Alternative titles; symbols
HGNC Approved Gene Symbol: C1QA
Cytogenetic location: 1p36.12 Genomic coordinates (GRCh38): 1:22,636,463-22,639,678 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.12 | C1q deficiency 1 | 613652 | Autosomal recessive | 3 |
The first component of complement is a calcium-dependent complex of the 3 subcomponents C1q, C1r (613785), and C1s (120580). Subcomponent C1q binds to immunoglobulin complexes with resulting serial activation of C1r (enzyme), C1s (proenzyme), and the other 8 components of complement. C1q is composed of 3 different species of chains, called A, B (C1QB; 120570), and C (C1QC; 120575).
For a review of the complement system and its components, see Degn et al. (2011).
Reid (1974) reported a partial amino acid sequence of 95 residues of the 191 residues in the oxidized A chain of human subcomponent C1q. This region of the A chain contains a repeating sequence of glycine-X-Y, where X is often proline and Y is often hydroxyproline, for 78 residues. The 5 hydroxylysine residues and 5 hydroxyproline residues in the oxidized A chain are all in these 78 residues and only in the Y position of the repeating sequence. Prolonged collagenase digestion of the oxidized A chain yielded a large, apparently C-terminal peptide containing most of the noncollagenous sequences present in the chain. Reid (1974) concluded that the A chain of C1q contains a collagen-like region that constitutes most of the N-terminal half of the chain.
Hedge et al. (1987) isolated a cDNA clone for the A chain of C1q from a human monocyte cDNA library using a variety of synthetic oligonucleotides as probes.
Bing et al. (1982) showed that fibronectin (see 135600) binds to C1q in the same manner that it binds collagen. A major function of fibronectins is in adhesion of cells to extracellular materials, such as solid substrata and matrices. Because fibronectin stimulates endocytosis and promotes clearance of particulate material from circulation, the results of Bing et al. (1982) suggest that fibronectin functions in clearance of C1q-coated material, such as immune complexes or cellular debris.
Diebolder et al. (2014) found that specific noncovalent interactions between Fc segments of IgG antibodies resulted in the formation of ordered antibody hexamers after antigen binding on cells. These hexamers recruited and activated C1, the first component of complement, thereby triggering the complement cascade. The interactions between neighboring Fc segments could be manipulated to block, reconstitute, and enhance complement activation and killing of target cells, using all 4 human IgG subclasses. Diebolder et al. (2014) offered a general model for understanding antibody-mediated complement activation and the design of antibody therapeutics with enhanced efficacy.
Using mouse models, Hong et al. (2016) showed that complement and microglia mediate synaptic loss early in Alzheimer disease (AD; 104300). C1q, the initiating protein of the classical complement cascade, was increased and associated with synapses before overt plaque deposition. Inhibition of C1q, C3 (120700), or the microglial complement receptor CR3 (CD11b/CD18; see 600065) reduced the number of phagocytic microglia, as well as the extent of early synapse loss. C1q was necessary for the toxic effects of soluble beta-amyloid (A-beta; 104760) oligomers on synapses and hippocampal long-term potentiation. Finally, microglia in adult brains engulfed synaptic material in a CR3-dependent process when exposed to soluble A-beta oligomers. Together, these findings suggested that the complement-dependent pathway and microglia that prune excess synapses in development are inappropriately activated and mediate synapse loss in AD.
By somatic cell hybrid analysis, Hedge et al. (1987) assigned the gene for the A chain of C1q to chromosome 1p, where the gene for the B chain had been assigned previously. The genes for the A, B, and C chains of C1q are tandemly arranged 5-prime to 3-prime in the order A-C-B on a 24-kb stretch of DNA (Sellar et al., 1991). A and C are separated by 4 kb and B and C are separated by 11 kb. Hybridization of cDNA probes to a hybrid cell line containing the derived X chromosome from an X;1(q21.2;p34) translocation described in a female patient with Duchenne muscular dystrophy (Lindenbaum et al., 1979; Boyd et al., 1988) showed that the A and B genes are located in the region 1p36.3-p34.1 (Sellar et al., 1992).
