Translational Mini-Review Series on Complement Factor H: Genetics and disease associations of human complement factor H

Clinical and Experimental Immunology

Volumn 151, Issue 1, 2008, Pages 1-13

  De Córdoba, S Rodríguez ^a,b   De Jorge, E Goicoechea ^a  

^a CENTRO DE INVESTIGACIÓN BIOMÉDICA EN RED DE ENFERMEDADES RARAS CIBERER   (Spain)

^b CENTRO DE INVESTIGACIONES BIOLÓGICAS   (Spain)

Author keywords

Age related macular degeneration (AMD); Factor H; Haemolytic uraemic syndrome (HUS); Membranoproliferative glomerulonephritis type II (MPGN2); RCA

Indexed keywords

COMPLEMENT FACTOR H; RNA;

CELL PROTECTION; COMPLEMENT ACTIVATION; COMPLEMENT SYSTEM; DISEASE ASSOCIATION; GENE CONTROL; GENE REARRANGEMENT; GENETIC ASSOCIATION; GENETIC VARIABILITY; GENOTYPE PHENOTYPE CORRELATION; HEMOLYTIC UREMIC SYNDROME; HOST CELL; HUMAN; MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS; MOLECULAR BIOLOGY; NONHUMAN; PRIORITY JOURNAL; RETINA MACULA AGE RELATED DEGENERATION; REVIEW; RNA TRANSLATION; TISSUE INJURY;

COMPLEMENT ACTIVATION; COMPLEMENT C3 CONVERTASE, ALTERNATIVE PATHWAY; COMPLEMENT FACTOR H; GENOTYPE; GLOMERULONEPHRITIS, MEMBRANOPROLIFERATIVE; HEMOLYTIC-UREMIC SYNDROME; HUMANS; MACULAR DEGENERATION; MUTATION; PHENOTYPE;

EID: 36849084660     PISSN: 00099104     EISSN: 13652249     Source Type: Journal    
DOI: 10.1111/j.1365-2249.2007.03552.x     Document Type: Review

References (108)

