Alternative titles; symbols
ORPHA: 169147; DO: 0060295;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p21.33 | C2 deficiency | 217000 | Autosomal recessive | 3 | C2 | 613927 |
A number sign (#) is used with this entry because complement component-2 deficiency (C2D) is caused by homozygous or compound heterozygous mutation in the C2 gene (613927) on chromosome 6p21.
The complement system is a set of plasma proteins that serves as an effector of several biologic functions associated with inflammation, immunoregulation, and cytotoxicity. Deficiency of complement component-2 (C2D) is the most common defect of the complement system in persons of western European descent. In type I C2 deficiency, no C2 protein is translated; in type II, there is a selective block in C2 secretion. More than half of individuals with homozygous C2 deficiency have rheumatologic disorders such as systemic lupus erythematosus, Henoch-Schonlein purpura, or polymyositis. Other individuals experience recurrent pyogenic infections, and some C2-deficient individuals are asymptomatic (summary by Johnson et al., 1992, Wetsel et al., 1996).
Klemperer et al. (1966, 1967) found C2 deficiency in multiple members of a kindred. No gene product was detected in those with the deficiency (homozygotes). In heterozygotes a partial deficiency of C2 was found. Restudy of the family examined by Silverstein (1960) demonstrated identical findings. None of the homozygotes has been unduly sensitive to bacterial infection or had other evident abnormality.
By means of monospecific antiserum, Polley (1968) showed that homozygotes have no second component of complement and heterozygotes have an intermediate amount. Thus, the defect is failure of synthesis rather than synthesis of an inactive analog.
Einstein et al. (1975) reported affected brother and sister. The sister had Henoch-Schonlein purpura and 2 previously reported patients with C2 deficiency had this disorder.
Friend et al. (1975) studied 3 unrelated persons with deficiency of C2 in association with lupus erythematosus, polyarteritis and membranoproliferative glomerulonephritis.
Provost et al. (1983) pointed out that heterozygous C2 deficiency has a frequency of 1 to 2%, that it usually segregates with the HLA-A25,B18,Dw2 haplotype, and that in about one-third of reported cases of homozygous C2 deficiency discoid (cutaneous) lupus and/or an SLE-like disorder is present.
Cole et al. (1985) stated that about half of the reported patients with C2 deficiency have autoimmune disease, most commonly systemic lupus erythematosus, Henoch-Schonlein purpura, or polymyositis. By molecular genetic studies of cultured blood monocytes, they concluded that C2 deficiency is not caused by a major gene deletion or rearrangement but is the result of a 'specific and selective pretranslational regulatory defect in C2 gene expression.' Serum from patients with C2 deficiency lack functionally and immunologically detectable C2 protein.
Johnson et al. (1992) reported 2 families with C2 deficiency. They designated the defect in the first family as type I; no detectable C2 protein was synthesized. In the second family, there appeared to be a selective block in C2 secretion; the cell lysate showed an increase in C2 and there was measurable C2 in the blood. The defect in the second family was designated as type II. Measurement of conventional C2 hemolytic functional activity did not distinguish between the defects in the 2 families. The type I defect was associated with the MHC haplotype that was found to be associated with C2 deficiency in approximately 94% of chromosomes in the series reported by Awdeh et al. (1981), i.e., haplotype A25, B18, Drw2, BFS, C2Q0, C4A4B2. In the family with type II, 2 different MHC haplotypes were associated with C2 deficiency.
D'Cruz et al. (1992) described a brother and sister with homozygous C2 deficiency who developed cutaneous vasculitis and sicca syndrome. The mother had seropositive rheumatoid arthritis. D'Cruz et al. (1992) pictured the vasculitic purpuric rash on the legs of the patient. The rash started as small, raised, maculopapular lesions, some of which progressed to necrosis and ulceration followed by healing.
Raum et al. (1976) concluded that the CFB locus (138470) and the C2 deficiency locus are close together (no recombinant was observed) and that the 2 loci are 3 to 5 centimorgans from the HLA-A (142800) and HLA-B (142830) loci on chromosome 6p. Two crossovers out of 57 were observed for C2 versus HLA-B, and 3 out of 72 for CFB versus HLA-B. The order of the genes was taken to be HLA-A, -B, -D, CFB, C2.
Cole et al. (1985) stated that C2 deficiency is the most frequent complement deficiency state among western European populations, occurring in about 1 in 10,000 white persons.
Friend et al. (1975) found that 3 unrelated persons with deficiency of C2 in association with lupus erythematosus, polyarteritis and membranoproliferative glomerulonephritis were homozygous for the mixed lymphocyte reaction determinant, short 7a (7a*). Since two were homozygous HLA-A10, Bw18 and the third was a (A10, B11) (A2, B12.2) heterozygote, the authors suggested linkage disequilibrium between C2 deficiency, A10 and BW18.
Awdeh et al. (1981) did C4 allotyping of 13 homozygous C2-deficient persons and found that 23 of 25 haplotypes were of the relatively rare type C4A*4B*2.
Simon et al. (1991) described a RFLP fragment that is a unique marker for C2 deficiency and for the uncommon C2*B allele which is associated with type I diabetes.
By sequencing of the entire C2 cDNA from 2 patients with type I C2 deficiency, Johnson et al. (1991) identified a homozygous 28-bp deletion (613927.0001); the deletion was not present in normal C2 genes or in type II C2-deficient genes.
In patients with type II C2 deficiency, Wetsel et al. (1996) identified compound heterozygosity for 2 missense mutations in the C2 gene (613927.0002-613927.0003).
Although guinea pigs with C2 and C4 deficiency appeared healthy, Bottger et al. (1986) found that they had serologic characteristics of immune complex disease.
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Bottger, E. C., Hoffmann, T., Hadding, U., Bitter-Suermann, D. Guinea pigs with inherited deficiencies of complement components C2 or C4 have characteristics of immune complex disease. J. Clin. Invest. 78: 689-695, 1986. [PubMed: 2427541] [Full Text: https://doi.org/10.1172/JCI112628]
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Gewurz, A., Lint, T. F., Roberts, J. L., Zeitz, H., Gewurz, H. Homozygous C2 deficiency with fulminant lupus erythematosus: severe nephritis via the alternative complement pathway. Arthritis Rheum. 21: 28-36, 1978. [PubMed: 341897] [Full Text: https://doi.org/10.1002/art.1780210106]
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