In patients with C1q deficiency (C1QD1; 613652), Topaloglu et al. (1996) and Petry et al. (1997) identified the same homozygous truncating mutation in the C1QA gene (Q186X; 120550.0001).
In 2 Sudanese sibs with C1q deficiency, Schejbel et al. (2011) identified a homozygous truncating mutation in the C1QA gene (W194X; 120550.0002).
The complement system plays a paradoxical role in development and expression of autoimmunity in humans. The activation of complement in SLE contributes to tissue injury. In contrast, inherited deficiency of classic pathway components, particularly C1q, is probably associated with development of SLE. This leads to the hypothesis that a physiologic action of the early part of the classic pathway protects against development of SLE and implies that C1q may play a key role in this respect. Botto et al. (1998) generated C1q-deficient (C1qa -/-) mice by gene targeting and monitored them for 8 months. C1qa -/- mice had increased mortality and higher titers of autoantibodies, compared with strain-matched controls. Of the C1qa -/- mice, 25% had glomerulonephritis with immune deposits and multiple apoptotic cell bodies. Among mice without glomerulonephritis, there were significantly greater numbers of glomerular apoptotic bodies in C1q-deficient mice compared with controls. The phenotype associated with C1q deficiency was modified by background genes. These findings are compatible with the hypothesis that C1q deficiency causes autoimmunity by impairment of the clearance of apoptotic cells.
Formation of mature neural circuits during development requires selective elimination of inappropriate synaptic connections. Using RT-PCR, in situ hybridization, and immunohistochemistry, Stevens et al. (2007) found that mouse C1q was expressed by postnatal neurons in response to immature astrocytes and was localized to synapses throughout the postnatal central nervous system (CNS) and retina. Mice lacking C1q (C1qa -/-) or the downstream complement protein C3 (120700), exhibited large, sustained defects in CNS synapse elimination. Neuronal C1q was downregulated in the CNS in adulthood. However, in a mouse model of glaucoma (see 137750), C1q exhibited upregulated expression and relocalization to adult retina early in the disease. Stevens et al. (2007) concluded that unwanted synapses are tagged by components of the classical complement cascade for elimination, and they proposed that complement-mediated synapse elimination may be aberrantly reactivated in neurodegenerative disease.
Lewis et al. (2009) generated mice lacking C1qa and/or serum IgM (147020) as well as Ldlr (606945) and studied them on both low- and high-fat semisynthetic diets. On both diets, serum IgM/Ldlr -/- mice developed substantially larger and more complex en face and aortic root atherosclerotic lesions, with accelerated cholesterol crystal formation and increased smooth muscle content in aortic root lesions. TUNEL analysis revealed increased apoptosis in both C1qa/Ldlr -/- and serum IgM/Ldlr -/- mice. Overall lesions were larger in mice lacking IgM rather than C1q, suggesting that IgM protective mechanisms are partially independent of classic complement pathway activation and apoptotic cell clearance. Lewis et al. (2009) concluded that IgM antibodies play a central role in protection against atherosclerosis.
Deficiency of C1q (613652), the initiator of the complement classical pathway, is associated with the development of SLE. Ling et al. (2018) used a mouse model of SLE to demonstrate that C1q, but not C3, restrains the response to self-antigens by modulating the mitochondrial metabolism of CD8 (186910)+ T cells, which can themselves propagate autoimmunity. C1q deficiency also triggers an exuberant effector CD8+ T cell response to chronic viral infection, leading to lethal immunopathology. Ling et al. (2018) concluded that these data established a link between C1q and CD8+ T cell metabolism and may explain how C1q protects against lupus, with implications for the role of viral infections in the perpetuation of autoimmunity.