1. Law SKA, Reid KBM. Complement, 2nd edn. Oxford : IRL Press, 1995.
2. Pangburn MK, Schreiber RD, Müller-Eberhard HJ. Human complement C3b inactivator: isolation, characterization, and demonstration of an absolute requirement for the serum protein beta1H for cleavage of C3b and C4b in solution. J Exp Med 1977 146 : 257 70.
3. Weiler JM, Daha MR, Austen KF, Fearon DT. Control of the amplification convertase of complement by the plasma protein beta1H. Proc Natl Acad Sci USA 1976 73 : 3268 72.
4. Whaley K, Ruddy S. Modulation of the alternative complement pathways by beta 1 H globulin. J Exp Med 1976 144 : 1147 63.
5. Fearon DT. Regulation by membrane sialic acid of beta1H-dependent decay-dissociation of amplification C3 convertase of the alternative complement pathway. Proc Natl Acad Sci USA 1978 75 : 1971 5.
6. Kazatchkine MD, Fearon DT, Austen KF. Human alternative complement pathway: membrane-associated sialic acid regulates the competition between B and beta1 H for cell-bound C3b. J Immunol 1979 122 : 75 81.
7. Pangburn MK, Schreiber RD, Muller-Eberhard HJ. C3b deposition during activation of the alternative complement pathway and the effect of deposition on the activating surface. J Immunol 1983 131 : 1930 5.
8. Ripoche J, Day AJ, Harris TJ, Sim RB. The complete amino acid sequence of human complement factor H. Biochem J 1988 249 : 593 602.
9. Kuhn S, Skerka C, Zipfel PF. Mapping of the complement regulatory domains in the human factor H-like protein 1 and in factor H1. J Immunol 1995 155 : 5663 70.
10. Alsenz J, Schulz TF, Lambris JD, Sim RB, Dierich MP. Structural and functional analysis of the complement component factor H with the use of different enzymes and monoclonal antibodies to factor H. Biochem J 1985 232 : 841 50.
11. Gordon DL, Kaufman RM, Blackmore TK, Kwong J, Lublin DM. Identification of complement regulatory domains in human factor H. J Immunol 1995 155 : 348 56.
12. Jokiranta TS, Zipfel PF, Hakulinen J et al. Analysis of the recognition mechanism of the alternative pathway of complement by monoclonal anti-factor H antibodies: evidence for multiple interactions between H and surface bound C3b. FEBS Lett 1996 393 : 297 302.
13. Prodinger WM, Hellwage J, Spruth M, Dierich MP, Zipfel PF. The C-terminus of factor H: monoclonal antibodies inhibit heparin binding and identify epitopes common to factor H and factor H-related proteins. Biochem J 1998 331 : 41 7.
14. Blackmore TK, Hellwage J, Sadlon TA et al. Identification of the second heparin-binding domain in human complement factor H. J Immunol 1998 160 : 3342 8.
15. Blackmore TK, Sadlon TA, Ward HM, Lublin DM, Gordon DL. Identification of a heparin binding domain in the seventh short consensus repeat of complement factor H. J Immunol 1996 157 : 5422 7.
16. Pangburn MK, Atkinson MA, Meri S. Localization of the heparin-binding site on complement factor H. J Biol Chem 1991 266 : 16847 53.
17. Ram S, Sharma AK, Simpson SD et al. A novel sialic acid binding site on factor H mediates serum resistance of sialylated neisseria gonorrhoeae. J Exp Med 1998 187 : 743 52.
18. Kaplan MH, Volanakis JE. Interaction of C-reactive protein complexes with the complement system. I. Consumption of human complement associated with the reaction of C-reactive protein with pneumococcal C-polysaccharide and with the choline phosphatides, lecithin and sphingomyelin. J Immunol 1974 112 : 2135 47.
19. Mold C, Kingzette M, Gewurz H. C-reactive protein inhibits pneumococcal activation of the alternative pathway by increasing the interaction between factor H and C3b. J Immunol 1984 133 : 882 5.
20. Giannakis E, Jokiranta TS, Male DA et al. A common site within factor H SCR 7 responsible for binding heparin, C-reactive protein and streptococcal M protein. Eur J Immunol 2003 33 : 962 9.
21. Rodriguez de Cordoba S, Esparza-Gordillo J, Goicoechea de Jorge E, Lopez-Trascasa M, Sanchez-Corral P. The human complement factor H: functional roles, genetic variations and disease associations. Mol Immunol 2004 41 : 355 67.
22. Morris KM, Aden DP, Knowles BB, Colten HR. Complement biosynthesis by the human hepatoma-derived cell line HepG2. J Clin Invest 1982 70 : 906 13.
23. Schwaeble W, Zwirner J, Schulz TF, Linke RP, Dierich MP, Weiss EH. Human complement factor H: expression of an additional truncated gene product of 43 kDa in human liver. Eur J Immunol 1987 17 : 1485 9.
24. Esparza-Gordillo J, Soria JM, Buil A et al. Genetic and environmental factors influencing the human factor H plasma levels. Immunogenetics 2004 56 : 77 82.
25. Chen M, Forrester JV, Xu H. Synthesis of complement factor H by retinal pigment epithelial cells is down-regulated by oxidized photoreceptor outer segments. Exp Eye Res 2007 84 : 635 45.
