Scientific background:

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

Molecule: 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.

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

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

Pathophysiology: 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.

Clinical signs: 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.

Methodology:

	clinical test	Method		Genomic sequencing of the entire coding region
		Turn-around time		25 working days
		Effort		medium
		Specimen		DNA
		Quality assessment		Internal quality control only
	All known and new missense, nonsense and splice mutations can be detected.
	clinical test	Method		Multiplex Ligation-Dependent Probe Amplification
		Turn-around time		25 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	clinical test	Method		Carrier testing
		Turn-around time		5 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	The test is only specific about the mutation already known in this kindred.

Literature: 

Vyse TJ et al. (1996) The molecular basis of hereditary complement factor I deficiency.
Caprioli J et al. (2006) Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome.
Dragon-Durey MA et al. (2005) Atypical haemolytic uraemic syndrome and mutations in complement regulator genes.
Vyse TJ et al. (1994) Hereditary complement factor I deficiency.
Vyse TJ et al. (1994) The organization of the human complement factor I gene (IF): a member of the serine protease gene family.
Goldberger G et al. (1984) Biosynthesis and postsynthetic processing of human C3b/C4b inactivator (factor I) in three hepatoma cell lines.
Goldberger G et al. (1987) Human complement factor I: analysis of cDNA-derived primary structure and assignment of its gene to chromosome 4.
Vyse TJ et al. (1994) The organization of the human complement factor I gene (IF): a member of the serine protease gene family.
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').
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.
Nürnberger J et al. (2009) Eculizumab for atypical hemolytic-uremic syndrome.
Noris M et al. (2010) Thrombotic microangiopathy after kidney transplantation.