile and normal plasma levels of factor H.
Age-Related Macular Degeneration 4
In a genomewide scan for polymorphisms associated with age-related macular degeneration (ARMD4; 610698), Klein et al. (2005) identified a common intronic variant (rs380390) of the CFH gene. Resequencing revealed a polymorphism in linkage disequilibrium with the risk allele representing a tyrosine-to-histidine change at amino acid 402 (Y402H; rs1061170). Haines et al. (2005) independently determined that the 1277T-C transition in exon 9 of the CFH gene, resulting in the Y402H variant, increased the risk of ARMD with odds ratios between 2.45 and 5.57. They stated that the Y402H variant likely explains approximately 43% of ARMD. Similar results were obtained by Edwards et al. (2005).
Zareparsi et al. (2005) found a strong association of the Y402H variant of the CFH gene with susceptibility to ARMD. They found that the frequency of the C allele was 0.61 in cases, versus 0.34 in age-matched controls. A multiplicative model fitted the data well, and they estimated the population frequency of the high-risk C allele to be 0.39 and the genotype relative risk to be 2.44 for TC heterozygotes and 5.93 for CC homozygotes.
Hageman et al. (2005) found significant association between the Y402H variant and ARMD among 954 cases. The authors stated that the Y402H variant is located in exon 9 within a region that binds heparin and C-reactive protein (CRP; 123260).
Clark et al. (2006) reported that the Y402H variant (Y384H in the mature protein) is adjacent to a heparin-binding site in complement control protein module-7 (CCP7) of CFH. They found that the variants differentially recognized heparin.
Gotoh et al. (2006) found no association between the Y402H polymorphism and exudative ARMD among 146 Japanese patients and 105 Japanese controls. The frequency of the C allele was much lower in Japanese controls (0.04) compared to Caucasians (see Zareparsi et al., 2005).
Li et al. (2006) observed strong association between ARMD disease status and the Y402H variant of CFH, although they found 20 other CFH variants showing even stronger association. Among 2 common susceptibility haplotypes, 2 common protective haplotypes, and a set of rare haplotypes which in the aggregate seemed to be associated with increased disease susceptibility, the C allele of Y402H was present in approximately 94% of chromosomes that carried the most common risk haplotype and was absent from the common protective haplotypes. However, the allele was also absent from chromosomes carrying the second most common risk haplotype.
Johnson et al. (2006) genotyped 28 postmortem donor eyes for the Y402H variant and found that there was no difference in ocular CFH-labeling patterns between genotypes. However, H/H eyes had significantly higher levels of the CFH-binding CRP in the choroidal stroma, with no differences in CFH transcription levels or evidence for local ocular CRP transcription. Johnson et al. (2006) suggested that increased levels of CRP in the choroid may reflect a state of chronic inflammation resulting from attenuated CFH complement-inhibitory activity in H/H individuals, and the authors also noted that there may be alterations in the CRP-binding site in CFH, which lies within the domain containing the Y402H polymorphism.
Seddon et al. (2006) analyzed the 1277T-C variant of CFH, body mass index (BMI), and smoking status in 574 cases of advanced ARMD and 280 controls, and found that the number of risk alleles was associated with advanced ARMD (OR, 2.7 for TC; OR, 7.4 for CC) and that smoking and BMI were independently related to ARMD (OR, 5.1 and 2.1, respectively). The CC genotype plus higher BMI or smoking conferred the greatest risks (OR, 5.9 and 10.2, respectively). Seddon et al. (2006) concluded that genetic and environmental factors are independently associated with ARMD, and that modifiable factors alter genetic susceptibility.
Adopting a structural approach, Herbert et al. (2007) characterized interaction of the Y402H site with chemically defined glycosaminoglycans (GAGs). They found that residue 402 occupies a critical position on a face of CCP7 that recognizes GAGs, suggesting that variation at this site would modulate the ability to distinguish between GAGs according to type and density of sulfation.
Sjoberg et al. (2007) showed that the H384 variant exhibited relatively poor binding to CRP and FMOD (600245) compared with Y384. In contrast, H384 bound more effectively to DNA and necrotic cells than Y384.
In a Central European population of Caucasoid descent, Wegscheider et al. (2007) found that the prevalence of the CFH 402HH genotype was significantly higher in patients with exudative ARMD than in controls (35.2% vs 8.6%, P less than 0.01). Homozygosity for the polymorphism was associated with an odds ratio of 5.78 for exudative ARMD. Subgroup analysis revealed that the CFH 402HH genotype was significantly more prevalent in eyes with predominantly classic with no occult choroidal neovascularization (CNV) than in those with either retinal angiomatous proliferation, occult with no classic CNV, or predominantly classic with occult CNV.