26. Friese MA, Hellwage J, Jokiranta TS et al. FHL-1/reconectin and factor H: two human complement regulators which are encoded by the same gene are differently expressed and regulated. Mol Immunol 1999 36 : 809 18.
27. Hageman GS, Anderson DH, Johnson LV et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA 2005 102 : 7227 32.
28. Estaller C, Schwaeble W, Dierich M, Weiss EH. Human complement factor H: two factor H proteins are derived from alternatively spliced transcripts. Eur J Immunol 1991 21 : 799 802.
29. Misasi R, Huemer HP, Schwaeble W, Sölder E, Larcher C, Dierich MP. Human complement factor H: an additional gene product of 43 kDa isolated from human plasma shows cofactor activity for the cleavage of the third component of complement. Eur J Immunol 1989 19 : 1765 8.
30. Zipfel PF, Skerka C. FHL-1/reconectin: a human complement and immune regulator with cell-adhesive function. Immunol Today 1999 20 : 135 40.
31. McRae JL, Cowan PJ, Power DA et al. Human factor H-related protein 5 (FHR-5). A new complement-associated protein. J Biol Chem 2001 276 : 6747 54.
32. Skerka C, Hellwage J, Weber W et al. The human factor H-related protein 4 (FHR-4). A novel short consensus repeat-containing protein is associated with human triglyceride-rich lipoproteins. J Biol Chem 1997 272 : 5627 34.
33. Zipfel PF, Jokiranta TS, Hellwage J, Koistinen V, Meri S. The factor H protein family. Immunopharmacology 1999 42 : 53 60.
34. Zipfel PF, Skerka C. Complement factor H and related proteins: an expanding family of complement-regulatory proteins? Immunol Today 1994 15 : 121 6.
35. Díaz-Guillén MA, Rodríguez de Córdoba S, Heine-Suñer D. A radiation hybrid map of complement factor H and factor H-related genes. Immunogenetics 1999 49 : 549 52.
36. McRae JL, Murphy BE, Eyre HJ, Sutherland GR, Crawford J, Cowan PJ. Location and structure of the human FHR-5 gene. Genetica 2002 114 : 157 61.
37. Perez-Caballero D, Gonzalez-Rubio C, Gallardo ME et al. Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome. Am J Hum Genet 2001 68 : 478 84.
38. Rodriguez de Cordoba S, Diaz-Guillen MA, Heine-Suñer D. An integrated map of the human regulator of complement activation (RCA) gene cluster on 1q32. Mol Immunol 1999 36 : 803 8.
39. Rodriguez de Cordoba S, Lublin DM, Rubinstein P, Atkinson JP. Human genes for three complement components that regulate the activation of C3 are tightly linked. J Exp Med 1985 161 : 1189 95.
40. Male DA, Ormsby RJ, Ranganathan S, Giannakis E, Gordon DL. Complement factor H: sequence analysis of 221 kb of human genomic DNA containing the entire fH, fHR-1 and fHR-3 genes. Mol Immunol 2000 37 : 41 52.
41. Hughes AE, Orr N, Esfandiary H, Diaz-Torres M, Goodship T, Chakravarthy U. A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat Genet 2006 38 : 1173 7.
42. Almasy L, Blangero J. Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 1998 62 : 1198 211.
43. Tortajada A, Hakobyan S, Goicoechea de Jorge E et al. Factor H allele-specific quantification in Tyr402His heterozygotes reveals the existence of low-expression alleles associated with atypical haemolytic uraemic syndrome. Mol Immunol 2007 44 : 3925.
44. Venables JP, Strain L, Routledge D et al. Atypical haemolytic uraemic syndrome associated with a hybrid complement gene. PLoS Med 2006 3 : e431.
45. Heinen S, Sanchez-Corral P, Jackson MS et al. De novo gene conversion in the RCA gene cluster (1q32) causes mutations in complement factor H associated with atypical hemolytic uremic syndrome. Hum Mutat 2006 27 : 292 3.
46. Zipfel PF, Edey M, Heinen S et al. Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome. PLoS Genet 2007 3 : e41.
47. Hageman GS, Hancox LS, Taiber AJ et al. Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications. Ann Med 2006 38 : 592 604.
48. Martínez-Barricarte B, Goicoechea de Jorge E, Recalde S et al. Complement factor H haplotypes and copy number variations of the factor H-related genes in renal and ocular disorders. Mol Immunol 2007 44 : 3919 20.
49. Dragon-Durey M-A, Fremeaux-Bacchi V, Loirat C et al. Heterozygous and homozygous factor H deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases. J Am Soc Nephrol 2004 15 : 787 95.
50. Levy M, Halbwachs-Mecarelli MC, Guber G et al. H deficiency in two brothers with atypical dense intramembraneous deposit disease. Kidney Int 1986 30 : 949 56.
51. Licht C, Heinen S, Jozsi M et al. Deletion of Lys224 in regulatory domain 4 of factor H reveals a novel pathomechanism for dense deposit disease (MPGN II). Kidney Int 2006 70 : 42 50.
52. López-Larrea C, Dieguez MA, Enguix A, Dominguez O, Marin B, Gomez E. A familial deficiency of complement factor H. Biochem Soc Trans 1987 15 : 648 9.
53. Caprioli J, Castelletti F, Bucchioni S et al. Complement factor H mutations and gene polymorphisms in haemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease. Hum Mol Genet 2003 12 : 3385 95.
