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:

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.

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.

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

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

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').

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

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

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.

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

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

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

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)