Wissenschaftliche Information:

Zusammenfassung: Dieses Gen kodiert einen wichtigen Faktor der Komplementkaskade. Mutationen sind für verantwortlich für das atypische hämolytisch urämische Syndrom, die membranoproliferative Glomerulonephritis und die altersabhängige Makuladegeneration.

Gen: Das Gen HF1, welches auch als beta1-H bekannt ist, besitzt eine Größe von 96 kb. In unmittelbarer Nachbarschaft befinden sich auf dem selben Chromosom 4 immunologisch und strukturell ähnliche Proteine (FHR1-4). Das Gen wird von 22 Exons gebildet.

Pathologie: Das Translationsprodukt ein Serumglykoprotein wird vornehmlich von der Leber sezerniert. Das Protein besteht aus 1309 Aminosäuren und besitzt im vollglykosilierten Zustand ein Molekulargewicht von 159 kD. Die Aminosäurenkette besteht aus 20 repetitiven Einheiten von jeweils 60 Aminosäuren, die als kurze konsensus Repeats (SCR) bezeichnet werden. Die Tertiärstruktur gleicht einem Griechischen Buchstaben a. Das Protein bindet polyanionische Zelloberflächen und C3b. Hierdurch begünstigt es den Abbau von C3b und damit eine Unterbrechung des alternativen Weges der Komplementaktivierung. Niedrige Plasmaspiegel von Faktor H führen zur Reduktion von C3 als Folge eines gesteigerten Verbrauches in einer ungezügelten Aktivierung.

Klinik: Mutationen dieses Gens wurden in einigen, allerdings nicht in allen, Familien mit familiärem Hämolytisch Urämischem Syndrom (HUS) gefunden. Weiterhin wurde eine Assoziation von Gendefekten mit der Nierenbeteiligung bei systemischem Lupus erythematodes, Typ 2 Membranoproliferativer Glomerulonephritis und Kollagen III Glomerulopathie beobachtet.
Die Polymorphismen I62V und Y402H erhöhen das Risiko an altersbedingter Makuladegeneration zu erkranken.

Epidemiologie: Zuverlässige epidemiologische Daten zur Mutationshäufigkeit und -lokalisation liegen nicht vor. Mutationen dieses Gens scheinen in allen Rassen vorzukommen.

Bewertung: Insbesondere Mutationen in den Exons 18-20 scheinen eine pathogenetische Bedeutung zu besitzen. Patienten mit einer nachgewiesenen Mutation haben eine schlechte Prognose nach Nierentransplantation. In 50-90% der Fälle kommt es zu einem Wiederauftretender Grunderkrankung und in 80-90% dieser Rezidive ist ein Transplantatverlust die Folge. Eine wesentlich bessere Prognose scheinen kombinierte Nieren- und Lebertransplantationen zu haben. Patienten mit nachgewiesener Mutation sollten für eine Supplemenation mit rekombinantem Faktor H vorgesehen werden. Eine Familienuntersuchung zur Risikoabschätzung könnte in Einzelfällen erwogen werden.

Untersuchungsstrategie: Eine bezüglich HUS belastete Familienanamnese, ein rezidivierender Verlauf und niedrige HF1 Spiegel könnten die Indikation für eine molekulargenetische Untersuchung begründen. Weiterhin könnte eine molekulargenetische Untersuchung bei familiärer Häufung von Nierenbeteiligung bei Lupus erythematode, Typ 2 Mesangioproliferativer Glomerulonephritis und Kollagen III Glomerulopathie erwogen werden.

Methodik:

	Klinische Diagnostik	Methode		Direkte Sequenzierung der proteinkodierenden Bereiche eines Gens
		Bearbeitungszeit		25 Arbeitstage
		Aufwand		mässig
		Untersuchungsmaterial		DNA
		Qualitätssicherung		Ausschließlich interne Qualitätskontrolle
	Mit dieser Methode werden bekannte sowie auch neue Missense-, Nonsense- und Spleißmutationen entdeckt.
	Klinische Diagnostik	Methode		Familienuntersuchung
		Bearbeitungszeit		5 Arbeitstage
		Aufwand		gering
		Untersuchungsmaterial		DNA
		Qualitätssicherung		Ausschließlich interne Qualitätskontrolle
	Die Untersuchung ist nur für die in dieser Familie bekannte Mutation spezifisch.
	Forschung/ Entwicklung	Methode		Multiplex ligationsabhängige Amplifikation
		Bearbeitungszeit		25 Arbeitstage
		Aufwand		gering
		Untersuchungsmaterial		DNA
		Qualitätssicherung		Ausschließlich interne Qualitätskontrolle