In 2 sibs with homozygous C1q deficiency (C1QD1; 613652), Topaloglu et al. (1996) identified homozygosity for a C-to-T transition in codon 186 of the A chain that resulted in a gln-to-stop (Q186X) substitution. The mutation was present in heterozygous state in both parents and in 2 unaffected sibs. Topaloglu et al. (1996) stated that the same mutation had been described in an affected member of a Slovakian family with C1q deficiency by Petry et al. (1995).
Petry et al. (1997) identified homozygosity for the Q186X mutation in affected members of 3 Turkish families. In 1 family, an asymptomatic sister of the proband was also found to be homozygous for the mutation. Petry et al. (1997) hypothesized that this defective allele is present in the population of southeast Europe and Turkey.
Schejbel et al. (2011) identified the Q186X mutation in an 8-year-old Iraqi boy with C1Q deficiency.
In 2 affected sibs from a Sudanese family segregating C1q deficiency (C1QD1; 613652), Schejbel et al. (2011) identified homozygosity for a trp194-to-ter (W194X) mutation in the C1QA gene. The mutation segregated with the deficiency. Schejbel et al. (2011) also numbered the mutation as g.7693G-A (NG_007282), resulting in a trp216-to-ter substitution.
Bing, D. H., Almeda, S., Isliker, H., Lahav, J., Hynes, R. O. Fibronectin binds to the C1q component of complement. Proc. Nat. Acad. Sci. 79: 4198-4201, 1982. [PubMed: 6981115] [Full Text: https://doi.org/10.1073/pnas.79.13.4198]
Botto, M., Dell'Agnola, C., Bygrave, A. E., Thompson, E. M., Cook, H. T., Petry, F., Loos, M., Pandolfi, P. P., Walport, M. J. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nature Genet. 19: 56-59, 1998. [PubMed: 9590289] [Full Text: https://doi.org/10.1038/ng0598-56]
Boyd, Y., Cockburn, D., Holt, S., Munro, E., van Ommen, G. J., Gillard, B., Affara, N., Ferguson-Smith, M., Craig, I. Mapping of 12 translocation breakpoints in the Xp21 region with respect to the locus for Duchenne muscular dystrophy. Cytogenet. Cell Genet. 48: 28-34, 1988. [PubMed: 3180845] [Full Text: https://doi.org/10.1159/000132581]
Degn, S. E., Jensenius, J. C., Thiel, S. Disease-causing mutations in genes of the complement system. Am. J. Hum. Genet. 88: 689-705, 2011. [PubMed: 21664996] [Full Text: https://doi.org/10.1016/j.ajhg.2011.05.011]
Diebolder, C. A., Beurskens, F. J., de Jong, R. N., Koning, R. I., Strumane, K., Lindorfer, M. A., Voorhorst, M., Ugurlar, D., Rosati, S., Heck, A. J. R., van de Winkel, J. G. J., Wilson, I. A., Koster, A. J., Taylor, R. P., Saphire, E. O., Burton, D. R., Schuurman, J., Gros, P., Parren, P. W. H. I. Complement is activated by IgG hexamers assembled at the cell surface. Science 343: 1260-1263, 2014. [PubMed: 24626930] [Full Text: https://doi.org/10.1126/science.1248943]
Gilmour, S., Randall, J. T., Willan, K. J., Dwek, R. A., Torbet, J. The confirmation of subcomponent C1q of the first component of human complement. Nature 285: 512-514, 1980. [PubMed: 7402297] [Full Text: https://doi.org/10.1038/285512a0]
Hedge, P. J., Seller, G. C., Reid, K. B. M., Solomon, E. Assignment of the A chain of C1q (C1QA) to the short arm of chromosome 1. (Abstract) Cytogenet. Cell Genet. 46: 627 only, 1987.