Using a population-based study among Latinos, Tedeschi-Blok et al. (2007) found that the CFH Y402H polymorphism was not a major risk factor for overall early ARMD, but may play an important role in susceptibility to bilateral early ARMD. Bilateral early ARMD cases were 1.7 times more likely to carry at least 1 copy of the his402 allele (P = 0.03) compared with controls and unilateral early ARMD cases.
Grassi et al. (2007) screened 50 patients with the cuticular drusen phenotype of ARMD, 700 patients with typical ARMD, and 252 controls for the Y402H substitution. The histidine variant was present in 70% of the cuticular cohort, 55% of the typical ARMD cases, and 34% of controls. The association between the cuticular drusen phenotype and the histidine allele was highly significant (P = 0.003); genotype distribution between the 3 groups was similarly significant (P less than 0.001). Grassi et al. (2007) suggested that the complement cascade might play a greater role in the pathogenesis of the cuticular drusen subtype than in ARMD as a whole. Grassi et al. (2007) stated the Y402H polymorphism results from a 1204T-C transition.
Scott et al. (2007) examined the potential gene-environment interaction between cigarette smoking and the CFH Y402H polymorphism, 2 strong risk factors for ARMD. Effects of both Y402H genotype and cigarette smoking were stronger when comparing neovascular (grade 5) ARMD with grade 1 controls than when comparing all cases (grades 3-5) with grades 1-2 controls. Scott et al. (2007) concluded that cigarette smoking and 1277T-C are independent risk factors for ARMD and that both risk factors are associated more strongly with neovascular (wet) ARMD than with all other forms of ARMD combined.
In a matched sample set from the Age-Related Eye Disease Study (AREDS) cohort involving 424 patients with ARMD and 215 patients without ARMD acting as controls, Bergeron-Sawitzke et al. (2009) confirmed association between ARMD and the CC genotype of rs1061170 (OR, 6.2; p = 1.9 x 10(-12)).
In a study of 2,167 individuals with the CFH Y402H mutation or the ARMS2 A69S mutation (611313.0001), Ho et al. (2011) found that high dietary intake of nutrients with antioxidant properties reduced the risk of early ARMD.
Weismann et al. (2011) demonstrated that the CFH polymorphism H402 markedly reduces the ability of CFH to bind malondialdehyde (MDA), a common lipid peroxidation product that accumulates in many pathophysiologic processes including ARMD.
Clark et al. (2010) found that the 402H variant of CFH bound less well than the 402Y form to heparan sulfate and dermatan sulfate within Bruch membrane when added exogenously as probes. Both bound equally well to RPE. The 2 variants also differed in their ability to interact with desulfated heparin.
Lauer et al. (2011) showed that the Y402H polymorphism affected surface recruitment of CFH by monomeric CRP (123260) to specific patches on necrotic RPE cells. Reduced monomeric CRP binding of the CFH H402 variant resulted in complement activation, generation of antiinflammatory mediators, inflammation, and pathology.
Basal Laminar Drusen
Boon et al. (2008) found compound heterozygosity for the Y402H variant of CFH and another mutation in affected members of 5 families with basal laminar drusen maculopathy (126700). The mutations found with Y402H included gln408 to ter (134370.0019), arg1078 to ser (134370.0020) and 350+6T-G (134370.0021). No signs of a renal disorder suggesting atypical hemolytic uremic syndrome or type II membranoproliferative glomerulonephritis were found in these patients. Boon et al. (2008) considered it possible that in these patients the residual CFH activity was sufficient for normal renal function, whereas the ocular environment may be more sensitive to deposition and damage.
History
Kardys et al. (2006) genotyped 5,520 men and women without a history of coronary heart disease for the Y402H polymorphism and found that after adjustment for age, gender, established cardiovascular risk factors, and CRP (123260) level, H/H homozygotes had a hazard ratio of 1.77 for myocardial infarction. However, in a prospective study of 335 Caucasian men with myocardial infarction and matched controls, Zee et al. (2006) found no association of the Y402H polymorphism with disease or with baseline levels of C-reactive protein. In addition, Stark et al. (2007) found no association of Y402H with MI in a total of 2,161 individuals from the German MI family study. Nicaud et al. (2007) studied 1,303 cases with CAD from the AtheroGene Study and 483 controls from Germany and 1,034 MI patients from the ECTIM Study and 1,039 controls from the United Kingdom and France and found no association between Y402H and heart disease.
Hageman et al. (2005) found significant association between an ile62-to-val (I62V; rs800292) variant in the CFH gene and age-related macular degeneration (ARMD4; 610698) among 954 patients. In 2 subsets of the cases, the I62V allele conferred increased odds ratio for disease development of 2.79 and 1.95, respectively. Hageman et al. (2005) stated that the I62V variant is located in exon 2 within a region that includes a C3b (120700)-binding site.
By structural analysis, Hocking et al. (2008) determined that the I62V mutation caused rearrangements within the core of CFH module-1 and increased thermal stability.
