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Functional analyses of rare genetic variants in complement component C9 identified in patients with age-related macular degeneration

Kremlitzka, Mariann LU ; Geerlings, Maartje J. ; De Jong, Sarah LU ; Bakker, Bjorn ; Nilsson, Sara C. LU ; Fauser, Sascha ; Hoyng, Carel B. ; De Jong, Eiko K. ; Den Hollander, Anneke I. and Blom, Anna M. LU (2018) In Human Molecular Genetics 27(15). p.2678-2688
Abstract

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... (More)

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.

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organization
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type
Contribution to journal
publication status
published
subject
in
Human Molecular Genetics
volume
27
issue
15
pages
11 pages
publisher
Oxford University Press
external identifiers
  • pmid:29767720
  • scopus:85054985181
ISSN
0964-6906
DOI
10.1093/hmg/ddy178
language
English
LU publication?
yes
id
25d26414-215e-4906-84e4-6c9b82ac5e66
date added to LUP
2018-11-09 12:40:47
date last changed
2020-09-30 05:48:21
@article{25d26414-215e-4906-84e4-6c9b82ac5e66,
  abstract     = {<p>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.</p>},
  author       = {Kremlitzka, Mariann and Geerlings, Maartje J. and De Jong, Sarah and Bakker, Bjorn and Nilsson, Sara C. and Fauser, Sascha and Hoyng, Carel B. and De Jong, Eiko K. and Den Hollander, Anneke I. and Blom, Anna M.},
  issn         = {0964-6906},
  language     = {eng},
  number       = {15},
  pages        = {2678--2688},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Functional analyses of rare genetic variants in complement component C9 identified in patients with age-related macular degeneration},
  url          = {http://dx.doi.org/10.1093/hmg/ddy178},
  doi          = {10.1093/hmg/ddy178},
  volume       = {27},
  year         = {2018},
}