Hong, S., Beja-Glasser, V. F., Nfonoyim, B. M., Frouin, A., Li, S., Ramakrishnan, S., Merry, K. M., Shi, Q., Rosenthal, A., Barres, B. A., Lemere, C. A., Selkoe, D. J., Stevens, B. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352: 712-716, 2016. [PubMed: 27033548] [Full Text: https://doi.org/10.1126/science.aad8373]
Lewis, M. J., Malik, T. H., Ehrenstein, M. R., Boyle, J. J., Botto, M., Haskard, D. O. Immunoglobulin M is required for protection against atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation 120: 417-426, 2009. [PubMed: 19620499] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.109.868158]
Lindenbaum, R. H., Clarke, G., Patel, C., Moncrieff, M., Hughes, J. T. Muscular dystrophy in an X;1 translocation female suggests that Duchenne locus is on X chromosome short arm. J. Med. Genet. 16: 389-392, 1979. [PubMed: 513085] [Full Text: https://doi.org/10.1136/jmg.16.5.389]
Ling, G. S., Crawford, G., Buang, N., Bartok, I., Tian, K., Thielens, N. M., Bally, I., Harker, J. A., Ashton-Rickardt, P. G., Rutschmann, S., Strid, J., Botto, M. C1q restrains autoimmunity and viral infection by regulating CD8+ T cell metabolism. Science 360: 558-563, 2018. [PubMed: 29724957] [Full Text: https://doi.org/10.1126/science.aao4555]
Petry, F., Berkel, A. I., Loos, M. Multiple identification of a particular type of hereditary C1q deficiency in the Turkish population: review of the cases and additional genetic and functional analysis. Hum. Genet. 100: 51-56, 1997. [PubMed: 9225968] [Full Text: https://doi.org/10.1007/s004390050464]
Petry, F., Le, D. T., Kirschfink, M., Loos, M. Non-sense and missense mutations in the structural genes of complement component C1qA and C chains are linked with two different types of complete selective C1q deficiencies. J. Immun. 155: 4734-4738, 1995. [PubMed: 7594474]
Reid, K. B. M. A collagen-like amino acid sequence in a polypeptide chain of human C1q (a subcomponent of the first component of complement). Biochem. J. 141: 189-203, 1974. [PubMed: 4375969] [Full Text: https://doi.org/10.1042/bj1410189]
Schejbel, L., Skattum, L., Hagelberg, S., Ahlin, A., Schiller, B., Berg, S., Genel, F., Truedsson, L., Garred, P. Molecular basis of hereditary C1q deficiency--revisited: identification of several novel disease-causing mutations. Genes Immun. 12: 626-634, 2011. [PubMed: 21654842] [Full Text: https://doi.org/10.1038/gene.2011.39]
Sellar, G. C., Blake, D. J., Reid, K. B. Characterization and organization of the genes encoding the A-, B-, and C-chains of human complement subcomponent C1q: the complete derived amino acid sequence of human C1q. Biochem. J. 274: 481-490, 1991. [PubMed: 1706597] [Full Text: https://doi.org/10.1042/bj2740481]
Sellar, G. C., Cockburn, D., Reid, K. B. M. Localization of the gene cluster encoding the A, B, and C chains of human C1q to 1p34.1-1p36.3. Immunogenetics 35: 214-216, 1992. [PubMed: 1537612] [Full Text: https://doi.org/10.1007/BF00185116]
Stevens, B., Allen, N. J., Vazquez, L. E., Howell, G. R., Christopherson, K. S., Nouri, N., Micheva, K. D., Mehalow, A. K., Huberman, A. D., Stafford, B., Sher, A., Litke, A. M., Lambris, J. D., Smith, S. J., John, S. W. M., Barres, B. A. The classical complement cascade mediates CNS synapse elimination. Cell 131: 1164-1178, 2007. [PubMed: 18083105] [Full Text: https://doi.org/10.1016/j.cell.2007.10.036]
Topaloglu, R., Bakkaloglu, A., Slingsby, J. H., Mihatsch, M. J., Pascual, M., Norsworthy, P., Morley, B. J., Saatci, U., Schifferli, J. A., Walport, M. J. Molecular basis of hereditary C1q deficiency associated with SLE and IgA nephropathy in a Turkish family. Kidney Int. 50: 635-642, 1996. [PubMed: 8840296] [Full Text: https://doi.org/10.1038/ki.1996.359]