The JI
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     
 

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dragon-Durey, M.-A.
Right arrow Articles by Fridman, W.-H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dragon-Durey, M.-A.
Right arrow Articles by Fridman, W.-H.
The Journal of Immunology, 2001, 166: 7612-7616.
Copyright © 2001 by The American Association of Immunologists

Molecular Basis of a Selective C1s Deficiency Associated with Early Onset Multiple Autoimmune Diseases1

Marie-Agnès Dragon-Durey2,3,*,{dagger}, Pierre Quartier2,{ddagger}, Véronique Frémeaux-Bacchi*,{dagger}, Jacques Blouin*, Claire de Barace§, Anne-Marie Prieur{ddagger}, Laurence Weiss*,{dagger} and Wolf-Herman Fridman*,¶

* Service d’Immunologie Biologique, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; {dagger} Institut National de la Santé et de la Recherche Médicale, Unité 430, Immunopathologie Humaine, Hôpital Broussais, Paris, France; {ddagger} Unité d’Immuno-Hématologie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France; § Service de Pédiatrie, Hôpital de Saint Brieuc, Saint Brieuc, France; and Institut National de la Santé et de la Recherche Médicale, Unité 255, Université Pierre et Marie Curie, les Cordeliers, Paris, France


   Abstract
Top
 Abstract
Introduction
 Patient and Methods
 Results
 Discussion
 References
 
We have investigated the molecular basis of selective and complete C1s deficiency in 2-year-old girl with complex autoimmune diseases including lupus-like syndrome, Hashimoto’s thyroiditis, and autoimmune hepatitis. This patient’s complement profile was characterized by the absence of CH50 activity, C1 functional activity <10%, and undetectable levels of C1s Ag associated with normal levels of C1r and C1q Ags. Exon-specific amplification of genomic DNA by PCR followed by direct sequence analysis revealed a homozygous nonsense mutation in the C1s gene exon XII at codon 534, caused by a nucleotide substitution from C (CGA for arginine) to T (TGA for stop codon). Both parents were heterozygous for this mutation. We used the new restriction site for endonuclease Fok-1 created by the mutation to detect this mutation in the genomic DNA of seven healthy family members. Four additional heterozygotes for the mutation were identified in two generations. Our data characterize for the first time the genetic defect of a selective and complete C1s deficiency in a Caucasian patient.


   Introduction
Top
 Abstract
 Introduction
Patient and Methods
 Results
 Discussion
 References
 
The C1 complex of human complement is composed of C1q, C1r, and C1s subcomponents, which are essential to initiate the classical pathway of complement activation. Activation of early acting components of the classical pathway plays an important role in the prevention of the formation and precipitation of large immune complexes, as illustrated by the high incidence of immune complex diseases in patients with homozygous deficiency of early acting classical pathway components. Hereditary deficiency of classical component C2 is the most common deficiency of the complement system in Caucasians, whereas C4 or C1q deficiencies are rare. Only two cases of selective C1s deficiency have been reported to date, both in Japanese patients (1, 2, 3). Human C1s, a 85-kDa glycoprotein, has protease activity and is able to activate the C4 and C2 components of the classical pathway. The C1s gene contains 12 exons and is located on the short arm of chromosome 12 within the C1r gene (4, 5, 6, 7). Exon XII encodes the C-terminal B chain domain, which contains the active site residues characteristic of serine proteases (8).

In the present study, we report for the first time a case of complete and selective C1s deficiency in a Caucasian family. The propositus was a 2-year-old girl with multiple autoimmune features. Selective homozygous C1s deficiency was demonstrated and analyzed genetically.


   Patient and Methods
Top
 Abstract
 Introduction
 Patient and Methods
Results
 Discussion
 References
 
Case report

A 27-month-old girl was hospitalized with a history of intermittent limping, edema of the feet and face, recurrent malar rash, and mild fever. She was the first child of healthy parents. At the age of 12 mo, she had an episode of bilateral malar rash after sun exposure. She had no evidence of increased susceptibility to infectious diseases. The patient’s main characteristics on admission are described in Table IGo. On examination, the girl was slightly hoarse and had mild swelling of the knees, ankles, and proximal interphalangeal joints of both hands, associated with aphthous ulcers, digital pulp vasculitis, and telangiectasias. Routine laboratory tests showed normal renal function and normal erythrocyte, leukocyte, and platelet counts but elevated erythrocyte sedimentation rate and liver enzymes. Thyroid abnormalities were also detected, including an increased level of thyroid-stimulating hormone and decreased level of T4, associated with the presence of a high antithyroid peroxidase Ab titer. A fluorescent antinuclear Ab was found with a speckled pattern associated with anti-Ro/SSA and anti-LA/SSB Abs. No anti-DNA Ab was found at this time.