54. Richards A, Buddles MR, Donne RL et al. Factor H mutations in hemolytic uremic syndrome cluster in exons 18-20, a domain important for host cell recognition. Am J Hum Genet 2001 68 : 485 90.
55. Warwicker P, Goodship THJ, Donne RL et al. Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney Int 1998 53 : 836 44.
56. Edwards AO, Ritter R, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science 2005 308 : 421 4.
57. Haines JL, Hauser MA, Schmidt S et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 2005 308 : 419 21.
58. Klein RJ, Zeiss C, Chew EY et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005 308 : 385 9.
59. Appel GB, Terence CH, Hageman G et al. Membranoproliferative glomerulonephritis type II (dense deposit disease): an update. J Am Soc Nephrol 2005 16 : 1392 403.
60. Ault BH, Schmidt BZ, Fowler NL et al. Human factor H deficiency. Mutations in framework cysteine residues and block in H protein secretion and intracellular catabolism. J Biol Chem 1997 272 : 25168 75.
61. Zipfel PF, Heinen S, Jozsi M, Skerka C. Complement and diseases: defective alternative pathway control results in kidney and eye diseases. Mol Immunol 2006 43 : 97 106.
62. Jokiranta TS, Solomon A, Pangburn MK, Zipfel PF, Meri S. Nephritogenic {lambda} light chain dimer: a unique human miniautoantibody against complement factor H. J Immunol 1999 163 : 4590 6.
63. Høgåsen K, Jansen JH, Mollnes TE, Hovdenes J, Harboe M. Hereditary porcine membranoproliferative glomerulonephritis type II is caused by factor H deficiency. J Clin Invest 1995 95 : 1054 61.
64. Pickering MC, Cook HT, Warren J et al. Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H. Nat Genet 2002 31 : 424 8.
65. Abrera-Abeleda MA, Nishimura C, Smith JLH et al. Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease). J Med Genet 2006 43 : 582 9.
66. Pickering MC, Goicoechea de Jorge E, Martinez-Barricarte R et al. Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains. J Exp Med 2007 204 : 1249 56.
67. Noris M, Remuzzi G. Hemolytic uremic syndrome. J Am Soc Nephrol 2005 16 : 1035 50.
68. Caprioli J, Bettinaglio P, Zipfel PF et al. The molecular basis of familial hemolytic uremic syndrome: mutation analysis of factor H gene reveals a hot spot in short consensus repeat 20. J Am Soc Nephrol 2001 12 : 297 307.
69. Manuelian T, Hellwage J, Meri S et al. Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome. J Clin Invest 2003 111 : 1181 90.
70. Esparza-Gordillo J, Goicoechea de Jorge E, Buil A et al. Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32. Hum Mol Genet 2005 14 : 703 12.
71. Fremeaux-Bacchi V, Kemp EJ, Goodship JA, et al. The development of atypical haemolytic-uraemic syndrome is influenced by susceptibility factors in factor H and membrane cofactor protein: evidence from two independent cohorts. J Med Genet 2005 42 : 852 6.
72. Noris M, Brioschi S, Caprioli J et al. Familial haemolytic uraemic syndrome and an MCP mutation. Lancet 2003 362 : 1542 7.
73. Richards A, Kemp EJ, Liszewski MK et al. Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. Proc Natl Acad Sci USA 2003 100 : 12966 71.
74. Fremeaux-Bacchi V, Dragon-Durey MA, Blouin J et al. Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome. J Med Genet 2004 41 : e84.
75. Kavanagh D, Kemp EJ, Mayland E et al. Mutations in complement factor I predispose to development of atypical hemolytic uremic syndrome. J Am Soc Nephrol 2005 16 : 2150 5.
76. Goicoechea de Jorge E, Harris CL, Esparza-Gordillo J et al. Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc Natl Acad Sci USA 2007 104 : 240 5.
77. Fremeaux-Bacchi V, Regnier C, Blouin J et al. Protective or aggressive: paradoxical role of C3 in atypical hemolytic uremic syndrome. Mol Immunol 2007 44 : 172.
78. Sánchez-Corral P, Pérez-Caballero D, Huarte O et al. Structural and functional characterization of factor H mutations associated with atypical hemolytic uremic syndrome. Am J Hum Genet 2002 71 : 1285 95.
79. Sanchez-Corral P, Gonzalez-Rubio C, Rodriguez de Cordoba S, Lopez-Trascasa M. Functional analysis in serum from atypical hemolytic uremic syndrome patients reveals impaired protection of host cells associated with mutations in factor H. Mol Immunol 2004 41 : 81 4.
80. Atkinson JP, Liszewski MK, Richards A, Kavanagh D, Moulton EA. Hemolytic uremic syndrome. An example of insufficient complement regulation on self-tissue. Ann NY Acad Sci 2005 1056 : 144 52.
81. Ohali M, Shalev H, Schlesinger M et al. Hypocomplementemic autosomal recessive hemolytic uremic syndrome with decreased factor H. Pediatr Nephrol 1998 12 : 619 24.
