Genetic analysis of complement C1s deficiency associated with systemic lupus erythematosus highlights alternative splicing of normal C1s gene

Amano, Mariane Tami; Ferriani, Virgínia Paes Leme; Florido, M.P.C.; Reis, Edimara S.; Delcolli, Maria Isabel; Azzolini, Ana Elisa Caleiro Seixas; Assis-Pandochi, Ana Isabel de; Sjöholm, Anders G.; Farah, Chuck S.; Jensenius, Jens Christian; Isaac, Lourdes

doi:10.1016/j.molimm.2007.09.034

Cited by 45 publications

(37 citation statements)

References 41 publications

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“…These conditions of the patients in this family appear to be different from those of previously reported cases (15)(16)(17)(18). It has been reported that a patient with a homozygous 4-bp deletion in exon X had SLE-like symptoms and chronic glomerulonephritis (15).…”

Section: Discussioncontrasting

confidence: 99%

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Unique Phenotypes of C1s Deficiency and Abnormality Caused by Two Compound Heterozygosities in a Japanese Family

Abe¹,

Endo

Nakazawa

et al. 2009

The Journal of Immunology

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A deficiency in the early components of complement is associated with an increased susceptibility to pyrogenic infections and multiple autoimmune diseases. We previously reported a Japanese case of selective C1s deficiency resulting from a compound heterozygosity for a 4-bp deletion in exon X and a nonsense mutation Glu597X in exon XII of the C1s gene. In this previous case, the patient suffered from unique symptoms including virus-associated hemophagocytic syndrome and died after a long period of loss of consciousness. In the present study, we report another patient from the same family, with C1s abnormality caused by a distinct compound-heterozygous genotype and who had a novel missense mutation Gly630Glu transmitted from the mother’s side and a previously identified nonsense mutation Glu597X from the father’s side. Thus three distinct mutations of the C1s gene were clustered and resulted in two distinct genotypes for C1s deficiency and C1s abnormality within this one family. The present patient showed symptoms that were similar in part to our previous patient, which were different from those of the cases reported in other families. The biochemical properties of C1s in the patient’s serum and the recombinant form were closely related to the undetectable or very low activity of complement activation. These results suggested that the uniqueness and severity of the symptoms observed here in the two patients might be under the control of a common C1s allele and distinct counterparts, respectively.

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Section: Discussioncontrasting

confidence: 99%

“…This case had multiple autoimmune diseases such as SLElike symptoms, Hashimoto's thyroiditis, and autoimmune hepatitis. Recently, it was reported that two of four C1s-deficient siblings in a Brazilian family, who were all homozygous for a new nonsense mutation Tyr204X in exon VI, developed SLE-like symptoms (17).…”

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confidence: 99%

Unique Phenotypes of C1s Deficiency and Abnormality Caused by Two Compound Heterozygosities in a Japanese Family

Abe¹,

Endo

Nakazawa

et al. 2009

The Journal of Immunology

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“…NHS were incubated at 56°C for 30 min to yield heat-inactivated NHS (HI-NHS). Mannose-binding lectin (MBL)-deficient serum was obtained from a healthy donor, and C1s-deficient serum was obtained as described by Amano et al (1). All serum samples were screened for the presence of antibodies reacting with leptospires by the microagglutination test and found to be negative.…”

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confidence: 99%

Immune Evasion ofLeptospiraSpecies by Acquisition of Human Complement Regulator C4BP

et al. 2009

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Leptospirosis is a spirochetal zoonotic disease of global distribution with a high incidence in tropical regions. In the last 15 years it has been recognized as an important emerging infectious disease due to the occurrence of large outbreaks in warm-climate countries and, occasionally, in temperate regions. Pathogenic leptospires efficiently colonize target organs after penetrating the host. Their invasiveness is attributed to the ability to multiply in blood, adhere to host cells, and penetrate into tissues. Therefore, they must be able to evade the innate host defense. The main purpose of the present study was to evaluate how several Leptospira strains evade the protective function of the complement system. The serum resistance of six Leptospira strains was analyzed. We demonstrate that the pathogenic strain isolated from infected hamsters avoids serum bactericidal activity more efficiently than the culture-attenuated or the nonpathogenic Leptospira strains. Moreover, both the alternative and the classical pathways of complement seem to be responsible for the killing of leptospires. Serum-resistant and serum-intermediate strains are able to bind C4BP, whereas the serumsensitive strain Patoc I is not. Surface-bound C4BP promotes factor I-mediated cleavage of C4b. Accordingly, we found that pathogenic strains displayed reduced deposition of the late complement components C5 to C9 upon exposure to serum. We conclude that binding of C4BP contributes to leptospiral serum resistance against host complement.

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“…The most drastically altered gene was C1s , which is involved in complement system. In humans, C1s deficiency has been reported to associate with lupus nephritis [13,14,15,16,17]. Although it has not been fully understood what activity of the early proteins in the classical pathway of complement protects normal humans from development of lupus nephritis, clearance of immune complexes is thought to be a candidate activity [18].…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Analysis Detected a Low Expression Level of <b><i>C1s</i></b> Gene in ICR-Derived Glomerulonephritis (ICGN) Mice

Tamura

Uchio‐Yamada

Manabe

et al. 2013

Nephron Exp Nephrol

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Background: ICR-derived glomerulonephritis (ICGN) strain is a novel inbred strain of mice with a hereditary nephrotic syndrome. Deletion mutation of tensin 2 (Tns2), a focal adhesion molecule, has been suggested to be responsible for nephrotic syndrome in ICGN mice; however, the existence of other associative factors has been suggested. Methods and Results: To identify additional associative factors and to better understand the onset mechanism of nephrotic syndrome in ICGN mice, we conducted a comprehensive gene expression analysis using DNA microarray. Immune-related pathways were markedly altered in ICGN mice kidney as compared with ICR mice. Furthermore, the gene expression level of complement component 1, s subcomponent (C1s), whose human homologue has been reported to associate with lupus nephritis, was markedly low in ICGN mouse kidney. Real-time quantitative reverse transcription-polymerase chain reaction confirmed a low expression level of C1s in ICGN mouse liver where the C1s protein is mainly synthesized. A high serum level of anti-dsDNA antibody and deposits of immune complexes were also detected in ICGN mice by enzyme-linked immunosorbent assay and immunohistochemical analyses, respectively. Conclusion: Our results suggest that the immune system, especially the complement system, is associated with nephrotic syndrome in ICGN mice. We identified a low expression level of C1s gene as an additional associative factor for nephrotic syndrome in ICGN mice. Further studies are needed to elucidate the role of the complement system in the onset of nephrotic syndrome in ICGN mice.

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Genetic analysis of complement C1s deficiency associated with systemic lupus erythematosus highlights alternative splicing of normal C1s gene

Cited by 45 publications

References 41 publications

Unique Phenotypes of C1s Deficiency and Abnormality Caused by Two Compound Heterozygosities in a Japanese Family

Unique Phenotypes of C1s Deficiency and Abnormality Caused by Two Compound Heterozygosities in a Japanese Family

Immune Evasion ofLeptospiraSpecies by Acquisition of Human Complement Regulator C4BP

Gene Expression Analysis Detected a Low Expression Level of <b><i>C1s</i></b> Gene in ICR-Derived Glomerulonephritis (ICGN) Mice

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