Alternative titles; symbols
ORPHA: 280133; DO: 8354;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19p13.3 | C3 deficiency | 613779 | Autosomal recessive | 3 | C3 | 120700 |
A number sign (#) is used with this entry because primary C3 deficiency is caused by homozygous or compound heterozygous mutation in the C3 gene (120700) on chromosome 19p13.
The main clinical manifestation of primary C3 deficiency is childhood-onset of recurrent bacterial infections, mainly caused by gram-negative bacteria, such as Neisseria meningitidis, Enterobacter aerogenes, Haemophilus influenzae, and Escherichia coli; infections with gram-positive bacteria also occur. Infections in the upper and lower respiratory tract, including pneumonia, episodes of sinusitis, tonsillitis, and otitis, are the most frequent consequence of the C3 deficiency. Approximately 26% of patients with C3 deficiency develop immune complex-mediated autoimmune diseases resembling systemic lupus erythematosus (see 152700), and about 26% of patients develop mesangiocapillary or membranoproliferative glomerulonephritis, resulting in renal failure (summary by Reis et al., 2006).
Alper et al. (1972) described a patient with a striking susceptibility to pyogenic infection who was apparently homozygous for C3 deficiency. Her C3 levels were one-thousandth or less of normal. Many relatives, including both parents, had approximately half-normal levels.
Pussell et al. (1980) described a family in which 3 children had homozygous C3 deficiency and both parents and 2 other children were heterozygous for a C3 null gene. The family was of Palestinian-Lebanese origin, living in Kuwait; the parents were thought to be cousins. The homozygous and heterozygous children were susceptible to infection. Proteinuria and/or microscopic hematuria were present in all 3 homozygous children, and a heterozygous child had membranoproliferative glomerulonephritis. The only child with normal complement had neither nephritis nor increased susceptibility to infection.
Sano et al. (1981) reported 2 sisters with C3 deficiency and systemic lupus erythematosus (SLE; 152700)-like symptoms.
Berger et al. (1983) and Borzy et al. (1988) observed C3-deficient homozygotes who developed mesangiocapillary glomerulonephritis. The association of C3 deficiency with nephritis was thought to be due to failure of a second physiologic activity of the complement system, that of promoting the disposal of immune complexes to the mononuclear phagocytic system.
Nilsson et al. (1992) described 3 sisters who were compound heterozygotes for a null allele inherited from the father and a dysfunctional C3 allele inherited from the mother. Alternative pathway complement function was absent, but classic pathway complement function was partially intact. One of the sisters, the proband, had an SLE-like disease. The proband's C3 proved normally susceptible to trypsin proteolysis and partially resistant to classical pathways, but completely resistant to alternative pathway, convertase-dependent cleavage.
Botto et al. (1990) studied a 10-year-old boy who had recurrent attacks of otitis media during the first 3 years of life. Between 5 and 8 years of age, he had more than 20 episodes of rash which affected his face, forearms, and hands and resembled the target lesions of erythema multiforme. Attacks were normally preceded by an upper respiratory infection, and a group A beta-hemolytic Streptococcus was isolated from his throat during 2 episodes. The parents were consanguineous ('share a common great-grandparent'). C3 could not be detected by RIA of serum from the patient.
McLean and Hoefnagel (1980) observed an association between partial lipodystrophy and familial C3 deficiency. A 16-year-old girl with familial C3 deficiency developed partial lipodystrophy affecting the face, arms and upper torso. The pattern was reminiscent of that observed in patients with acquired partial lipodystrophy who do not have familial C3 deficiency (608709).
By segregation of C3S and C3F allotypes within a family in which a child had C3 deficiency, Botto et al. (1990) confirmed the presence of a null C3 allele (120700.0003), for which the patient was homozygous. Both parents were heterozygous for the null allele.
In an Afrikaner patient with C3 deficiency described by Alper et al. (1972), Botto et al. (1992) demonstrated homozygosity for a partial deletion of the C3 gene (120700.0004) as the molecular basis of the deficiency.
In a 22-year-old Japanese male patient with C3 deficiency and systemic lupus erythematosus, born of consanguineous parents, Tsukamoto et al. (2005) identified a homozygous splice site mutation in the C3 gene (120700.0009). Complement assay detected no C3 in serum and only a trace amount of C3 hemolytic activity. Both parents and 2 sibs were heterozygous for the mutation, and all had reduced levels of C3 hemolytic activity. The patient had suffered from photosensitivity, recurrent fever, and facial erythema from childhood.