82. Pichette V, Querin S, Schurch W, Brun G, Lehner-Netsch G, Delage JM. Familial hemolytic-uremic syndrome and homozygous factor H deficiency. Am J Kidney Dis 1994 24 : 936 41.
83. Rougier N, Kazatchkine MD, Rougier JP et al. Human complement factor H deficiency associated with hemolytic uremic syndrome. J Am Soc Nephrol 1998 9 : 2318 26.
84. Thompson RA, Winterborn MH. Hypocomplementaemia due to a genetic deficiency of beta 1H globulin. Clin Exp Immunol 1981 46 : 110 19.
85. Schreiber RD, Pangburn MK, Lesavre PH, Müller-Eberhard HJ. Initiation of the alternative pathway of complement: recognition of activators by bound C3b and assembly of the entire pathway from six isolated proteins. Proc Natl Acad Sci USA 1978 75 : 3948 52.
86. Neumann HPH, Salzmann M, Bohnert-Iwan B et al. Haemolytic uraemic syndrome and mutations of the factor H gene: a registry-based study of German speaking countries. J Med Genet 2003 40 : 676 81.
87. Esparza-Gordillo J, Goicoechea de Jorge E, Abarrategui Garrido C et al. Insights into hemolytic uremic syndrome: segregation of three independent predisposition factors in a large, multiple affected pedigree. Mol Immunol 2006 43 : 1769 75.
88. Dragon-Durey M-A, Loirat C, Cloarec S et al. Anti-factor H autoantibodies associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol 2005 16 : 555 63.
89. Jozsi M, Strobel S, Dahse HM et al. Anti factor H autoantibodies block C-terminal recognition function of factor H in hemolytic uremic syndrome. Blood 2007 110 : 1516 18.
90. Dragon-Durey M-A, Loirat C, Ranchin B et al. Development of anti-factor H auto-antibodies genetically predisposed in atypical HUS. Mol Immunol 2007 44 : 3922.
91. Józsi M, Strobel S, Zipfel SLH et al. Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency and affect recognition functions. Mol Immunol 2007 44 : 3024.
92. Anderson DH, Mullins RF, Hageman GS, Johnson LV. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 2002 134 : 411 31.
93. Scholl HP, Fleckenstein M, Charbel Issa P, Keilhauer C, Holz FG, Weber BH. An update on the genetics of age-related macular degeneration. Mol Vis 2007 13 : 196 205.
94. Rivera A, Fisher SA, Fritsche LG et al. Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet 2005 14 : 3227 36.
95. Herbert AP, Deakin JA, Schmidt CQ et al. Structure shows glycosaminoglycan- and protein-recognition site in factor H is perturbed by age-related macular degeneration-linked SNP. J Biol Chem 2007 282 : 18960 8.
96. Clark SJ, Higman VA, Mulloy B et al. His-384 allotypic variant of factor H associated with age-related macular degeneration has different heparin binding properties from the non-disease-associated form. J Biol Chem 2006 281 : 24713 20.
97. Prosser BE, Johnson S, Roversi P et al. Structural basis for complement factor H linked age-related macular degeneration. J Exp Med 2007 204 : 2277 83.
98. Skerka C, Lauer N, Weinberger AAWA et al. Defective complement control of factor H (Y402H) and FHL-1 in age-related macular degeneration. Mol Immunol 2007 44 : 3398 406.
99. Laine M, Jarva H, Seitsonen S et al. Y402H polymorphism of complement factor H affects binding affinity to C-reactive protein. J Immunol 2007 178 : 3831 6.
100. Sjoberg AP, Trouw LA, Clark SJ et al. The factor H variant associated with age-related macular degeneration (His-384) and the non-disease-associated form bind differentially to C-reactive protein, fibromodulin, DNA, and necrotic cells. J Biol Chem 2007 282 : 10894 900.
101. Fernández-Alonso C, Goicoechea de Jorge E, Jiménez M, Rodriguez de Cordoba S, Germán R. Analytical ultracentrifugation analysis of the human complement factor H variants 402His and 402Tyr. Mol Immunol 2007 44 : 3982.
102. Hakobyan S, Harris CL, van den Berg C, Pepys MB, Morgan BP. Binding of factor H to C-reactive protein occurs only when the latter has undergone non-physiologic denaturation. Mol Immunol 2007 44 : 3983 4.
103. Li M, Atmaca-Sonmez P, Othman M et al. CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration. Nat Genet 2006 38 : 1049 54.
104. Maller J, George S, Purcell S et al. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet 2006 38 : 1055 9.
105. Gold B, Merriam JE, Zernant J et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet 2006 38 : 458 62.
106. Kuttner-Kondo L, Muqim N, Crabb JW, Hollyfield JG, Medof ME. Effects on factor H function of polymorphisms linked to age-related macular degeneration. Mol Immunol 2007 44 : 201.
107. Lokki ML, Koskimies SA. Allelic differences in hemolytic activity and protein concentration of BF molecules are found in association with particular HLA haplotypes. Immunogenetics 1991 34 : 242 6.
108. Mullins RF, Aptsiauri N, Hageman GS. Structure and composition of drusen associated with glomerulonephritis: implications for the role of complement activation in drusen biogenesis. Eye 2001 15 : 390 5.