Literatur: 

Zipfel PF et al. (2003) Genetic screening in haemolytic uraemic syndrome.
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).
Clark SJ et al. (2006) His-384 allotypic variant of factor H associated with age-related macular degeneration has different heparin binding properties from the non-disease-associated form.
Day AJ et al. (1988) Sequence polymorphism of human complement factor H.
Klein RJ et al. (2005) Complement factor H polymorphism in age-related macular degeneration.
Caprioli J et al. (2006) Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome.
Nürnberger J et al. (2009) Eculizumab for atypical hemolytic-uremic syndrome.
Abrera-Abeleda MA et al. (2006) Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease).
Ault BH et al. (2000) Factor H and the pathogenesis of renal diseases.
Ault BH et al. (1997) Human factor H deficiency. Mutations in framework cysteine residues and block in H protein secretion and intracellular catabolism.
Bergeron-Sawitzke J et al. (2009) Multilocus analysis of age-related macular degeneration.
Boon CJ et al. (2008) Basal laminar drusen caused by compound heterozygous variants in the CFH gene.
Brai M et al. (1988) Combined homozygous factor H and heterozygous C2 deficiency in an Italian family.
Buddles MR et al. (2000) Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome.
Caprioli J et al. (2003) Complement factor H mutations and gene polymorphisms in haemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease.
Coffey PJ et al. (2007) Complement factor H deficiency in aged mice causes retinal abnormalities and visual dysfunction.
Díaz-Guillén MA et al. (1999) A radiation hybrid map of complement factor H and factor H-related genes.
Dragon-Durey MA et al. (2004) Heterozygous and homozygous factor h deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases.
Edelsten AD et al. (1978) Familial haemolytic uraemic syndrome.
Edwards AO et al. (2005) Complement factor H polymorphism and age-related macular degeneration.
Estaller C et al. (1991) Human complement factor H: two factor H proteins are derived from alternatively spliced transcripts.
Fletcher JC et al. (1997) Refusal of employment or insurance.
Gotoh N et al. (2006) No association between complement factor H gene polymorphism and exudative age-related macular degeneration in Japanese.
Grassi MA et al. (2007) Complement factor H polymorphism p.Tyr402His and cuticular Drusen.
Hageman GS et al. (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration.
Haines JL et al. (2005) Complement factor H variant increases the risk of 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.
Hing S et al. (1988) Assignment of complement components C4 binding protein (C4BP) and factor H (FH) to human chromosome 1q, using cDNA probes.
Hocking HG et al. (2008) Structure of the N-terminal region of complement factor H and conformational implications of disease-linked sequence variations.
Høgåsen K et al. (1995) Hereditary porcine membranoproliferative glomerulonephritis type II is caused by factor H deficiency.
Johnson PT et al. (2006) Individuals homozygous for the age-related macular degeneration risk-conferring variant of complement factor H have elevated levels of CRP in the choroid.
Józsi M et al. (2005) FHR-4A: a new factor H-related protein is encoded by the human FHR-4 gene.
Kardys I et al. (2006) A common polymorphism in the complement factor H gene is associated with increased risk of myocardial infarction: the Rotterdam Study.
Klein RJ et al. (2005) Complement factor H polymorphism in age-related macular degeneration.
Kömpf J et al. (1989) Linkage analyses of human peptidase C (PEPC), human factor H (HF), and coagulation factor XIIIB (F13B).
Kömpf J et al. (1988) Human factor H (beta 1H-globulin): linkage analysis.
Kristensen T et al. (1986) Structural analysis of human complement protein H: homology with C4b binding protein, beta 2-glycoprotein I, and the Ba fragment of B2.
Kunert A et al. (2007) Immune evasion of the human pathogen Pseudomonas aeruginosa: elongation factor Tuf is a factor H and plasminogen binding protein.
Levy M et al. (1986) H deficiency in two brothers with atypical dense intramembranous deposit disease.
Li M et al. (2006) CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration.
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).
Lukiw WJ et al. (2008) An NF-kappaB-sensitive micro RNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells.
Maller J et al. (2006) Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration.
Manuelian T et al. (2003) Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome.
Misasi R et al. (1989) Human complement factor H: an additional gene product of 43 kDa isolated from human plasma shows cofactor activity for the cleavage of the third component of complement.
