Genetic variants in the complement system predisposing to age-related macular degeneration: A review

Schramm, Elizabeth C.; Clark, Simon J.; Triebwasser, Michael; Raychaudhuri, Soumya; Seddon, Johanna M.; Atkinson, John P.

doi:10.1016/j.molimm.2014.06.032

Cited by 112 publications

(124 citation statements)

References 67 publications

(90 reference statements)

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“…The complement system comprises ∼20 proteins synthesized by the liver and the RPE (28). Chronic activation of complement is thought to play a role in the development and progression of retinopathies, such as AMD (29). For example, complement proteins such as C3 (30), CFB (31), and CFP (32), all dysregulated here in the mutant animals, are found in histologic specimens of AMD eyes, whereas variants of several genes encoding complement proteins are associated with a modulated risk to develop AMD.…”

Section: Discussionmentioning

confidence: 99%

Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization

Issa

Barnard

Herrmann

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

102

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Stargardt disease, an ATP-binding cassette, subfamily A, member 4 (ABCA4)-related retinopathy, is a genetic condition characterized by the accelerated accumulation of lipofuscin in the retinal pigment epithelium, degeneration of the neuroretina, and loss of vision. No approved treatment exists. Here, using a murine model of Stargardt disease, we show that the propensity of vitamin A to dimerize is responsible for triggering the formation of the majority of lipofuscin and transcriptional dysregulation of genes associated with inflammation. Data further demonstrate that replacing vitamin A with vitamin A deuterated at the carbon 20 position (C20-D 3 -vitamin A) impedes the dimerization rate of vitamin A-by approximately fivefold for the vitamin A dimer A2E-and subsequent lipofuscinogenesis and normalizes the aberrant transcription of complement genes without impairing retinal function. Phenotypic rescue by C20-D 3 -vitamin A was also observed noninvasively by quantitative autofluorescence, an imaging technique used clinically, in as little as 3 months after the initiation of treatment, whereas upon interruption of treatment, the age-related increase in autofluorescence resumed. Data suggest that C20-D 3 -vitamin A is a clinically amiable tool to inhibit vitamin A dimerization, which can be used to determine whether slowing the dimerization of vitamin A can prevent vision loss caused by Stargardt disease and other retinopathies associated with the accumulation of lipofuscin in the retina.S targardt disease, first described in 1909, is an autosomal recessive macular dystrophy affecting ∼1 in 10,000 people. The majority of people affected by the disease present with uncorrectable, decreased visual acuity during their teenage years, which most often progresses to legal blindness. To date, there is no approved intervention. Stargardt disease is marked by premature accumulation of lipofuscin in the retinal pigment epithelium (RPE), degeneration of the neuroretina, and subsequent loss of vision. The condition results from mutations in the ATPbinding cassette, subfamily A, member 4 (ABCA4) gene (1), which encodes a transmembrane flippase localized in photoreceptor outer segments. The flippase transports the phosphatidyl-ethanolamineretinaldehyde Schiff base between the cytosol and the cytoplasmic disk surfaces (2). Mutations in ABCA4 also result in retinitis pigmentosa and cone-rod dystrophy and have been linked to age-related macular degeneration (AMD) (3, 4).The accumulation of lipofuscin in the RPE is a common denominator in retinopathies associated with mutations in the ABCA4 gene. Also known as "wear and tear pigment," lipofuscin accumulates as a byproduct of cumulative damage during aging. The brown-yellow, autofluorescent, electron-dense material is also found in cells of the liver, kidney, heart muscle, adrenals, nerve, and ganglion and is considered one of the most consistent morphologic features of aging with a rate of accumulation inversely related to longevity (5, 6). In Stargardt disease, changes in RPE lipof...

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Section: Discussionmentioning

confidence: 99%

Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization

Issa

Barnard

Herrmann

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

102

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“…Although initial studies focused on the deposition of complement proteins in or around drusen, a major breakthrough came in 2005 when different groups independently showed a significant association with a common variant in the gene coding for the important complement regulatory gene CFH [45]. A single-nucleotide polymorphism, rs1061170, resulting in a histidine at position 402 instead of a tyrosine in the CFH protein was associated with an odds ratio (OR) of 2.3 and 5.2 in heterozygotes and homozygotes, respectively [46].…”

Section: Association Of Amd With Common or Rare Genetic Variants Of Tmentioning

confidence: 99%

“…Further studies have shown that the CFH risk allele has functional consequences, in that it affects the binding of CFH to various substances such as C-reactive protein, bacterial proteins, glycosaminoglycans, sulfated polyanions and malondialdehydes [45]. CFH regulates the alternative complement pathway by binding to complement-activating surfaces and enhancing the breakdown of the C3 convertase, thereby terminating this pathway before inflammatory byproducts such as C3b, C3a, C5a and C5b-9 can be formed [26].…”

Section: Association Of Amd With Common or Rare Genetic Variants Of Tmentioning

confidence: 99%

Age-Related Macular Degeneration: A Complementopathy?

