Molecular Immunology 36 (1999) 863±867 www.elsevier.com/locate/molimm Review Properdin de®ciency: molecular basis and disease association C.A.P. Fijen a,*, R. van den Bogaard b, M. Schipper b, M. Mannens b, M. Schlesinger c, Fredrikson G. Nordin d, J. Dankert a, M.R. Daha e, A.G. SjoÈholm f, L. Truedsson f, E.J. Kuijper a a Department of Medical Microbiology, AMC/University of Amsterdam, Amsterdam, The Netherlands b Department of Clinical Genetics, AMC/University of Amsterdam, Amsterdam, The Netherlands c Department of Pediatrics, Barzilai Medical Center, Ashkelon, Israel d Department of Medicine, Section For Exp. Cardiovasc. Res., Wallenberg Lab., MalmoÈ University Hospital, MalmoÈ, Sweden e Department of Nephrology, University of Leiden, Leiden, The Netherlands f Department of Lab. Medicine, Section MIG, Lund University, Lund, Sweden Keywords: Properdin; Complement; Meningococci; Neisseria meningitidis; Alternative pathway 1. Introduction 2. The protein The ®rst description of the properdin system of complement activation by Pillemer et al. in 1954, based on his observations of complement activation by baker's yeast, was initially met with great interest (Pillemer et al., 1954), but then with scienti®c scepticism. Properdin was held as a contaminant. Only in the late 1960's it became clear that the initial observations by Pillemer were reproducible and represented an alternative pathway of complement activation, involving C3, Factor B, Factor D and properdin. These factors were puri®ed and identi®ed in the early 70's (GoÈtze and MuÈller-Eberhard, 1971). So the alternative pathway became established. In 1992 the sequence of the properdin gene became available (Nolan et al., 1992). The ®rst properdin de®cient family was found in Sweden in 1982, and properdin de®ciency was associated with fulminant meningococcal disease (SjoÈholm et al., 1982). In 1994 the ®rst description of the genetic basis of a properdin de®ciency was published (Nordin et al., 1994). Properdin is a basic glycoprotein of 442 amino acids with a carbohydrate content of 9.8% (Nolan et al., 1992). Serum concentration of the protein is about 25 mg/L. The protein is present as a mixture of cyclic oligomers, composed of asymmetric monomers (Pangburn,1989). The molecular mass of the unglycosylated monomer is 53,267 Da (Nolan, 1990). By head to tail interactions they form dimers, trimers and tetramers in plasma. The tetramer is, on a molar base, ten times more active than the dimer (Pangburn,1989). This is believed to result from increased anity due to the presence of multiple binding sites in the tetramer. The properdin molecule is composed of distinct Nand C- terminal regions ¯anking 6 tandemly repeated units related to the type I repeat sequence (TSR) ®rst identi®ed in thrombospondin (Goundis and Reid, 1988). TSR consist of about 60 amino acids. TSRs are thought to be involved in binding to molecular structures. Central in the activation of the alternative pathway of complement activation is the generation of the C3 convertase, C3bBb, by the interactions of the components C3b, Factor B and Factor D. Properdin ampli®es activation by binding to the C3 convertase and stabilizes this complex against intrinsic decay of Bb from the complex, prolonging the half-life from 1± * Corresponding author. Fax: +31-75-6502803. E-mail address: ®[email protected] (C.A.P. Fijen). 0161-5890/99/$ - see front matter # 1999 Elsevier Science Ltd. All rights reserved. PII: S 0 1 6 1 - 5 8 9 0 ( 9 9 ) 0 0 1 0 7 - 8 Swiss The Netherlands Sweden Israel (Tunesian) Israel (Moroccan) The Netherlands Sweden The Netherlands The Netherlands South America The Netherlands The Netherlands Israel (Tunesian) Sweden Denmark The Netherlands 1 1 1 5 1 1 1 3 1 1 3 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 3 4 4 5 5 5 6 6 7 7 8 8 8 8 4 8 9 Codon change Type Type Type Type Type Type Type Type Type Type Type Type Type Type Type Type De®ciencies of properdin are rather uncommon and so far 82 de®cient persons, all Caucasians, have been described (Figueroa and Densen, 1991; Fijen et al., 1996). On the basis of immunochemical and functional analyses, three dierent types of properdin de®ciency have been described (SjoÈholm, 1990). Type 1 is characterized by the total absence of the properdin antigen and function. This type is the most common. In the Position exon 4. The de®ciencies Table 1 Molecular genetic characterisation of properdin de®ciences from 24 families The properdin gene has been localized on the short arm of the X-chromosome in the Xp11.3-Xp11.23 band (Coleman et al., 1991). Two polymorphic dinucleotide repeat regions, interrupted by 83 bp, are present 16 kb downstream of the properdin gene and cosegregate with the gene (Fijen et al., 1996). The