Scientific background:

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

Gene: 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.

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.

Clinical signs: 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.
Age-related macular degeneration is related to polymorphisms I62V and Y402H.

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

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.

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.

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.
	research test	Method		Multiplex Ligation-Dependent Probe Amplification
		Turn-around time		25 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only

Literature: 

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Richards A et al. (2001) Factor H mutations in hemolytic uremic syndrome cluster in exons 18-20, a domain important for host cell recognition.
Hageman GS et al. (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration.
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.
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).
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