View this table:
[in this window]
[in a new window]
  		Table I. Patient characteristics on admission

 
The HLA haplotypes were A1-28, B8-14, C7-8, and DR 3-13. Phenotypic characterization of circulating lymphocytes was performed by flow cytometry and showed no abnormality (Table IGo). T cell functions assessed by in vitro mitogen- (phytohemagglutinin) and recall Ag (Candida, tetanus toxoid, tuberculin)-induced T cell proliferation assays were also normal.

Capillaroscopy showed lupus-like abnormalities. Liver biopsy showed slight lobular hepatitis with mononuclear infiltrates sometimes surrounding a necrotic hepatocyte.

The patient was treated with prednisone (1 mg/kg/day) in combination with L-thyroxin (3 µg/kg/day). Treatment resulted in a marked clinical improvement, although digital pulp vasculitis persisted. Liver enzymes returned to normal values. After an episode of Streptococcus pneumoniae pneumonia responding to i.v. third-generation cephalosporin, it was decided to administer prophylactic penicillin V therapy. After 22 mo, once the dose of prednisone had been gradually tapered to 0.3 mg/kg/day, the patient presented with cytolytic and cholestatic hepatitis associated with hypergammaglobulinemia of 33 g/L and, for the first time, positive anti-double-strand DNA Abs as assessed by Farr radioimmunoassay. A second liver biopsy was performed showing chronic hepatitis lesions with mild to moderate periportal lymphocytic infiltrates associated with early stage portal fibrosis. Azathioprine was introduced at the dose of 2 mg/kg/day. Prednisone dose was increased to 2 mg/kg/day and then progressively tapered. At the most recent follow-up, 3 years and 3 mo after admission, the child was alive and well while still receiving azathioprine (2 mg/kg/day), prednisone (0.6 mg/kg/day), and penicillin V.

Complement assays

Freshly drawn EDTA plasma was obtained from the propositus and her parents. Measurement of CH50 activity and hemolytic assays for C1, C4, and C2 were performed as previously described (9). Results of hemolytic assays were expressed as the percentage of mean values obtained with a reference plasma prepared from 100 healthy blood donors (normal range, 100 ± 30%). Plasma concentrations of C3 and C4 Ags were determined by nephelometry (Beckman, Gagny, France). Normal concentrations ranged between 0.85 ± 0.20 and 0.24 ± 0.12 g/L for C3 and C4, respectively. Plasma C1q and C1s concentrations were determined by ELISA, as previously described (10, 11). C1r levels were determined by single radial immunodiffusion (The Binding Site, Birmingham, U.K.).

Western blot analysis of C1s

From 1 to 4 µl plasma and 0.1 µg purified C1s protein (Sigma-Aldrich, Steinheim, Germany) were loaded on a polyacrylamide gel (5.0 to 12.5% acrylamide) with a 3% stacking gel, under reducing and nonreducing conditions. Proteins were transferred onto nitrocellulose membranes at 190 mA using a Miniprotean II system (Bio-Rad Laboratories, Hercules, CA). Membranes were saturated for 1 h at 20°C with 10% fat-free dry milk in PBS and then incubated overnight at 4°C with polyclonal anti-C1s Ab (Quidel, San Diego, CA) diluted (1:200) in the same buffer. After extensive washing (PBS, 0.1% Tween 20), membranes were further incubated with rabbit anti-goat Ig Ab conjugated to alkaline phosphatase diluted (1:500) in PBS with 10% fat-free milk for 1 h at 20°C. After additional washing, the second Ab was revealed using the 5-bromo-4-chloro-3-indolyl phosphate-nitroblue tetrazolium liquid substrate system (Sigma-Aldrich, Saint Quentin Fallavier, France).