human properdin gene is composed of 10 exons spanning approximately 6.0 kb (Nolan et al., 1992). Exon 1 remains untranslated, exon 2 includes the translation start site and a sequence encoding 24 amino acids of leader peptide and exon 3 encodes the N-terminal region of the mature properdin protein. TSRs 1±5 are encoded by exons 4±8, one TSR per exon. The ®rst 38 amino acids of TSR6 are encoded by exon 9 while the remaining part of TSR6 and the C-terminal region of properdin are contained in exon 10. A region of 25 amino acids containing the glycosylation site is inserted in TSR6 (Higgins et al., 1995, Nolan et al., 1992). Number of families 3. The gene Arg 52 Stop Arg 52 Stop Arg 134 Stop Gln 160 Stop Gln 160 Stop Ser 179 Stop 197 Del Cys+frameshift, Stop 235 Del Gly Pro+frameshift Gly 271 Val Trp 294 Gly Trp 294 Gly Trp 294 Ser Arg 319 Cyst Arg 73 Trp Gln 316 Arg Tyr 387 Asp Origin Reference 2 to 18 min (Fearon and Austen, 1975). The C3bBbP complex is also more resistant than C3bBb to the inactivation events mediated by the regulatory components factor H and I. Studies with mutant forms of properdin, lacking a single TSR showed that the C3b binding site resides in TSR5 (Higgins et al., 1995). It is reported that during complement activation C3b may also become covalently bound to properdin (Whiteman et al., 1995). TSR4 has a function in the stabilization of the C3bBb complex but is not a binding site for C3b. Properdin lacking TSR6 is unable to form oligomers (Higgins et al., 1995). Blood monocytes, neutrophil granulocytes, T-cells, hepatocytes (human Hep-G2 cell line) and astrocytes may contribute to properdin synthesis in vivo. Properdin synthesis does not rise in the acute phase response. At which stage properdin polymerizes into functional oligomers still needs to be clari®ed, but monomers of properdin are present intracellularly before secretion. Spath et al. (1999) Fijen et al. (1996), van den Bogaard et al. (1999) . Sjoholm et al. (1982), Westberg et al. (1995) Manuscript in preparation Manuscript in preparation Fijen et al. (1996), Bogaard et al. (1999) Truedsson et al. (1997) Fijen et al. (1996), Bogaard et al. (1999) Fijen et al. (1996), Bogaard et al. (1999) Truedsson et al. (1997) Fijen et al. (1996), Bogaard et al. (1999) Fijen et al. (1996), Bogaard et al. (1999) Manuscript in preparation SjoÈholm (1988a), Westberg et al. (1995) Nordin et al. (1998) SjoÈholm et al. (1998b), Nordin et al. (1996) C.A.P. Fijen et al. / Molecular Immunology 36 (1999) 863±867 De®ciency phenotype 864 C.A.P. Fijen et al. / Molecular Immunology 36 (1999) 863±867 865 Fig. 1. Alignment of thrombospondin type 1 repeats from the human properdin-derived protein sequences with indication of amino acid changes causing properdin de®ciency. type 2 de®ciency state, properdin antigen serum levels are 1±10% of the normal level, and the properdin appeared to be functionally active in one family (SjoÈholm et al., 1988a). Type 2 de®ciency has been recognized in Denmark and Sweden (SjoÈholm, 1990). The properdin antigen serum levels are normal, but functionally defective in type 3 de®ciency. So far it has only been detected in one large Dutch family (SjoÈholm et al.,1988b). Molecular genetic characterisation of properdin de®ciencies from 24 families is presented in Table 1. Properdin type I de®ciency shows a remarkable allelic heterogeneity. In the Netherlands many dierent alleles causing de®ciency were found, whereas in Israel a distinct regional founders eect has been observed. Point mutations giving rise to a stop codon were found in exons 4, 5 and 6. In individuals of one of these families studied no properdin was detected intracellularly in monocytes but the transcription to mRNa was not impaired (Westberg et al., 1995). A truncated molecule is supposed to be formed and to be rapidly degraded, intracellularly. Most probably, the fate of properdin is similar in families with type 1 de®ciency due to non-synonymous mutations or deletions resulting in frameshifts. In Fig. 1 it is indicated that the non-synonymous mutations of the type 1 de®cient families occurred all in amino acids highly conserved between the various TSRs from humans and mice (Higgins et al., 1995), suggesting that they are essential for the protein structure. Type 2 properdin de®ciency occurred in two families with distinct mutations resulting in substitution of not conserved or not-completely conserved amino acids (Fig. 1). Remarkably, the mutation changing arginine to tryptophan at amino acid 73 in TSR1 resulted in type 2 de®ciency, but a change on an equivalent place in TSR5 at amino acid 319 from arginine to cysteine resulted in type 1 de®ciency. A study of monocytes from one of the de®cient persons showed that properdin is