Laboratory for Molecular Diagnostics
Center for Nephrology and Metabolic Disorders

Complement factor I

The complement factor coded by this gene plays an important role in complement inactivation. If deficient, complement activation occurs exuberantly and atypical HUS can ensue.

Gene Structure

The gene is located on chromosome 4 (4q25). It comprises 13 exons and spans about 63 kb.

Protein Structure

Mature factor I is a glycoprotein, which consists of two polypeptide chains connected by two disulfide bonds. The heterodimer has a molecular weight of 88,000 Dalton, 50,000 and 38,000 each of the components.

As many other complement proteins Factor I has a modular structure. The heavy chain is formed by two low-density lipoprotein receptor domains, a CD5 domain and a module that is also found in complement factors 6 and 7. The light chain is the serine proteinase region, its structure is similar to trypsin.

Expression

Factor I is a plasma protein. Its normal concentration is 35µg/ml.

Phenotype

Patients with hereditary factor I deficiency have a consumptive loss of C3 and factor B, and also show reduced levels of factor H. The clinical picture is equivalent to C3 deficiency and characterized by recurrent pyogenic infections. The median age of clinical manifestation of factor I deficiency is 17 month. Vasculitis and thromboembolic microangiopathies are also common in these patients.

The importance of other cofactors or environmental influences is underlined by the fact that several individuals with complete factor I deficiency exist who do not suffer clinical symptoms.

Pathology

In factor I deficiency, a consumptive depletion of C3 results because of unregulated activation of the alternative pathway.

Gene Regulation

Factor I is synthesized predominantly in the liver. The translation product is a sngle chain precursor protein of 265 amino acids. Before secretion into the plasma, two disulfide links stabilize the structure, and four basic amino acids are excised.

The physiological role of factor I is regulation of the complement cascade. Both the classical and the alternative pathways are inhibited by cleaving the alpha-chains of activated complement factors C4b and C3b. The cleavage of C4b, classical pathway, requires C4-binding protein as a cofactor. In the alternative pathway, complement factor H (CFH) is the essential cofactor to cut C3b. Destroying C3b impedes the formation of the alternative pathway C3 convertase (C3bBb), which has an important physiological impact on stopping the alternative amplification loop.

Genetests:

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

References:

1.

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

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2.

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

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3.

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

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4.

Vyse TJ et al. (1996) The molecular basis of hereditary complement factor I deficiency.

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5.

Nagasawa S et al. () Mechanism of action of the C3b inactivator: requirement for a high molecular weight cofactor (C3b-C4bINA cofactor) and production of a new C3b derivative (C3b').

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6.

Dragon-Durey MA et al. (2005) Atypical haemolytic uraemic syndrome and mutations in complement regulator genes.

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7.

Goldberger G et al. (1987) Human complement factor I: analysis of cDNA-derived primary structure and assignment of its gene to chromosome 4.

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8.

Pangburn MK et al. (1977) Human complement C3b inactivator: isolation, characterization, and demonstration of an absolute requirement for the serum protein beta1H for cleavage of C3b and C4b in solution.

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9.

Goldberger G et al. (1984) Biosynthesis and postsynthetic processing of human C3b/C4b inactivator (factor I) in three hepatoma cell lines.

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10.

Vyse TJ et al. (1994) The organization of the human complement factor I gene (IF): a member of the serine protease gene family.

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11.

Vyse TJ et al. (1994) Hereditary complement factor I deficiency.

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12.

NCBI article

NCBI 3426 [^]
13.

OMIM.ORG article

Omim 217030 [^]
14.

Orphanet article

Orphanet ID 119371 [^]
15.

Wikipedia article

Wikipedia EN (Complement_factor_I) [^]
Update: April 29, 2019