Genomic C1s DNA sequencing

DNA was extracted from whole blood cells by the proteinase K-phenol method (12). Uncloned genomic DNA was amplified by PCR using oligonucleotides flanking the serine protease domain of C1s (exon XII), described in Ref. 5 . Direct DNA sequencing of the purified PCR product (QiaQuick PCR Purification Kit; Qiagen, Courtaboeuf, France) was then conducted by the dye terminator cycle sequencing method (Applied Biosystems, Courtaboeuf, France). To confirm this sequence, a second PCR was performed with the 5'-TGTATGTTGGGTCCACCTCAGT-3' and 5'-CTGGTAGGCAGATGGGAGAGAC-3' primers to amplify a 196-bp genomic DNA region. PCR was performed in a 50-µl volume containing 1x buffer, 2.5 mM concentrations of each dNTP, 10 pM forward and reverse primers, genomic DNA (250 ng), and Taq polymerase (2.5 U) (Super Taq, ATCG Biotechnologie, Noisy-le-Grand, France). The thermocycling protocol was denaturation at 94°C (5 min), 1 cycle, followed by 30 cycles of denaturation at 94°C (30 s), annealing at 64°C (30 s), and hybridization at 72°C (45 s) with a third step consisting of 7 min at 72°C. Direct sequencing was then conducted.

Specific PCR amplification and restriction analysis

In addition to sequence analysis, exon XII was also investigated by restriction analysis. Genomic DNA was amplified using oligonucleotides that flank the serine protease domain of the C1s gene (exon XII) (5). PCR products (35 µl) were digested by 1 U of the restriction endonuclease Fok-1 (New England Biolabs, Hitchin, U.K.) for 1 h at 37°C. Digested products were then subjected to electrophoresis on 5% (w/v) agarose gel.

mRNA analysis

Total mRNA was extracted from total blood cells using the QIAamp RNA Blood miniKit (Qiagen) according to the manufacturer’s procedure. After reverse transcription (First Strand cDNA Synthesis kit for RT-PCR; Boehringer Mannheim, Indianapolis, IN), a C1s cDNA fragment was amplified using the 5'-CCTTGACAGTTTAGTTTTTGT-3' and 5'-TACTCCCCACCTCCTATTT-3' primer localized at nucleotides 924 and 1424 of the C1s cDNA sequence, respectively. Control cDNA amplification was performed using {beta}-actin primers (5'-TTCTGCAGGGAGGAGCTGGAAGCA-3', 5'-TCGTCGACAACGGCTCCGGCATGT-3').

Microsatellite polymorphism genotyping

Two microsatellite polymorphisms flanking the C1s gene were analyzed. D12S1695 upper flanked the gene (accession number z1369) at 0.25 cM in males and 0.75 cM in females and was amplified using the 5'-CAAAGTGCTGGAAGTACAGAT-3' upper primer labeled with 6-FAM (MWG Biotech, Courtaboeuf, France) and the 5'-ATTGGTAGAGCTGGATATTGA-3' lower primer. D12S77(or STS AFM026tb5 from the Généthon 1994 genetic map), lower flanked the gene at 0.23 cM in males and 0.99 cM in females and was amplified using the 5'-GAAGGGCAACAACAGTGA-3' (6-FAM labeled) (MWG BIOTECH) and 5'-CTTTTTTTTCTCCCCCACTC-3' primers. Three hundred nanograms of genomic templates were amplified in total volumes of 50 µl containing 1x buffer, 200 µM concentrtions of each dNTP, 0.2 µM forward and reverse primers, and Taq polymerase (1.25 U; AmpliTaq Gold, Applied Biosystems). The thermocycling protocol was denaturation at 96°C (10 min), 1 cycle, followed by 30 cycles of denaturation at 94°C (45 s), annealing at 60°C (45 s), and hybridization at 72°C (60 s), with a third step consisting of 30 min at 72°C.

Amplified DNA was mixed with the GENESCAN 350 ROX Size Standard (Applied Biosystems) in formamide (Applied Biosystems), loaded on a 3700 ABI Prism DNA 96-capillary analyzer (Applied Biosystems), and analyzed using GENESCAN 3.5 software.


