The rare C9 P167S risk variant for age-related macular degeneration increases polymerization of the terminal component of the complement cascade.
The rare C9 P167S risk variant for age-related macular degeneration increases polymerization of the terminal component of the complement cascade.
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DOI：
10.1093/hmg/ddab086
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发表时间：
2021-06-17
影响因子：
3.5
通讯作者：
Kavanagh D
中科院分区：
文献类型：
--
作者：
McMahon O;Hallam TM;Patel S;Harris CL;Menny A;Zelek WM;Widjajahakim R;Java A;Cox TE;Tzoumas N;Steel DHW;Shuttleworth VG;Smith-Jackson K;Brocklebank V;Griffiths H;Cree AJ;Atkinson JP;Lotery AJ;Bubeck D;Morgan BP;Marchbank KJ;Seddon JM;Kavanagh D
年龄相关性黄斑变性（AMD）是一种复杂的神经退行性眼病，具有行为和遗传病因，是老年白种人不可逆视力丧失的主要原因。补体替代途径中功能显著的遗传变异与疾病密切相关。最近，补体终末通路中的一种罕见变异与风险增加有关，即补体成分9 (C9) P167S。为了评估这种变异的功能后果，在两个独立的AMD患者队列中测量了C9水平。在这两个队列中，证明P167S变异与低C9血浆水平相关。进一步分析显示，与非晚期AMD患者相比，晚期AMD患者的sC5b-9水平升高，尽管这与P167S多态性无关。用重组产生的野生型和P167S C9产生的膜攻击复合物（MAC）的电镜显示相同的MAC环结构。在功能分析中，P167S变体显示出更高的聚合倾向，并且当将其添加到c9缺失的血清中时，其诱导绵羊红细胞溶血的能力略有增加。C9 P167S AMD风险多态性显示聚合和功能活性增加，这为正在进行的sCD59抑制AMD补体终末途径的基因治疗试验提供了理论依据。
Age-related macular degeneration (AMD) is a complex neurodegenerative eye disease with behavioral and genetic etiology and is the leading cause of irreversible vision loss among elderly Caucasians. Functionally significant genetic variants in the alternative pathway of complement have been strongly linked to disease. More recently, a rare variant in the terminal pathway of complement has been associated with increased risk, Complement component 9 (C9) P167S. To assess the functional consequence of this variant, C9 levels were measured in two independent cohorts of AMD patients. In both cohorts, it was demonstrated that the P167S variant was associated with low C9 plasma levels. Further analysis showed that patients with advanced AMD had elevated sC5b-9 compared to those with non-advanced AMD, although this was not associated with the P167S polymorphism. Electron microscopy of membrane attack complexes (MACs) generated using recombinantly produced wild type or P167S C9 demonstrated identical MAC ring structures. In functional assays, the P167S variant displayed a higher propensity to polymerize and a small increase in its ability to induce hemolysis of sheep erythrocytes when added to C9-depleted serum. The demonstration that this C9 P167S AMD risk polymorphism displays increased polymerization and functional activity provides a rationale for the gene therapy trials of sCD59 to inhibit the terminal pathway of complement in AMD that are underway.
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DOI：
10.1177/1352458512438238
发表时间：
2012-10
期刊：
Multiple sclerosis (Houndmills, Basingstoke, England)
影响因子：
--
作者：
Ingram G;Hakobyan S;Hirst CL;Harris CL;Loveless S;Mitchell JP;Pickersgill TP;Robertson NP;Morgan BP
通讯作者：
Morgan BP
影响因子：
3.5
作者：
Kavanagh D;Yu Y;Schramm EC;Triebwasser M;Wagner EK;Raychaudhuri S;Daly MJ;Atkinson JP;Seddon JM
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Seddon JM
DOI：
10.1073/pnas.0501536102
发表时间：
2005-05-17
影响因子：
11.1
作者：
Hageman, GS;Anderson, DH;Allikmets, R
通讯作者：
Allikmets, R
影响因子：
8.1
作者：
Geerlings, Maartje J.;Kremlitzka, Mariann;den Hollander, Anneke I.
通讯作者：
den Hollander, Anneke I.
DOI：
10.1016/s0140-6736(08)61348-3
发表时间：
2008-11-22
期刊：
Lancet (London, England)
影响因子：
--
作者：
Ennis S;Jomary C;Mullins R;Cree A;Chen X;Macleod A;Jones S;Collins A;Stone E;Lotery A
通讯作者：
Lotery A