In a matched sample set from the Age-Related Eye Disease Study (AREDS) cohort involving 424 patients with ARMD and 215 patients without ARMD acting as controls, Bergeron-Sawitzke et al. (2009) confirmed association between ARMD and the GG genotype of rs800292 (OR, 3.7; p = 8.0 x 10(-4)).
To identify genetic factors that modify the risk of exudative ARMD in the Japanese population, Arakawa et al. (2011) conducted a genomewide association study and a replication study using a total of 1,536 individuals with exudative AMD and 18,894 controls. Arakawa et al. (2011) confirmed association of the rs800292 SNP in CFH (p = 4.23 x 10(-15)).
In a patient with complement factor H deficiency (CFHD; 609814) who developed membranoproliferative glomerulonephritis, previously reported by Levy et al. (1986), Dragon-Durey et al. (2004) identified a homozygous T-to-A transversion in the CFH gene, resulting in a cys431-to-ser (C431S) substitution in SCR7. Plasma factor H levels were undetectable.
In a 34-year-old man with atypical hemolytic uremic syndrome (AHUS1; 235400), Warwicker et al. (1998) identified a heterozygous 4-bp deletion in exon 1 of the CFH gene, resulting in premature termination of the protein. He had no family history of the disorder.
In 2 children with relapsing atypical hemolytic uremic syndrome (AHUS1; 235400) in a consanguineous Turkish family (Rougier et al., 1998), Dragon-Durey et al. (2004) identified a homozygous T-to-A transversion in the CFH gene, resulting in a tyr899-to-ter (Y899X) substitution in SCR15.
In 2 Turkish brothers with factor H deficiency (CFHD; 609814) and membranoproliferative glomerulonephritis, Dragon-Durey et al. (2004) identified a homozygous G-to-T transversion in the CFH gene, resulting in an arg127-to-leu (R127L) substitution in SCR2.
In 2 sisters with complement factor H deficiency (CFHD; 609814) and membranoproliferative glomerulonephritis, Licht et al. (2006) identified a homozygous 3-bp deletion in the CFH gene, resulting in deletion of a lysine residue at codon 224. The girls were born of consanguineous Turkish parents; both parents were heterozygous for the mutation. In vitro functional expression studies showed that the mutation affected binding of factor H to C3b and the mutant protein showed defective complement regulation.
Li et al. (2006) found that a synonymous single-nucleotide polymorphism (SNP) in exon 10 of the CFH gene, rs2274700, showed the strongest association with age-related macular degeneration (ARMD4; 610698) in a study of 84 SNPs in a 123-kb region overlapping CFH in 544 unrelated affected individuals and 268 controls (chi square = 135.42, p less than 10(-30)).
In a case-control study of 1,238 unrelated affected individuals with advanced age-related macular degeneration (ARMD4; 610698) and 934 controls, all of European descent, Maller et al. (2006) observed the strongest association with a SNP in intron 14 of the CFH gene rs1410996 (p = 2.65 x 10(-61)). The association was independent of Y402H (134370.0008). Li et al. (2006) observed this SNP to have the second strongest association in their study (chi square = 132.70, p less than 10(-29)).
In a matched sample set from the Age-Related Eye Disease Study (AREDS) cohort involving 424 patients with ARMD and 215 patients without ARMD acting as controls, Bergeron-Sawitzke et al. (2009) confirmed association between ARMD and the GG genotype of rs1410996 (OR, 6.6; p = 8.7 x 10(-11)).
Complement Component H Deficiency
In a patient with complement factor H deficiency (CFHD; 609814), Servais et al. (2007) identified a heterozygous mutation in the CFH gene, resulting in an arg1210-to-cys (R1210C) substitution in the SCR20 region. The patient developed glomerulonephritis with isolated C3 deposits.
Atypical Hemolytic Uremic Syndrome 1, Susceptibility To
Manuelian et al. (2003) reported a patient with atypical hemolytic uremic syndrome (AHUS1; 235400) in whom they identified a heterozygous 3701C-T transition in the CFH gene, resulting in the R1210C substitution. In vitro functional expression studies showed that the mutant protein had decreased binding to heparin, C3b/C3d, and human endothelial cells.
Age-Related Macular Degeneration 4, Susceptibility To
Raychaudhuri et al. (2011) phased genotypes for 20 common SNPs spanning the CFH-CFHR1-CFHR3 region and a common CFHR1-CFHR3 deletion in 711 individuals with advanced age-related macular degeneration (see ARMD4; 610698) and 1,041 controls, and identified a rare high-risk haplotype ('H5') that lacked both the Y402H (134370.0008) and rs10737680-rs1410996 (134370.0016) risk alleles, but contained the R1210C substitution. Genotyping R1210C in 2,423 ARMD cases and 1,122 controls demonstrated high penetrance (present in 40 cases vs 1 control; p = 7.0 x 10(-6)) and an association with a 6-year-earlier onset of disease (p = 2.3 x 10(-6)). Because R1210C is known to cause familial renal disease, Raychaudhuri et al. (2011) assessed renal function in 17 unrelated R1210C heterozygotes with advanced ARMD but found no evidence of clinically significant renal dysfunction; in addition, comparing renal function in the R1210C heterozygotes to that of 17 ARMD patients matched for disease severity, age, and gender, but without R1210C, there was no significant difference.
