Laboratory for Molecular Diagnostics
Center for Nephrology and Metabolic Disorders

Complement factor H

This gene encodes an important factor in the complemant cascade. Mutations account for atypical haemolytic uremic syndrome, membranoproliferative glomerulonephritis, and age-related macula degeneration.

Epidemiology

Reliable epidemiological data are not available. Mutations seems to occur in all races.

Gene Structure

The gene HF1, otherwise known as bata-1H, spans about 96 kb. 4 structurally and immunologically related proteins (FHR1-4) are located in vicinity on the same chromosome. The gene consists of 22 exons.

Phenotype

Mutations in this gene have been found in several but not all families with hereditary hemolytic uremic syndrome (HUS). In contrary, mutations of this gene have been associated with other diseases such as renal involvement in lupus erythematosus, type 2 membranoproliferative glomerulonephritis, and collagen III glomerulopathy.<br>Age-related macular degeneration is related to polymorphisms I62V and Y402H.

Pathology

The translation product is a serum glycoprotein secreted predominantly by the liver. The protein contains 1309 amino acids and has a size of 150 kD. The protein is composed of 20 repetitive units of 60 amino acids called short consensus repeats (SCR). Its tertiary structure has the form of the Greek letter a. The protein binds to polyanionic cell surfaces and to C3b. Its physiological role is inhibition of alternative pathway complement activation by facilitating C3b inactivation. Low plasma levels of protein H are associated with low plasma levels of C3. This results from uncontrolled activation of complement along the alternative pathway that consequently leads to C3 consumption.

Test Strategy

Family history of HUS, recurrent HUS, and low plasma levels of HF1 may be indications for molecular genetic investigation. Additionally the molecular diagnostic might be considered in families with type 2 membranoproliferative glomerulonephritis and collagen III glomerulopathy.

Interpretation

Especially mutations in exons 18-20 seems to contribute to protein dysfunction. Patients with confirmed mutation have a poor outcome after renal transplantation. The disease recurs in 50-90% of cases and graft loss follows in 80-90% of recurrences. A combined kidney and liver transplantations seems to have a much better outcome. These patients are also candidates for recombinant HF1 supplementation in the future.

Genetests:

Clinic Method Carrier testing
Turnaround 5 days
Specimen type genomic DNA
Clinic Method Multiplex Ligation-Dependent Probe Amplification
Turnaround 20 days
Specimen type genomic DNA
Clinic Method Genomic sequencing of the entire coding region
Turnaround 20 days
Specimen type genomic DNA
Clinic Method Massive parallel sequencing
Turnaround 25 days
Specimen type genomic DNA

Related Diseases:

Hemolytic-Uremic Syndrome
ADAMTS13
C3
C4BPA
C4BPB
CD46
CFB
CFH
CFHR1
CFHR2
CFHR3
CFHR4
CFHR5
CFI
CLU
DGKE
Methylmalonic aciduria
Methylmalonic aciduria and homocystinuria cblC
MMACHC
Methylmalonic aciduria and homocystinuria cblD
MMADHC
Methylmalonic aciduria type mut
MUT
PIGA
PLG
THBD
Membranoproliferative glomerulonephritis (MPGN)
ADAMTS13
C1QA
C1QB
C1QC
C3
CD46
CFB
CFD
CFH
CFHR1
CFHR2
CFHR3
CFHR4
CFHR5
CFI
CLU
CR1 deficiency
CR1
Complement component C1q deficiency
C1QA
C1QB
C1QC
Complement component C1s deficiency
C1S
DGKE
PIGA
THBD
Age-related macula degeneration 01
APOE
ARMS2
C2
C3
CFH
CFHR1
CFHR3
KCNT2
Meningococcal infection susceptibility
C3
C5
C7
C8A
C8B
C8G
C9
CD46
CFB
CFD
CFH
CFP

References:

1.

Hing S et al. (1988) Assignment of complement components C4 binding protein (C4BP) and factor H (FH) to human chromosome 1q, using cDNA probes.

[^]
2.

Rodriguez de Cordoba S et al. (1985) Human genes for three complement components that regulate the activation of C3 are tightly linked.

[^]
3.

Weis JH et al. (1987) A complement receptor locus: genes encoding C3b/C4b receptor and C3d/Epstein-Barr virus receptor map to 1q32.

[^]
4.

Nürnberger J et al. (2009) Eculizumab for atypical hemolytic-uremic syndrome.

[^]
5.

Rey-Campos J et al. (1988) A physical map of the human regulator of complement activation gene cluster linking the complement genes CR1, CR2, DAF, and C4BP.

[^]
6.

Pickering MC et al. (2006) Prevention of C5 activation ameliorates spontaneous and experimental glomerulonephritis in factor H-deficient mice.