   Results
Top
 Abstract
 Introduction
 Patient and Methods
 Results
Discussion
 References
 
Western blot assays of complement components and C1s

The patient’s complement profile was characterized by the absence of CH50 activity, C1 functional activity <10%, undetectable level of C1s Ag, and normal immunochemical levels of C1r and C1q associated with normal levels of C4, C2, and C3 (Table IIGo).


View this table:
[in this window]
[in a new window]
  		Table II. Results of measurements of complement components in the propositus and her parents

 
The results of determinations of classical and alternative pathway proteins excluded the possibility that complement deficiency was secondary to complement consumption. Functional and immunochemical levels of the complement components in the patient’s plasma remained stable for 3 years of follow-up. The addition of normal plasma or purified C1s to the patient’s plasma restored its ability to sustain classical pathway activation (data not shown). No protein was seen on Western blot using a polyclonal anti-C1s Ab regardless of the technical conditions (SDS-PAGE from 5.0 to 12.5% of polyacrylamide under reducing and nonreducing conditions; Fig. 1Go).



View larger version (23K):
[in this window]
[in a new window]
  		FIGURE 1. Anti-C1s Western blot analysis of plasma from the propositus and her parents compared with a normal human plasma and with purified C1s protein.

 
The patient’s parents presented normal CH50 activity, but decreased immunochemical levels of C1s (Table IGo). C1s Western blot analysis showed normal weight C1s proteins in their plasma, and no additional band was revealed (Fig. 1Go).

Characterization of the genetic defect

The last exon of C1s gene encoding the serine-protease active center was analyzed first. The entire exon XII of the propositus was amplified and directly sequenced using forward and reverse primers. We detected a homozygous nonsense mutation at codon 534 of a cDNA sequence caused by a nucleotide substitution from C (CGA for arginine) to T (TGA for stop codon). No other abnormality was detected. This mutation was then confirmed by a second sequence analysis of a 196 bp region containing the mutation. Sequence analysis was then performed on the mother’s and father’s genomic DNA, showing that both parents were heterozygous (C/T) for the same mutation at codon 534 (Fig. 2Go).



View larger version (36K):
[in this window]
[in a new window]
  		FIGURE 2. Detection of the C1s mutation in genomic DNA. C1s genomic sequences: A, wild-type allele; B, the patient with the reduced amino acid sequence; C, the father; D, the mother. The patient’s genotype was homozygous for the nonsense mutation (C to T), and her parents were heterozygous.

 
The new restriction site created by the mutation for the Fok-1 enzyme (GGATG) (Fig. 3Go) was used to detect this mutation in the genomic DNA of all family members. The amplified DNA region containing exon XII of the C1s gene was digested by endonuclease Fok-1. In wild-type allele, the amplified DNA was cut into three bands at 396, 256, and 142 bp. In the presence of the mutation, a new digestion site was created, and the 142-bp fragment was digested into two new 116- and 26-bp fragments. Three bands of 396, 256, and 116 bp were therefore demonstrated (the 26-bp band could not be revealed under the electrophoresis conditions) when the mutation was homozygous, and four bands (396, 256, 142, and 116 bp) were demonstrated when the mutation was heterozygous. Seven family members were investigated. These experiments also confirmed that the patient was homozygous, whereas her parents were heterozygous for the mutation. The paternal grandmother and maternal grandfather were heterozygous. Paternal and maternal aunts also exhibited the heterozygous mutation. The paternal uncle presented with homozygous wild-type allele (Fig. 4Go).



View larger version (19K):
[in this window]
[in a new window]
  		FIGURE 3. Nucleotide sequence of C1s serine-protease domain (exon XII). Plain arrows indicate the primers used to amplify the totality of the domain, and dashed arrows indicate the primers used to amplify the 196-bp region containing the mutation (CGA to TGA, arrowhead). The nucleotide number according to the mRNA C1s sequence (accession number M18767) is indicated in italics. Restriction sites for endonuclease Fok-1 are shown (F).

 


View larger version (42K):
[in this window]
[in a new window]
  		FIGURE 4. Detection of the mutation by specific amplification and digestion by endonuclease Fok-1 in each member of the family. In the presence of the mutation, a new site of digestion was created, and the 142-bp fragment was digested into two new fragments of 116 and 26 bp. The 26-bp fragment cannot be revealed.

