Scientific background:

Summary: The CFB gene encodes a stimulating factor to the alternative complement pathway. Gain-of-function mutations have been described in atypical HUS and age-related macula degeneration.

Molecule: The N-terminal fragment, Ba, is released during activation. It is composed of three complement control protein (CCP) domains. The active fragment Bb attains a dumbbell shape, and consists of two domains, one on each side. The N-terminal is a von Willebrand factor type A (vWFA) domain, and the C-terminal domain is a serine protease (SP). The vWFA domain (202 residues) shows structural similarities to the I domain of integrins. This domain contains a motif called Mg ion-dependent adhesion site (MIDAS), which is supposed to take part in C3b binding and SP activation. The Asn residue at codon position 260 is glycosylated. The SP domain consists of 283 residues. The proteolytic site is opposite the MIDAS motif.

Molecular anatomy: Before activation, factor B circulates in the blood as a single polypeptide chain.

Pathophysiology: Nativ Factor B is cleaved and activated by Factor D when bound to C3b. Ba is released, and the remaining complex C3bBb is a proficient C3-convertase that accelerates C3 activation by a positive feedback loop. The complex C3bBb is inherently unstable and easily dissociates. This inactivation is promoted by MCP, CFH, and CFI.

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		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: 

Wyatt RJ et al. (1981) Properdin deficiency with IgA nephropathy.
Maller J et al. (2006) Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration.
Gold B et al. (2006) Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration.
Goicoechea de Jorge E et al. (2007) Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome.
Zheng XL et al. (2008) Pathogenesis of thrombotic microangiopathies.
Kavanagh D et al. (2006) Does complement factor B have a role in the pathogenesis of atypical HUS?
Ponnuraj K et al. (2004) Structural analysis of engineered Bb fragment of complement factor B: insights into the activation mechanism of the alternative pathway C3-convertase.
Nürnberger J et al. (2009) Eculizumab for atypical hemolytic-uremic syndrome.