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

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Functional analyses of rare genetic variants in complement component C9 identified in patients with age-related macular degeneration. / Kremlitzka, Mariann; Geerlings, Maartje J.; De Jong, Sarah; Bakker, Bjorn; Nilsson, Sara C.; Fauser, Sascha; Hoyng, Carel B.; De Jong, Eiko K.; Den Hollander, Anneke I.; Blom, Anna M.

I: Human Molecular Genetics, Vol. 27, Nr. 15, 2018, s. 2678-2688.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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Kremlitzka, Mariann ; Geerlings, Maartje J. ; De Jong, Sarah ; Bakker, Bjorn ; Nilsson, Sara C. ; Fauser, Sascha ; Hoyng, Carel B. ; De Jong, Eiko K. ; Den Hollander, Anneke I. ; Blom, Anna M. / Functional analyses of rare genetic variants in complement component C9 identified in patients with age-related macular degeneration. I: Human Molecular Genetics. 2018 ; Vol. 27, Nr. 15. s. 2678-2688.

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TY - JOUR

T1 - Functional analyses of rare genetic variants in complement component C9 identified in patients with age-related macular degeneration

AU - Kremlitzka, Mariann

AU - Geerlings, Maartje J.

AU - De Jong, Sarah

AU - Bakker, Bjorn

AU - Nilsson, Sara C.

AU - Fauser, Sascha

AU - Hoyng, Carel B.

AU - De Jong, Eiko K.

AU - Den Hollander, Anneke I.

AU - Blom, Anna M.

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

U2 - 10.1093/hmg/ddy178

DO - 10.1093/hmg/ddy178

M3 - Article

VL - 27

SP - 2678

EP - 2688

JO - Human Molecular Genetics

T2 - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 15

ER -