[^]
7.

Caprioli J et al. (2006) Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome.

[^]
8.

Warwicker P et al. (1998) Genetic studies into inherited and sporadic hemolytic uremic syndrome.

[^]
9.

Schmidt BZ et al. (1999) Disruption of disulfide bonds is responsible for impaired secretion in human complement factor H deficiency.

[^]
10.

Díaz-Guillén MA et al. (1999) A radiation hybrid map of complement factor H and factor H-related genes.

[^]
11.

Zipfel PF et al. (1999) The factor H protein family.

[^]
12.

Ying L et al. (1999) Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome.

[^]
13.

Buddles MR et al. (2000) Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome.

[^]
14.

Sánchez-Corral P et al. (2000) Molecular basis for factor H and FHL-1 deficiency in an Italian family.

[^]
15.

Ault BH et al. (2000) Factor H and the pathogenesis of renal diseases.

[^]
16.

Pérez-Caballero D et al. (2001) Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome.

[^]
17.

Richards A et al. (2001) Factor H mutations in hemolytic uremic syndrome cluster in exons 18-20, a domain important for host cell recognition.

[^]
18.

Fletcher JC et al. (1997) Refusal of employment or insurance.

[^]
19.

Pickering MC et al. (2002) Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H.

[^]
20.

Pangburn MK et al. (2002) Cutting edge: localization of the host recognition functions of complement factor H at the carboxyl-terminal: implications for hemolytic uremic syndrome.

[^]
21.

Sánchez-Corral P et al. (2002) Structural and functional characterization of factor H mutations associated with atypical hemolytic uremic syndrome.

[^]
22.

Hegasy GA et al. (2002) The molecular basis for hereditary porcine membranoproliferative glomerulonephritis type II: point mutations in the factor H coding sequence block protein secretion.

[^]
23.

Manuelian T et al. (2003) Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome.

[^]
24.

Neumann HP et al. (2003) Haemolytic uraemic syndrome and mutations of the factor H gene: a registry-based study of German speaking countries.

[^]
25.

Zipfel PF et al. (2003) Genetic screening in haemolytic uraemic syndrome.

[^]
26.

Caprioli J et al. (2003) Complement factor H mutations and gene polymorphisms in haemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease.

[^]
27.

Dragon-Durey MA et al. (2004) Heterozygous and homozygous factor h deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases.

[^]
28.

Józsi M et al. (2005) FHR-4A: a new factor H-related protein is encoded by the human FHR-4 gene.

[^]
29.

Haines JL et al. (2005) Complement factor H variant increases the risk of age-related macular degeneration.

[^]
30.

Edwards AO et al. (2005) Complement factor H polymorphism and age-related macular degeneration.

[^]
31.

Klein RJ et al. (2005) Complement factor H polymorphism in age-related macular degeneration.

[^]
32.

Hageman GS et al. (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration.

[^]
33.

Zareparsi S et al. (2005) Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration.

[^]
34.

Zee RY et al. (2006) Complement factor H Y402H gene polymorphism, C-reactive protein, and risk of incident myocardial infarction, ischaemic stroke, and venous thromboembolism: a nested case-control study.

[^]
35.

Saunders RE et al. (2006) An interactive web database of factor H-associated hemolytic uremic syndrome mutations: insights into the structural consequences of disease-associated mutations.

[^]
36.

Abrera-Abeleda MA et al. (2006) Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease).

[^]
37.

Licht C et al. (2006) Deletion of Lys224 in regulatory domain 4 of Factor H reveals a novel pathomechanism for dense deposit disease (MPGN II).

[^]
38.

Kardys I et al. (2006) A common polymorphism in the complement factor H gene is associated with increased risk of myocardial infarction: the Rotterdam Study.

[^]
39.

Gotoh N et al. (2006) No association between complement factor H gene polymorphism and exudative age-related macular degeneration in Japanese.

[^]
40.

Clark SJ et al. (2006) His-384 allotypic variant of factor H associated with age-related macular degeneration has different heparin binding properties from the non-disease-associated form.

[^]
41.

Seddon JM et al. (2006) CFH gene variant, Y402H, and smoking, body mass index, environmental associations with advanced age-related macular degeneration.

[^]
42.

Maller J et. al. (2006) Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration.

[^]
43.

Li M et al. (2006) CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration.

[^]
44.

Servais A et al. (2007) Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome.

[^]
45.

Johnson PT et al. (2006) Individuals homozygous for the age-related macular degeneration risk-conferring variant of complement factor H have elevated levels of CRP in the choroid.

[^]
46.

Tedeschi-Blok N et al. (2007) Population-based study of early age-related macular degeneration: role of the complement factor H Y402H polymorphism in bilateral but not unilateral disease.