Nakamura S et al. (1990) Genetic polymorphism of human factor H (beta 1H globulin).
Neumann HP et al. (2003) Haemolytic uraemic syndrome and mutations of the factor H gene: a registry-based study of German speaking countries.
Nicaud V et al. (2007) Lack of association between complement factor H polymorphisms and coronary artery disease or myocardial infarction.
Ohali M et al. (1998) Hypocomplementemic autosomal recessive hemolytic uremic syndrome with decreased factor H.
Pangburn MK et al. (2002) Cutting edge: localization of the host recognition functions of complement factor H at the carboxyl-terminal: implications for hemolytic uremic syndrome.
Pérez-Caballero D et al. (2001) Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome.
Pickering MC et al. (2002) Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H.
Pickering MC et al. (2006) Prevention of C5 activation ameliorates spontaneous and experimental glomerulonephritis in factor H-deficient mice.
Rey-Campos J et al. (1990) Physical linkage of the human genes coding for complement factor H and coagulation factor XIII B subunit.
Rey-Campos J et al. (1988) A physical map of the human regulator of complement activation gene cluster linking the complement genes CR1, CR2, DAF, and C4BP.
Richards A et al. (2001) Factor H mutations in hemolytic uremic syndrome cluster in exons 18-20, a domain important for host cell recognition.
Ripoche J et al. (1988) The complete amino acid sequence of human complement factor H.
Rodriguez de Cordoba S et al. (1985) Human genes for three complement components that regulate the activation of C3 are tightly linked.
Rodriguez de Cordoba S et al. (1987) New alleles of C4-binding protein and factor H and further linkage data in the regulator of complement activation (RCA) gene cluster in man.
Rodríguez de Córdoba S et al. (1984) Genetic polymorphism of human factor H (beta 1H).
Rougier N et al. (1998) Human complement factor H deficiency associated with hemolytic uremic syndrome.
Sánchez-Corral P et al. (2000) Molecular basis for factor H and FHL-1 deficiency in an Italian family.
Sánchez-Corral P et al. (2002) Structural and functional characterization of factor H mutations associated with atypical hemolytic uremic syndrome.
Saunders RE et al. (2006) An interactive web database of factor H-associated hemolytic uremic syndrome mutations: insights into the structural consequences of disease-associated mutations.
Schmidt BZ et al. (1999) Disruption of disulfide bonds is responsible for impaired secretion in human complement factor H deficiency.
Schneider MC et al. (2009) Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates.
Schwaeble W et al. (1991) Human complement factor H. Tissue specificity in the expression of three different mRNA species.
Schwaeble W et al. (1987) Human complement factor H: expression of an additional truncated gene product of 43 kDa in human liver.
Scott WK et al. (2007) Independent effects of complement factor H Y402H polymorphism and cigarette smoking on risk of age-related macular degeneration.
Seddon JM et al. (2006) CFH gene variant, Y402H, and smoking, body mass index, environmental associations with advanced age-related macular degeneration.
Servais A et al. (2007) Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome.
Ståhl AL et al. (2008) Factor H dysfunction in patients with atypical hemolytic uremic syndrome contributes to complement deposition on platelets and their activation.
Stark K et al. (2007) The common Y402H variant in complement factor H gene is not associated with susceptibility to myocardial infarction and its related risk factors.
Tedeschi-Blok N et al. (2007) Population-based study of early age-related macular degeneration: role of the complement factor H Y402H polymorphism in bilateral but not unilateral disease.
Vogt BA et al. (1995) Inherited factor H deficiency and collagen type III glomerulopathy.
Warwicker P et al. (1998) Genetic studies into inherited and sporadic hemolytic uremic syndrome.
Wegscheider BJ et al. (2007) Association of complement factor H Y402H gene polymorphism with different subtypes of exudative age-related macular degeneration.
Weis JH et al. (1987) A complement receptor locus: genes encoding C3b/C4b receptor and C3d/Epstein-Barr virus receptor map to 1q32.
Ying L et al. (1999) Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome.
Zareparsi S et al. (2005) Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration.
Zee RY et al. (2006) Complement factor H Y402H gene polymorphism, C-reactive protein, and risk of incident myocardial infarction, ischaemic stroke, and venous thromboembolism: a nested case-control study.
Zipfel PF et al. (1999) The factor H protein family.
Noris M et al. (2010) Thrombotic microangiopathy after kidney transplantation.