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

Dragon-Durey, Marie-Agnès; Quartier, Pierre; Frémeaux‐Bacchi, Véronique; Blouin, Jacques; Barace, Claire de; Prieur, Anne‐Marie; Weiss, Laurence; Fridman, Wolf‐Herman

doi:10.4049/jimmunol.166.12.7612

Cited by 60 publications

(31 citation statements)

References 22 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: 51%

“…It has been reported that a patient with a homozygous 4-bp deletion in exon X had SLE-like symptoms and chronic glomerulonephritis (15). A patient with a homozygous Arg534X in exon XII had SLE-like symptoms, Hashimoto's thyroiditis, and autoimmune hepatitis (16). Thus the previous cases had in common immune complexrelated diseases or autoimmune diseases, especially SLE-like symptoms.…”

Section: Discussionmentioning

confidence: 96%

“…One of the two mutations, a 4-bp deletion in exon X, was also identified in another Japanese family as a homozygote, and the patient had symptoms like systemic lupus erythematosus (SLE) 3 and chronic glomerulonephritis (15). In a Caucasian patient with selective C1s deficiency, a third mutation was identified as homozygosity and was a nonsense mutation, Arg534X, in exon XII (16). This case had multiple autoimmune diseases such as SLElike symptoms, Hashimoto's thyroiditis, and autoimmune hepatitis.…”

mentioning

confidence: 99%

“…Several cases of human complement C1 deficiency have been reported (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16), in which the deficiency was caused by the absence of the subcomponents C1q (6, 9 -13), C1r (3,4,8), C1s (7, 14 -17), or both C1r and C1s (5). The molecular basis for hereditary C1q deficiency is well defined, where homozygosity for nonsense mutations in the C1q A-chain and B-chain genes (6,10,12,13) and deletion, nonsense, and missense mutations in the C1q C-chain gene (10,11) have been demonstrated.…”

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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: 51%

Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

mentioning

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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“…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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Complement: Deficiency Diseases

Blom¹

2010

Encyclopedia of Life Sciences

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The complement system is crucial for defence against pathogens, removal of unwanted materials such as dying cells or immune complexes as well as for development of adaptive immune responses. Genetically determined deficiencies of components of the complement system are usually relatively rare but they result in many severe diseases such as an increased susceptibility to recurrent, severe infections, autoimmune disorders (systemic lupus erythematosus), glomerulonephritis including membranoproliferative glomerulonephritis type II, paroxysmal nocturnal haemoglobinuria or angioedema. Recently, mutations and polymorphisms in complement proteins, particularly complement inhibitors, have been associated with atypical haemolytic uremic syndrome and age‐related macular degeneration. The elucidation of the pathophysiological basis for the different clinical presentations of complement‐deficient individuals has contributed to a better understanding of the physiological role of complement in normal individuals as well as to the development of emerging therapies. Key Concepts The majority of complement deficiencies are rare but cause severe diseases. Deficiencies of the early components of the classical pathway (C1q/r/s, C4, C2) predispose to systemic lupus erythematosus. The majority of complement deficiencies predispose to infections either with Neisseria species (deficiency of Factor D, Properdin, C5, C6, C7, C8, C9) or Gram‐positive bacteria (C1q/r/s, mannose‐binding lectin, C2, C4, C3, factor I). Mutations in C1q/r/s, C2, C4, C3 and factor I can cause glomerulonephritis. Paroxysmal nocturnal haemoglobinuria is caused by deficiency of complement inhibitors CD55 and CD59. Hereditary angioedema is found in patients with dysfunctional C1‐inhibitor. Atypical haemolytic uremic syndrome is mainly associated with mutations and polymorphisms in complement inhibitors. Age‐related macular degeneration is associated with polymorphisms in complement inhibitor factor H.

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

Cited by 60 publications

References 22 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

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

Complement: Deficiency Diseases

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