 
Using this technique, the mutation was investigated in a large DNA bank (200 chromosomes), including DNA from patients with systemic lupus erythematosus (SLE4 73%) and unrelated Caucasian controls, including some subjects native to the same geographic region as the family studied (11% of the total population tested). No mutation was found.

To further investigate probable consanguinity, we performed a study using microsatellite analysis (upper flank: D12S1695, 0.25 cM in males and 0.75 cM in females; and lower flank: D12S77 0.23 cM in males and 0.99 cM in females). The propositus was homozygous for these microsatellites, indicating that the mutation was transmitted with a common haplotype (data not shown).

In addition, to determine whether the mutant allele was translated, we performed mRNA extraction from total blood cells followed by reverse transcription and specific C1s PCR. A small amount of C1s cDNA fragment was detected under these conditions, compared with a control cDNA extract (Fig. 5Go).



View larger version (101K):
[in this window]
[in a new window]
  		FIGURE 5. RT-PCR of C1s and {beta}-actin cDNA in a total mRNA blood cell extract from the propositus (lane a), from an unrelated control (lane b), and in a total mRNA extract of cultured fibroblasts (lane c).

 

   Discussion
Top
 Abstract
 Introduction
 Patient and Methods
 Results
 Discussion
References
 
For the first time, selective and complete C1s deficiency has been demonstrated and genetically analyzed in a Caucasian patient. We used exon-specific PCR followed by direct sequencing of the target exon. We identified a homozygous C to T transversion of the first nucleotide of codon 534 of the C1s cDNA sequence in the genomic DNA of the proband, leading to a stop codon (TGA) instead of an arginine (CGA). The abnormal gene encodes a truncated C1s protein that lacks the 154 C-terminal amino acids including the Ser631 active site (4). We used the new restriction site for endonuclease Fok-1 created by the mutation to confirm this result and to easily detect the mutation in the genomic DNA of the family, and we demonstrated that this mutation was inherited. We detected the same heterozygous C/T mutation in both the father’s and the mother’s genomic DNA. This mutation was also transmitted from the paternal grandmother and the maternal grandfather. Thus, in 10 family members, we detected 1 homozygote for the mutation, the proband, 6 heterozygotes, and 3 homozygotes for the wild-type allele. Results obtained in the parents showed that plasma C1s levels but not CH50 levels were correlated with the genotype. Because all of the heterozygous family members were healthy, the present study suggests an autosomal recessive mode of inheritance of the disease. No evidence of consanguinity was found in this family, but distant ancestors came from the same area, and a genealogical study revealed probable common ancestors six generations ago. Microsatellite polymorphism analysis confirmed the presence of a founder effect.

Selective C1s deficiency has been previously reported in only two patients, both from Japan (2, 3). Two other different molecular defects were detected in these cases. The first defect was a 4-bp deletion (TTTG) in exon X of the C1s gene. This deletion was homozygous in the first patient and heterozygous in the second, in whom it was associated with a nonsense mutation in exon XII (G to T). The present study therefore describes the second nonsense mutation in exon XII of the C1s gene. In both previously reported cases and in our case, no truncated protein could be detected in the patient’s serum by Western blot analysis. A small amount of C1s mRNA was detected in a total blood cell extract from the patient, suggesting that the truncated RNA and/or the short C1s protein was possibly unstable.

