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Functional analyses...
Functional analyses of rare genetic variants in complement component C9 identified in patients with age-related macular degeneration
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- Kremlitzka, Mariann (author)
- Lund University,Lunds universitet,Proteinkemi, Malmö,Forskargrupper vid Lunds universitet,Protein Chemistry, Malmö,Lund University Research Groups
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- Geerlings, Maartje J. (author)
- Radboud University Medical Center
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- De Jong, Sarah (author)
- Lund University,Lunds universitet,Proteinkemi, Malmö,Forskargrupper vid Lunds universitet,Protein Chemistry, Malmö,Lund University Research Groups,Radboud University Medical Center
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- Bakker, Bjorn (author)
- Radboud University Medical Center
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- Nilsson, Sara C. (author)
- Lund University,Lunds universitet,Proteinkemi, Malmö,Forskargrupper vid Lunds universitet,Protein Chemistry, Malmö,Lund University Research Groups
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- Fauser, Sascha (author)
- University Hospital of Cologne,F. Hoffmann-La Roche AG
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- Hoyng, Carel B. (author)
- Radboud University Medical Center
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- De Jong, Eiko K. (author)
- Radboud University Medical Center
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- Den Hollander, Anneke I. (author)
- Radboud University Medical Center
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- Blom, Anna M. (author)
- Lund University,Lunds universitet,Proteinkemi, Malmö,Forskargrupper vid Lunds universitet,Protein Chemistry, Malmö,Lund University Research Groups
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(creator_code:org_t)
- 2018-05-14
- 2018
- English 11 s.
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 27:15, s. 2678-2688
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http://dx.doi.org/10...
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https://doi.org/10.1...
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Abstract
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- Age-related macular degeneration (AMD) is a progressive disease of the central retina and the leading cause of irreversible vision loss in the western world. The involvement of abnormal complement activation in AMD has been suggested by association of variants in genes encoding complement proteins with disease development. A low-frequency variant (p.P167S) in the complement component C9 (C9) gene was recently shown to be highly associated with AMD; however, its functional outcome remains largely unexplored. In this study, we reveal five novel rare genetic variants (p.M45L, p.F62S, p.G126R, p.T170I and p.A529T) in C9 in AMD patients, and evaluate their functional effects in vitro together with the previously identified (p.R118Wand p.P167S) C9 variants. Our results demonstrate that the concentration of C9 is significantly elevated in patients' sera carrying the p.M45L, p.F62S, p.P167S and p.A529T variants compared with non-carrier controls. However, no difference can be observed in soluble terminal complement complex levels between the carrier and non-carrier groups. Comparing the polymerization of the C9 variants we reveal that the p.P167S mutant spontaneously aggregates, while the other mutant proteins (except for C9 p.A529T) fail to polymerize in the presence of zinc. Altered polymerization of the p.F62S and p.P167S proteins associated with decreased lysis of sheep erythrocytes and adult retinal pigment epithelial-19 cells by carriers' sera. Our data suggest that the analyzed C9 variants affect only the secretion and polymerization of C9, without influencing its classical lytic activity. Future studies need to be performed to understand the implications of the altered polymerization of C9 in AMD pathology.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Oftalmologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Ophthalmology (hsv//eng)
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- By the author/editor
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Kremlitzka, Mari ...
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Geerlings, Maart ...
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De Jong, Sarah
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Bakker, Bjorn
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Nilsson, Sara C.
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Fauser, Sascha
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show more...
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Hoyng, Carel B.
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De Jong, Eiko K.
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Den Hollander, A ...
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Blom, Anna M.
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Ophthalmology
- Articles in the publication
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Human Molecular ...
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Lund University