Alper, C. A., Colten, H. R., Rosen, S. F., Rabson, A. R., MacNab, G. M., Gear, J. S. S. Homozygous deficiency of C3 in a patient with repeated infections. Lancet 300: 1179-1181, 1972. Note: Originally Volume II. [PubMed: 4117597] [Full Text: https://doi.org/10.1016/s0140-6736(72)92598-6]
Berger, M., Balow, J. E., Wilson, C. B., Frank, M. M. Circulating immune complexes and glomerulonephritis in a patient with congenital absence of the third component of complement. New Eng. J. Med. 308: 1009-1012, 1983. [PubMed: 6835307] [Full Text: https://doi.org/10.1056/NEJM198304283081706]
Borzy, M. S., Gewurz, A., Wolff, L., Houghton, D., Lovrien, E. Inherited C3 deficiency with recurrent infections and glomerulonephritis. Am. J. Dis. Child. 142: 79-83, 1988. [PubMed: 2963536] [Full Text: https://doi.org/10.1001/archpedi.1988.02150010089032]
Botto, M., Fong, K. Y., So, A. K., Barlow, R., Routier, R., Morley, B. J., Walport, M. J. Homozygous hereditary C3 deficiency due to a partial gene deletion. Proc. Nat. Acad. Sci. 89: 4957-4961, 1992. [PubMed: 1350678] [Full Text: https://doi.org/10.1073/pnas.89.11.4957]
Botto, M., Fong, K. Y., So, A. K., Koch, C., Walport, M. J. Molecular basis of polymorphisms of human complement component C3. J. Exp. Med. 172: 1011-1017, 1990. [PubMed: 1976733] [Full Text: https://doi.org/10.1084/jem.172.4.1011]
Grace, H. J., Brereton-Stiles, G. G., Vos, G. H., Schonland, M. A family with partial and total deficiency of complement C3. S. Afr. Med. J. 50: 139-140, 1976. [PubMed: 1251291]
McLean, R. H., Hoefnagel, D. Partial lipodystrophy and familial C3 deficiency. Hum. Hered. 30: 149-154, 1980. [PubMed: 7358404] [Full Text: https://doi.org/10.1159/000153119]
McLean, R. H., Weinstein, A., Chapitis, J., Lowenstein, M., Rothfield, N. F. Familial partial deficiency of the third component of complement (C3) and the hypocomplementemic cutaneous vasculitis syndrome. Am. J. Med. 68: 549-558, 1980. [PubMed: 7369233] [Full Text: https://doi.org/10.1016/0002-9343(80)90305-8]
Nilsson, U. R., Nilsson, B., Storm, K.-E., Sjolin-Forsberg, G., Hallgren, R. Hereditary dysfunction of the third component of complement associated with a systemic lupus erythematosus-like syndrome and meningococcal meningitis. Arthritis Rheum. 35: 580-586, 1992. [PubMed: 1575793] [Full Text: https://doi.org/10.1002/art.1780350516]
Osofsky, S. G., Thompson, B. H., Lint, T. F., Gewurz, H. Hereditary deficiency of 3rd component of complement in a child with fever, skin rash, and arthralgias--response to transfusion of whole blood. J. Pediat. 90: 180-186, 1977. [PubMed: 318684] [Full Text: https://doi.org/10.1016/s0022-3476(77)80626-4]
Pussell, B. A., Bourke, E., Nayef, M., Morris, S., Peters, D. K. Complement deficiency and nephritis: a report of a family. Lancet 315: 675-677, 1980. Note: Originally Volume I. [PubMed: 6103091]
Reis, E. S., Falcao, D. A., Isaac, L. Clinical aspects and molecular basis of primary deficiencies of complement component C3 and its regulatory proteins factor I and factor H. Scand. J. Immun. 63: 155-168, 2006. [PubMed: 16499568] [Full Text: https://doi.org/10.1111/j.1365-3083.2006.01729.x]
Sano, Y., Nishimukai, H., Kitamura, H., Nagaki, K., Inai, S., Hamasaki, Y., Maruyama, I., Igata, A. Hereditary deficiency of the third component of complement in two sisters with systemic lupus erythematosus-like symptoms. Arthritis Rheum. 24: 1255-1260, 1981. [PubMed: 7306227] [Full Text: https://doi.org/10.1002/art.1780241005]
Tsukamoto, H., Horiuchi, T., Kokuba, H., Nagae, S., Nishizaka, H., Sawabe, T., Harashima, S., Himeji, D., Koyama, T., Otsuka, J., Mitoma. H., Kimoto, Y., Hashimura, C., Kitano, E., Kitamura, H., Furue, M., Harada, M. Molecular analysis of a novel hereditary C3 deficiency with systemic lupus erythematosus. Biochem. Biophys. Res. Commun. 330: 298-304, 2005. [PubMed: 15781264] [Full Text: https://doi.org/10.1016/j.bbrc.2005.02.159]