Kijlstra¹,

Berendschot²

2015

Ophthalmic Res

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Age-related macular degeneration (AMD) is a progressive eye disease affecting many elderly individuals. It has a multifactorial pathogenesis and is associated with numerous environmental (e.g. smoking, light and nutrition) and genetic risk factors. A breakthrough in the mechanisms causing AMD is emerging; the involvement of the alternative pathway of the complement system appears to play a pivotal role. This has led to the statement that AMD is a disease caused by a hyperactive complement system, allowing the term ‘complementopathy' to define it more precisely. Abundant evidence includes: the identification of drusen components as activators of complement, immunohistochemical data showing the presence of many species of the complement system in the retinal pigment epithelium-Bruch's membrane-choroidocapillary region of AMD eyes, a strong association of AMD with certain genetic complement protein variants, raised complement levels in blood from AMD patients and the preliminary successful treatments of geographic atrophy with complement factor D (FD) inhibitors. FD is the rate-limiting enzyme of the alternative complement pathway, and is produced by adipose tissue. Recent findings suggest that nutrition may play a role in controlling the level of FD in the circulation. Addressing modifiable risk factors such as smoking and nutrition may thus offer opportunities for the prevention of AMD.

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“…8 Unregulated activation of the complement system, particularly the alternative pathway, has been strongly implicated in the etiology of AMD. Drusen contain complement components, 9,10 while mutations and AMD-associated polymorphisms have been identified in several proteins of the complement system, including the alternative pathway inhibitor complement factor H. [11][12][13][14] In particular, a common factor H polymorphism (Y402H) confers an increased risk for developing AMD [15][16][17] and has been shown to impair the protein's interaction with Bruch's membrane and choroidal vessels. 18 Therefore, choroidal endothelial cells (chEnCs) likely play a central role in both the ''dry'' and ''wet'' form of AMD.…”

Section: Discussionmentioning

confidence: 99%

A Novel Choroidal Endothelial Cell Line Has a Decreased Affinity for the Age-Related Macular Degeneration–Associated Complement Factor H Variant 402H

Loeven

Gemst

Schophuizen

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Choroidal endothelial cells play a central role in the pathogenesis of age-related macular degeneration (AMD). Protocols for isolating primary choroidal endothelial cells have been described but require access to human donor eyes, which is a limiting factor. Therefore, a conditionally immortalized choroidal endothelial cell (ciChEnC) line has been established. METHODS.Choroidal endothelial cells were selected by magnetic-activated cell sorting and conditionally immortalized using temperature-sensitive simian virus 40 large T antigen and human telomerase. The cell line obtained was characterized based on expression of endothelial marker proteins and endothelial cell-specific responses to various stimuli. Binding of AMDassociated and non-AMD variants of complement factor H in the context of a recombinant CCP6-8 (complement control protein domains 6-8) construct was determined using ELISA.RESULTS. ciChEnCs maintained morphology and von Willebrand factor and vascular endothelial cadherin expression for up to 27 passages. The cells internalized acetylated low-density lipoprotein, formed tubes on Matrigel, and increased intercellular adhesion molecule-1 expression in response to tumor necrosis factor-a. Cells grew into dense monolayers with barrier function and showed characteristics of choriocapillary cells, such as expression of plasmalemma vesicle-associated protein, human leukocyte antigen ABC, carbonic anhydrase IV, and membrane indentations reflecting fenestrations. ciChEnCs synthesized glycosaminoglycans chondroitin sulfate and the complement factor H ligand heparan sulfate. Interestingly, binding of the AMD-associated 402H variant of factor H to ciChEnC was significantly decreased compared to the 402Y variant. CONCLUSIONS.A novel ciChEnC cell line with choriocapillary characteristics has been established and should greatly facilitate investigation of the pathogenesis of AMD in the context of the choriocapillary microenvironment.

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Genetic variants in the complement system predisposing to age-related macular degeneration: A review

Cited by 112 publications

References 67 publications

Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization

Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization

Age-Related Macular Degeneration: A Complementopathy?

A Novel Choroidal Endothelial Cell Line Has a Decreased Affinity for the Age-Related Macular Degeneration–Associated Complement Factor H Variant 402H

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