Hereditary Deficiency of the Third Component of Complement in Two Sisters With Systemic Lupus Erythematosus‐like Symptoms

Sano, Yuji; Nishimukai, Hiroaki; Kitamura, Hajime; Nagaki, K; Inai, Shinya; Hamasaki, Yasuteru; Maruyama, Ikuro; Igata, Akihiro

doi:10.1002/art.1780241005

Cited by 53 publications

(21 citation statements)

References 22 publications

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“…B lymphocytes were separated and transformed by Epstein-Barr virus (EBV). EBVtransformed B-cell lines were cultured in RPMI 1640 medium supplemented with 10% fetal calf serum in the presence or absence of lipopolysaccharide (5 ,ug/ml). mRNA was extracted by the guanidinium isothiocyanate/cesium chloride method (15).…”

Section: Methodsmentioning

confidence: 99%

Homozygous hereditary C3 deficiency due to a partial gene deletion.

Botto

Fong

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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The molecular mechanism of C3 deficiency in an Afrikaans patient with recurrent pyogenic infections was studied. Restriction enzyme analysis showed a gene deletion of 800 base pairs (bp) mapping to the a chain of C3. Amplification of genomic DNA, using the PCR, demonstrated that the deletion included exons 22 and 23 of the C3 gene. Truncated mRNA was shown in an Epstein-Barr virus-transformed B-cell line by PCR amplification of first-strand cDNA. A consequence of this deletion was that the RNA transcribed 3' to the deletion was out of frame, resulting in formation of a stop codon 19 bp downstream from the deletion. The molecular basis of the deletion was compatible with homologous recombination between two Alu sequences located in introns 21 and 23. An unrelated nonconsanguineous relative and two of a sample of 174 Afrikaansspeaking individuals were heterozygous carriers of the same gene deletion. The wide prevalence of this null allele in this population is probably due to the effects of a small founder population. The presence of this deletion in the C3 gene is not compatible with production ofany functional C3, supporting the idea that study of such patients offers a valid model for understanding physiological activities of C3 in vivo in humans.Analysis of patients with hereditary deficiencies of complement proteins has given insight into the physiological actions in vivo of the complement system in host defense against pyogenic infections and disease mediated by immune complexes. Complement protein C3 is the major protein of the complement system in plasma in terms of quantitative expression, at -1 g/liter. Cleavage of C3 by C3 convertase enzymes results in release of the anaphylatoxin C3a. The other product of the initial cleavage of C3, C3b, covalently fixed to surfaces, acts as a focus for formation of the C5 convertase enzyme and, together with its further cleavage product, iC3b, is a ligand for complement receptors CR1 and CR3. Absence of C3 is a rare condition in humans and provides the best opportunity for investigating the physiological activities of this protein in vivo in humans.To date 15 patients, who suffered from recurrent pyogenic infections and/or rashes and nephritis (1-10), have been described with inherited homozygous C3 deficiency. Characterization of the full genomic organization of the human C3 gene (11) allowed us to identify a splice site mutation as the molecular basis for C3 deficiency in a 10-year-old English patient (12).

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Section: Methodsmentioning

confidence: 99%

Homozygous hereditary C3 deficiency due to a partial gene deletion.

Botto

Fong

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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“…The details of clinical and laboratory findings in this family have been reported previously (4). Briefly, patient 1 was a 36-year-old womanborn by normal delivery after an uneventful pregnancy.…”

Section: Patients ' Reportmentioning

confidence: 99%

“…Since 1972, over 20 inherited C3 deficiency cases have been described, however the responsible gene mutations, such as point mutation, gene deletions and splice site mutations in the C3 genome, have been reported in only a few of these families (1)(2)(3). Wepreviously reported two sisters with hereditary C3 deficiency exhibiting SLE-like symptoms (4). To clarify the molecular mechanismin these sisters, weanalyzed the sequence of the C3 gene and the expression of the gene in culture cells.…”

Section: Introductionmentioning

confidence: 99%

Molecular Analysis of Hereditary Deficiency of the Third Component of Complement (C3) in Two Sisters.

et al. 2001

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Wereport two sisters with hereditary deficiency of the third complement component (C3) and a homozygous mutation at C3303G (Tyrl081Stop) of the gene. They developed systemic lupus erythematosus-like symptomsduring adolescence. Their C3 were not detected in serum immunochemically. Their mother and a brother had half of the normal C3 levels and a heterozygous mutation in the same position. Western blot analysis of murine L-cells transfected with the mutant C3 CDNAshowed no C3 protein, however mRNA was detectable using reverse-transcriptase polymerase chain reaction. To the best of our knowledge, this is the first report of C3 deficiency due to a stop codon in the gene.

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“…The study of human subjects with hereditary C3 deficiency provides the best evidence for the physiological activities of the complement system in vivo. 15 such individuals (6)(7)(8)(9)(10)(11)(12)(13)(14)(15) have been described, 12 of whom have suffered from recurrent pyogenic infections, which emphasizes the important physiological role of C3 as an opsonin for bacteria. Two patients have developed mesangiocapillary glomerulonephritis (7,10), and three hematuria and/or proteinuria ( 14).…”

Section: Introductionmentioning

confidence: 99%

Molecular basis of hereditary C3 deficiency.

Botto

Fong²,

So³

et al. 1990

J. Clin. Invest.

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Hereditary deficiency of complement component C3 in a 10-yr-old boy was studied. C3 could not be detected by RIA of serum from the patient. Segregation of C3 S and C3 F allotypes within the family confirmed the presence of a null gene for C3, for which the patient was homozygous. 30 exons have been characterized, spanning the entire ft chain of C3 and the a chain as far as the C3d region. Sequence analysis of the exons derived from the C3 null gene showed no abnormalities in the coding sequences. A GT-AT mutation at the 5' donor splice site of the intervening sequence 18 was found in the C3 null gene. Exons 17-21 were amplified by the polymerase chain reaction (PCR) from first-strand cDNA synthesized from mRNA obtained from peripheral blood monocytes stimulated with LPS. This revealed a 61-bp deletion in exon 18, resulting from splicing of a cryptic 5' donor splice site in exon 18 with the normal 3' splice site in exon 19. This deletion leads to a disturbance of the reading frame of the mRNA with a stop codon 17 bp downstream from the abnormal splice in exon 18. His parents had both the normal and abnormal C3 mRNA and were shown to be heterozygous for this mutation by sequence analysis of genomic DNA amplified by PCR. Similar splice mutants have previously been reported in the ft-globin, phenylalanine hydroxylase, and porphobilinogen deaminase genes. This mutation is sufficient to cause the deficiency of C3 in the patient.

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Hereditary Deficiency of the Third Component of Complement in Two Sisters With Systemic Lupus Erythematosus‐like Symptoms

Cited by 53 publications

References 22 publications

Homozygous hereditary C3 deficiency due to a partial gene deletion.

Homozygous hereditary C3 deficiency due to a partial gene deletion.

Molecular Analysis of Hereditary Deficiency of the Third Component of Complement (C3) in Two Sisters.

Molecular basis of hereditary C3 deficiency.

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