synthesized and secreted in normal amounts, but that the oligomerization to tri- and tetramers is impaired (Nordin et al., 1998). The low serum levels of properdin are probably due to increased catabolism of the abnormal properdin molecules. In the properdin type 3 de®cient family a point mutation in exon 9 gives rise to replacement of tyrosine by aspartic acid. This amino acid substitution did not aect oligomerization, synthesis or secretion, and neither could one demonstrate a direct eect of the amino acid substitution on the C3b binding of a decapeptide based on the modi®ed properdin sequence (Nordin et al., 1996). However, the dysfunctional properdin did not bind C3b in a ELISA system. So it was concluded that the dysfunction was due to defective C3b binding, which was most likely caused by conformational changes. The dierence in frequency of properdin de®ciency between various countries, and the restriction of the founder eect within national borders may suggest that the gene mutations causing the de®ciencies are rather recent. However, these ®ndings may also be explained by an incomplete ascertainment of properdin de®ciencies. 5. The inheritance pattern From the ®rst described properdin de®cient family it 866 C.A.P. Fijen et al. / Molecular Immunology 36 (1999) 863±867 became clear that the de®ciency was inherited in an Xlinked pattern (SjoÈholm et al., 1982). This inheritance pattern applies to all 3 kinds of de®ciency and is explained by the properdin gene localisation on the short arm of the X-chromosome. The mean level of properdin in female carriers was half the level in the normal population, with a range from nearly total de®ciency to a normal level (Fijen et al., 1996). A study among 28 obligate female carriers revealed normal serum levels of properdin in 2 (7%) of them, emphasizing the application of molecular biological tools to ®nd all female carriers (Bogaard et al., 1999; Fijen et al., 1996; SpaÈth et al., 1999). Both study of the proportion of monocytes producing properdin and of the percentage of the aected chromosomes inactivated indicate an uneven inactivation of the X-chromosome among the female carriers, in accordance with the Lyon hypothesis (van den Bogaard et al., 1999; Nordin et al., 1996). 6. Clinical disease associated with the de®ciencies The ®rst type 1 properdin de®ciency was identi®ed in a family with four cases of fulminant lethal meningococcal disease (SjoÈholm et al., 1982). Subsequently, more families were detected with properdin de®ciency by studying patients with familial meningococcal disease, severe meningococcal disease, meningococcal disease over the age of 10 years or meningococcal disease by uncommon meningococcal serogroups W135, X, Y, Z or non-groupable meningococci (Fijen et al., 1999a; Nielsen et al., 1989; Schlesinger et al., 1993). These strategies were successful but induced a bias in the concept of properdin de®ciency associated disease. A study among relatives of the properdin type 1 de®cient patients revealed that 18% of the de®cient relatives developed meningococcal disease (Fijen et al., 1999a) and suggested that only meningococcal disease is signi®cantly associated with the de®ciency. The risk for contracting meningococcal disease in properdin type 1 de®cient persons was 250 times higher than that in the general population (Fijen et al., 1999a). Two properdin type 1 de®cient persons with recurrent meningococcal disease have been reported, either representing an ascertainment bias or indicating a higher risk for recurrent disease in the properdin de®cient patients than in the general population (Cunlie et al., 1995, Nielsen et al., 1990). Remarkable among the reported properdin de®cient patients is the high age at the time of infection (mean 14 years) and the frequent occurrence of uncommon serogroups (Figueroa and Densen, 1991; Fijen et al., 1999a; Nielsen et al., 1989; Schlesinger et al., 1993; SjoÈholm, 1990). Although most disease histories are less fulminant than in the ®rst described family (Schlesinger et al., 1993; SjoÈholm et al., 1982), the development of sepsis and the lethality seem higher in the properdin de®cient patients than in non-de®cient patients (Fijen et al., 1999a). The meningococcal disease among properdin type 2 and type 3 de®cient persons has similar characteristics (SjoÈholm, 1990). The association of properdin de®ciency with meningococcal disease at ages at which normally protective antibodies have been developed is not yet understood. In the presence of an intact classical pathway the association may be explained by the strong need for ampli®cation at the C3 level of the classical pathway induced complement activation by the alternative pathway. 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