Factor H

Source: Wikipedia, the free encyclopedia.
CFH
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000000971

ENSMUSG00000026365

UniProt

P08603

P06909

RefSeq (mRNA)

NM_001014975
NM_000186

NM_009888

RefSeq (protein)

NP_000177
NP_001014975

NP_034018

Location (UCSC)Chr 1: 196.65 – 196.75 MbChr 1: 140.01 – 140.11 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Factor H (FH) is a member of the regulators of complement activation family and is a

viruses. There are however, important exceptions, such as for example the bacterial pathogen, Neisseria meningitidis (also called the meningococcus). This human pathogen has evolved mechanisms to recruit human FH and down-regulate the alternative pathway.[8] Binding of FH permits the bacteria to proliferate in the bloodstream and cause disease.[9]

The ability of Factor H to exert its protective action on self cells and self surfaces is thought to be the result of Factor H having the ability to adopt conformations with lower or higher activities as a cofactor for C3 cleavage or decay accelerating activity.

glycosaminoglycans (GAGs) and or sialic acids that are generally present on host cells but not, normally, on pathogen surfaces ensuring that self surfaces are protected whilst complement fixation proceeds unabated on foreign surfaces.[11][12]

Structure

The molecule is made up of 20

C3d (that corresponds to the thioester domain of C3b)[26][27] have also been determined. Although an atomic resolution structure for intact factor H has not yet been determined, low resolution techniques indicate that it may be bent back in solution.[28] Information available to date indicates that CCP modules 1–4 is responsible for the cofactor and decay acceleration activities of factor H, whereas self/non-self discrimination occurs predominantly through GAG binding to CCP modules 7 and/or GAG or sialic acid binding to 19–20.[28][29]

Clinical significance

Due to the central role that factor H plays in the regulation of complement, there are a number of clinical implications arising from aberrant factor H activity. Overactive factor H may result in reduced complement activity on pathogenic cells – increasing susceptibility to microbial infections. Underactive factor H may result in increased complement activity on healthy host cells – resulting in autoimmune diseases. It is not surprising, therefore, that rare

single nucleotide polymorphisms (SNPs) in the complement factor H gene (CFH) often result in pathologies. Moreover, the complement inhibitory activities of factor H, and other complement regulators, are often used by pathogens to increase virulence
.

Age-related macular degeneration

In 2005, several independent research groups identified an SNP in CFH, which results in the protein change p.Y402H, as a risk factor for AMD present in around a third of Europeans.

polyanions and pentraxins) and to regulate the activation of complement and immune cells.[30] The SNP has also been shown to affect the function of factor H-like protein 1, an alternatively spliced version of factor H consisting of CCPs 1 to 7 only, which is thought to have a greater role in intraocular complement regulation.[30] However, the genetic variants in CFH with the greatest effect on an individual's risk of AMD have been shown to affect CCPs 1 to 4, which are involved in dampening the effects of the alternative pathway of complement.[30] A rare functional coding change, p.R1210C, in CFH results in a functional deficiency in factor H and leads to a substantially higher risk of macular degeneration as well as complement-mediated renal conditions.[30][31]

Variation in other genes of the regulators of complement activation locus, such as complement factor H-related genes, as well as in other complement proteins (e.g. factor I, C2/factor B, and C3) have also been associated with greater AMD risk.[30] The current theory is that complement dysregulation is a key driver of chronic inflammation in AMD.[30]

Atypical hemolytic uremic syndrome

Hemolytic uremic syndrome (HUS) is a disease associated with microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. It can be either acquired (e.g. following infection with shigatoxigenic Escherichia coli), or inherited (also known as atypical hemolytic uremic syndrome, aHUS). aHUS has been strongly linked to mutations in genes of the complement system, especially factor H.[30] In contrast to AMD and C3 glomerulopathy (another complement-mediated renal disorder) which are mainly associated with variation in the N-terminus (CCPs 1 to 4), predisposing mutations in factor H mainly affect the C-terminus of the protein (CCP modules 19 and 20),[30] which has been shown to be responsible for adherence to renal tissues and the regulation of complement components and their downstream effectors.[30][32][33]

Schizophrenia

Alterations in the immune response are involved in pathogenesis of many neuropsychiatric disorders including schizophrenia. Recent studies indicated alterations in the complement system, including those which may result in the overactivation of the alternative complement pathway, may predispose to schizophrenia. For example, the CFH SNP rs424535 (2783-526T>A) was positively associated with schizophrenia.[34]

Ischemic stroke

It was found that rs800292(184G >A) SNP was positively associated with stroke and rs800912 minor allele of the CFH gene might be considered as a risk factor for ischemic stroke.[34]

Recruitment by pathogens

Given the central role of factor H in protecting cells from complement, it is not surprising that several important human

B. recurrentis; Candida albicans;[35] Francisella tularensis; Haemophilus influenzae; Neisseria gonorrhoeae;[36] N. meningitidis; Streptococcus pneumoniae;[10] and Streptococcus pyogenes
. The Gram-negative bacterium B. burgdorferi has five Factor H binding proteins: CRASP-1, CRASP-2, CRASP-3, CRASP-4 and CRASP-5.[37] Each CRASP protein also binds plasminogen.[37] It is possible that the allele frequency of CFH variants across the globe reflects selective pressure from infectious diseases.[30]

Interactions

Factor H has been shown to

interact with complement component 3, amongst other complement proteins and factors, leading to regulation of the alternative pathway of complement in particular.[30][38][39]

Recombinant production

Biologically active Factor H has been produced by

Pichia pastoris.[41]

Potential use as a therapeutic drug

Age-related macular degeneration

Gemini Therapeutics Inc. is a Massachusetts based precision medicine company focused on the development of new therapies through a deeper understanding of disease. Based on the biological activity of human factor H, Gemini is developing a recombinant human factor H protein, GEM103, for the treatment of dry AMD. Gemini recently announced the completion of enrollment in a Phase 2a Trial of GEM103 in Dry Age-Related Macular Degeneration (AMD) in Patients with High-Risk Genetic Variants. Top line data are expected in 1H 2021.

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000000971 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000026365 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  29. S2CID 25095717
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Further reading

External links
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