C1s protein belongs to the complement C1 complex. The C1 complex consists of one molecule of C1q and two molecules each of C1s and C1r and constitutes the first step of the classical pathway of complement activation. After recognition and binding of immune complexes by C1q in the presence of calcium, C1r is autoactivated and proteolytically activates C1s (13). C1s in turn proteolytically activates C4 and C2 in the complement cascade reactions. Homozygous deficiencies of the early proteins of the classical complement pathway have been suggested to be associated with an increased risk for autoimmune diseases because of their role in inhibiting immune complex precipitation (14) and the development of a normal humoral response (15). In the complete absence of C1s protein, the classical pathway cannot be activated. Moreover, a specific role for C1q in the clearance of apoptotic cells has been emphasized (16), and studies in C1q knockout mice have indicated that C1q deficiency may lead to SLE-like disease in animals with a certain genetic background (17). Whereas C1q deficiency has been described to be strongly associated with SLE in humans (17), little was known about C1s deficiency because of its extreme rarity. The first detailed report of selective C1s deficiency was a man who developed a lupus-like syndrome at the age of 26 (1, 2). Virus-associated hemophagocytic syndrome was reported in another patient who died at the age of 7 years (3). Combined and partial C1s and C1r deficiency has also been reported in several patients including four siblings, two of whom developed discoid lupus and rheumatoid arthritis (18), and a 60-year-old woman with SLE (19). The genetic defect of combined C1r/C1s deficiency has not yet been elucidated but might be related to the close location of the two genes on chromosome 12 (12p13) (7). A few cases of selective C1r deficiency have also been reported, associated with lupus-like syndrome (20, 21) or susceptibility to infection (22, 23).

In the present case, selective C1s deficiency was associated with autoimmune diseases including SLE-like syndrome, Hashimoto’s thyroiditis, and autoimmune hepatitis starting in early childhood. The case described here is particularly severe compared with the two previously reported cases, and other susceptibility factors for autoimmune disease might have contributed to these clinical features. The association of certain HLA alleles with SLE has been described, such as HLA allele DRB1*03, present in this case (24). Moreover, because SLE is a multigenic disease, other genes predisposing to autoimmunity could also be involved.

Finally, as in C1q deficiency, this report of complete and selective C1s deficiency emphasizes the role of activation of the early components of the complement system in preventing autoimmune diseases.


   Acknowledgments
 
We thank Dr. Mickael Loos and Dr. Frantz Petri for their technical assistance in the determination of C1s and C1q Ag levels; Françoise Le Deist for phenotypic characterization of circulating lymphocytes and in vitro T cell proliferation assays; and Jean-Laurent Casanova, Mario Tosi, and Christiane Duponchel for helpful discussion.


   Footnotes
 
1 This work was supported in part by the Institut National de la Santé et de la Recherche Médicale. Back

2 M.-A.D.-D. and P.Q. contributed equally to this study. Back

3 Address correspondence and reprint requests to Dr. Marie-Agnès Dragon-Durey, Service d’Immunologie Biologique, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75 015 Paris, France. E-mail address: marie-agnes.durey{at}brs.ap-hop-paris.fr Back

4 Abbreviation used in this paper: SLE, systemic lupus erythematosus. Back

Received for publication May 23, 2000. Accepted for publication April 11, 2001.


   References
Top
 Abstract
 Introduction
 Patient and Methods
 Results
 Discussion
 References
 