[^]
47.

Grassi MA et al. (2007) Complement factor H polymorphism p.Tyr402His and cuticular Drusen.

[^]
48.

Scott WK et al. (2007) Independent effects of complement factor H Y402H polymorphism and cigarette smoking on risk of age-related macular degeneration.

[^]
49.

Nicaud V et al. (2007) Lack of association between complement factor H polymorphisms and coronary artery disease or myocardial infarction.

[^]
50.

Wegscheider BJ et al. (2007) Association of complement factor H Y402H gene polymorphism with different subtypes of exudative age-related macular degeneration.

[^]
51.

Stark K et al. (2007) The common Y402H variant in complement factor H gene is not associated with susceptibility to myocardial infarction and its related risk factors.

[^]
52.

Kunert A et. al. (2007) Immune evasion of the human pathogen Pseudomonas aeruginosa: elongation factor Tuf is a factor H and plasminogen binding protein.

[^]
53.

Coffey PJ et al. (2007) Complement factor H deficiency in aged mice causes retinal abnormalities and visual dysfunction.

[^]
54.

Boon CJ et al. (2008) Basal laminar drusen caused by compound heterozygous variants in the CFH gene.

[^]
55.

Hocking HG et al. (2008) Structure of the N-terminal region of complement factor H and conformational implications of disease-linked sequence variations.

[^]
56.

Estaller C et al. (1991) Human complement factor H: two factor H proteins are derived from alternatively spliced transcripts.

[^]
57.

Ståhl AL et al. (2008) Factor H dysfunction in patients with atypical hemolytic uremic syndrome contributes to complement deposition on platelets and their activation.

[^]
58.

Schwaeble W et al. (1991) Human complement factor H. Tissue specificity in the expression of three different mRNA species.

[^]
59.

Lukiw WJ et al. (2008) An NF-kappaB-sensitive micro RNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells.

[^]
60.

Schneider MC et al. (2009) Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates.

[^]
61.

Bergeron-Sawitzke J et. al. (2009) Multilocus analysis of age-related macular degeneration.

[^]
62.

Noris M et al. (2010) Thrombotic microangiopathy after kidney transplantation.

[^]
63.

Nakamura S et al. (1990) Genetic polymorphism of human factor H (beta 1H globulin).

[^]
64.

Rey-Campos J et al. (1990) Physical linkage of the human genes coding for complement factor H and coagulation factor XIII B subunit.

[^]
65.

Schwaeble W et al. (1987) Human complement factor H: expression of an additional truncated gene product of 43 kDa in human liver.

[^]
66.

Kömpf J et al. (1989) Linkage analyses of human peptidase C (PEPC), human factor H (HF), and coagulation factor XIIIB (F13B).

[^]
67.

Misasi R et al. (1989) Human complement factor H: an additional gene product of 43 kDa isolated from human plasma shows cofactor activity for the cleavage of the third component of complement.

[^]
68.

Kristensen T et al. (1986) Structural analysis of human complement protein H: homology with C4b binding protein, beta 2-glycoprotein I, and the Ba fragment of B2.

[^]
69.

Levy M et al. (1986) H deficiency in two brothers with atypical dense intramembranous deposit disease.

[^]
70.

Rodriguez de Cordoba S et al. (1987) New alleles of C4-binding protein and factor H and further linkage data in the regulator of complement activation (RCA) gene cluster in man.

[^]
71.

Day AJ et al. (1988) Sequence polymorphism of human complement factor H.

[^]
72.

Ripoche J et al. (1988) The complete amino acid sequence of human complement factor H.

[^]
73.

Brai M et al. (1988) Combined homozygous factor H and heterozygous C2 deficiency in an Italian family.

[^]
74.

Kömpf J et al. (1988) Human factor H (beta 1H-globulin): linkage analysis.

[^]
75.

Rodríguez de Córdoba S et al. (1984) Genetic polymorphism of human factor H (beta 1H).

[^]
76.

Edelsten AD et al. (1978) Familial haemolytic uraemic syndrome.

[^]
77.

Vogt BA et al. (1995) Inherited factor H deficiency and collagen type III glomerulopathy.

[^]
78.

Høgåsen K et al. (1995) Hereditary porcine membranoproliferative glomerulonephritis type II is caused by factor H deficiency.

[^]
79.

Ault BH et al. (1997) Human factor H deficiency. Mutations in framework cysteine residues and block in H protein secretion and intracellular catabolism.

[^]
80.

Ohali M et al. (1998) Hypocomplementemic autosomal recessive hemolytic uremic syndrome with decreased factor H.

[^]
81.

Rougier N et al. (1998) Human complement factor H deficiency associated with hemolytic uremic syndrome.

[^]
Update: Sept. 26, 2018