Zhan et al. (2013) sequenced 2,335 ARMD cases and 789 controls in 10 candidate loci (57 genes) and then augmented their control set with ancestry-matched exome-sequenced controls. An analysis of coding variation in 2,268 ARMD cases and 2,268 ancestry-matched controls identified 2 large-effect rare variants: R1210C in the CFH gene, with a case frequency of 0.51%, control frequency of 0.02%, and odds ratio of 23.11; and K155Q in the C3 gene (120700.0010), with a case frequency of 1.06%, control frequency of 0.39%, and odds ratio of 2.68. The variants suggested decreased inhibition of C3 by CFH, resulting in increased activation of the alternative complement pathway, as a key component of disease biology.
Ferrara and Seddon (2015) analyzed images from a total of 143 ARMD patients (283 eyes), including 62 patients with the R1210C variant. Patients with the R1210C variant compared to those without this variant had the highest level of macular and total macular drusen scores (57.9% vs 16.7% and 52.0% vs 14.2%, respectively; p less than .001 for both scores) as well as a greater likelihood of having advanced disease (odds ratio, 7.0; 95% CI, 3.1-16.2; p less than .001). A higher prevalence of geographic atrophy was observed among patients carrying the R1210C variant (odds ratio, 13.7%; 95% CI, 5.0-37.7; p less than .001).
In a patient with atypical hemolytic uremic syndrome (AHUS1; 235400), Manuelian et al. (2003) identified a heterozygous 3587G-T transversion in the CFH gene, resulting in a glu1172-to-ter (E1172X) substitution within the SCR20 region. In vitro functional expression studies showed that the mutant protein had severely decreased binding to C3b/C3d and heparin, and did not bind at all to human endothelial cells.
In 7 patients in 2 families, Boon et al. (2008) found that early-onset drusen (126700) were associated with compound heterozygosity of tyr402-to-his (Y402H; 134370.0008) and a gln408-to-stop (Q408X) mutation in the CFH gene.
In 3 individuals from a family with early-onset drusen (126700), Boon et al. (2008) found compound heterozygosity of tyr402-to-his (Y402H; 134370.0008) and an arg1078-to-ser (R1078S) mutation in the CFH gene.
In a patient with early-onset drusen (126700), Boon et al. (2008) found compound heterozygosity for the tyr402-to-his variant (Y402H; 134370.0008) and a variant in the splice donor site of exon 3 of the CFH gene: 350+6T-G. This variant was predicted to affect splicing severely, given that the splice prediction score was reduced from 0.97 to 0.59. Moreover, this residue was completely conserved between human and all species for which the genome sequence of CFH was available.
In a 5-year-old German boy with atypical hemolytic uremic syndrome (AHUS1; 235400), Stahl et al. (2008) reported a heterozygous mutation in the CFH gene, resulting in a glu1198-to-ter (E1198X) substitution. He had decreased factor H function and renal failure. In vitro studies showed that the E1198X mutant exhibited decreased binding to normal platelets compared to wildtype factor H. Addition of patient serum containing mutant factor H to control platelets resulted in complement activation, deposition of C3 and C9, release of platelet-derived microparticles, and platelet aggregation, indicating platelet activation. Similar findings were obtained with other aHUS-associated CFH mutations. Preincubation of normal platelets with factor H reduced these effects. The findings indicated that mutant CFH results in complement activation on the surface of platelets and platelet activation, which may contribute to thrombocytopenia.
In 3 affected sibs from an Amish family with age-related macular degeneration (ARMD4; 610698), Hoffman et al. (2014) identified heterozygosity for a C-to-G transversion in the CFH gene, resulting in a pro503-to-ala (P503A) substitution at a residue with strong conservation across mammalian species. Case-control analysis using self-reported affection status in an Amish sample population showed significant association of ARMD with P503A (p = 9.27 x 10(-13)). This sample consisted of 1,150 individuals connected into a single 13-generation pedigree, including 128 individuals with ARMD, 728 without ARMD, and 294 with no information. Results were consistent in the subanalysis of individuals with clinically confirmed ARMD (p = 5.21 x 10(-7)). Carriers of the variant could be traced back 4 generations to a shared common ancestor, suggesting a recent founder event. The P503A variant was not found in a non-Amish Caucasian dataset consisting of 1,456 cases and 791 controls.
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