  1. Endo, Y., K. Kanno, M. Takahashi, K. Yamaguchi, Y. Kohno, T. Fujita. 1999. Molecular basis of human complement C1s deficiency. J. Immunol. 162:2180.[Abstract/Free Full Text]
  2. Suzuki, Y., Y. Ogura, O. Otsubo, K. Akagi, T. Fujita. 1992. Selective deficiency of C1s associated with a systemic lupus erythematosus-like syndrome. Arthritis Rheum. 35:576.[Medline]
  3. Inoue, N., T. Saito, R. Masuda, Y. Suzuki, M. Ohtomi, H. Sakiyama. 1998. Selective complement C1s deficiency caused by homozygous four-base deletion in the C1s gene. Hum Genet. 103:415.[Medline]
  4. Tosi, M., C. Duponchel, T. Meo, C. Julier. 1987. Complete cDNA sequence of human complement C1s and close physical linkage of the homologous genes C1s and C1r. Biochemistry 26:8516.[Medline]
  5. Tosi, M., C. Duponchel, T. Meo, E. Couture-Tosi. 1989. Complement genes C1r and C1r feature an intronless serine protease domain closely related to haptoglobulin. J. Mol. Biol. 208:709.[Medline]
  6. Nguyen, V., M. Tosi, M. Gross, O. Cohen-Haguenauer, C. Jegou-Foubert, M. de Tand, T. Meo, J. Frezal. 1988. Assignment of the complement serine protease genes C1r and C1s to chromosome 12p13. Hum. Genet. 78:363.[Medline]
  7. Kusumoto, H., S. Hirosawa, J. Salier, F. Hagen, K. Kurachi. 1988. Human genes for complement components C1r and C1s in a close tail-to-tail arrangement. Proc. Natl. Acad. Sci. USA 85:7307.[Abstract/Free Full Text]
  8. Endo, Y., M. Takahashi, M. Nakao, H. Saiga, M. Matsushita, M. Nonaka, T. Fujita. 1998. Two lineages of mannose binding lectin-associated serine protease (MASP) in vertebrate. J. Immunol. 161:4924.[Abstract/Free Full Text]
  9. Kazatchkine, M., G. Haupmann, U. Nydegger. 1985. Techniques du Complement Institut National de la Santé et de la Recherche Médicale, Paris.
  10. Antes, U., H. Heinz, M. Loos. 1984. Enzyme-linked immunosorbent assay for C1q in human serum by use of monoclonal antibodies. J. Immunol. Methods 74:299.[Medline]
  11. Storm, D., M. Loos, M. Kaul. 1996. Biotinylation of proteins via amino groups can induce binding to U937 cells, HL-60 cells, monocytes and granulocytes. J. Immunol. Methods 199:87.[Medline]
  12. Jeanpierre, M.. 1987. A rapid method for the purification of DNA from blood. Nucleic Acids Res. 15:9611.[Free Full Text]
  13. Arlaud, G., M. Colomb, J. Gagnon. 1987. A functional model of the human C1 complex. Immunol. Today 8:106.
  14. Walport, M., K. Davies. 1996. Complement and immune complexes. Res. Immunol. 2:103.
  15. Caroll, M., M. Fischer. 1997. Complement and the immune response. Curr. Opin. Immunol. 9:64.[Medline]
  16. Korb, L., J. Ahearn. 1997. C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes: complement deficiency and systemic lupus erythematosus revisited. J. Immunol. 158:4525.[Abstract]
  17. Walport, M., K. Davies, M. Botto. 1998. C1q and systemic lupus erythematosus. Immunobiology 199:265.[Medline]
  18. Lee, S., S. Wallace, R. Barone, L. Blum, P. Chase. 1978. Familial deficiency of two subunits of the first component of complement: C1r and C1s associated with a lupus erythematosus-like disease. Arthritis Rheum. 21:958.[Medline]
  19. Chevailler, A., C. Drouet, D. Ponard, C. Alibeu, S. Suraniti, F. Carrere, G. Renier, D. Hurez, M. Colomb. 1994. Non coordinated biosynthesis of early complements component in a deficiency of complement protein C1r and C1s. Scand J. Immunol. 40:383.[Medline]
  20. Moncada, B., N. Day, R. Good, D. Windhorst. 1972. Lupus erythematosus-like syndrome with familial defect of complement. N. Engl. J. Med. 286:689.
  21. de Bracco, M., D. Windhorst, R. Stroud, B. Moncada. 1974. The autosomal recessive mode of inheritance of C1r deficiency in a large Puerto Rican family. Clin. Exp. Immunol. 16:183.
  22. Ellison, R., J. Curd, P. Kohler, L. Reller, F. Judson. 1987. Underlying complement deficiency in a patient with disseminated gonococcal infection. Sex. Transm. Dis. 14:201.[Medline]
  23. Garty, B., M. Conley, S. Douglas, G. Kolski. 1987. Recurrent infections and staphylococcal liver abscess in a child with C1r deficiency. J. Allergy Clin. Immunol. 80:631.[Medline]
  24. Vyse, T. J., B. L. Kotzin. 1998. Genetic susceptibility to systemic lupus erythematosus. Annu. Rev. Immunol. 16:261.[Medline]



This article has been cited by other articles:


Home page
 J. Immunol.Home page
K. Abe, Y. Endo, N. Nakazawa, K. Kanno, M. Okubo, T. Hoshino, and T. Fujita
Unique Phenotypes of C1s Deficiency and Abnormality Caused by Two Compound Heterozygosities in a Japanese Family
J. Immunol., February 1, 2009; 182(3): 1681 - 1688.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dragon-Durey, M.-A.
Right arrow Articles by Fridman, W.-H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dragon-Durey, M.-A.
Right arrow Articles by Fridman, W.-H.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS