Alternative titles; symbols
HGNC Approved Gene Symbol: C1QC
Cytogenetic location: 1p36.12 Genomic coordinates (GRCh38): 1:22,643,633-22,648,108 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.12 | C1q deficiency 3 | 620322 | Autosomal recessive | 3 |
C1q, the first subcomponent of C1, has a complicated 18-chain structure: 6 A, 6 B, and 6 C chains. Each chain has a stretch of about 80 amino acids with the collagenous triplet Gly-X-Y where X and Y can include hydroxyproline and hydroxylysine. The A (120550), B (120570), and C chains combine to form 6 heteromeric triple helices in the collagenous regions of the chains (Sellar et al., 1991).
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.
Sellar et al. (1991) found that the genes encoding the A, B, and C chains of human C1q are aligned, 5-prime to 3-prime, in the same orientation in the order A-C-B on a 24-kb stretch of DNA on chromosome 1p. 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).
The A- (120550), B- (120570), and C-chain C1q genes are approximately 2.5, 2.6, and 3.2 kb long, respectively, and each contains 1 intron located within a codon for a glycine residue found halfway along the collagen-like region present in each chain. These glycine residues are located just before the point where the triple-helical portions of the C1q molecule appear to bend when viewed by electron microscopy. Southern blot analysis showed that there is only one gene per chain.
In patients with C1q deficiency-3 (C1QD3; 620322), Slingsby et al. (1996) identified homozygous mutations in the C1QC gene (120575.0001-120575.0003).
In a 10-year-old boy from Kosova with C1q deficiency, Schejbel et al. (2011) identified a mutation in the C1QC gene (R69X; 120575.0002) that was previously reported by Slingsby et al. (1996).
In patients with C1QD3 from 2 racially distinct groups, Slingsby et al. (1996) and Kirschfink et al. (1993) described the same homozygous missense mutation in the C1QC gene (G6R; 120575.0004).
In a man from a Spanish family segregating C1QD3, previously described by Mampaso et al. (1981), Lopez-Lera et al. (2014) identified homozygosity for a missense mutation in the C1QC gene (G164S; 120575.0005).
In a patient with C1q deficiency (C1QD3; 620322), Slingsby et al. (1996) identified a homozygous deletion of a C nucleotide in codon 43 of the C1QC gene, resulting in a premature stop at codon 108.
In a patient with C1q deficiency-3 (C1QD3; 620322), Slingsby et al. (1996) identified homozygosity for a C-to-T transition the C1QC gene, resulting in an arg41-to-ter substitution and deletion of 176 amino acids. The patient had no detectable C1q protein.
In a 10-year-old boy from Kosova with C1QD3, Schejbel et al. (2011) identified the same mutation, which they reported as a g.8626C-T transition (NG_007565), resulting in an arg69-to-ter substitution.
In patients with C1Q deficiency (C1QD3; 620322) from 2 racially distinct groups, Slingsby et al. (1996) and Kirschfink et al. (1993) described the same homozygous point mutation: a G-A transition in the first base of the sixth codon in the C1QC gene, resulting in a gly6-to-arg (G6R) substitution.
In an affected 40-year-old man from a Spanish family segregating C1Q deficiency (C1QD3; 613642), previously described by Mampaso et al. (1981), Lopez-Lera et al. (2014) identified homozygosity for a c.490G-A transition in exon 3 of the C1QC gene, resulting in a gly164-to-ser (G164S) substitution.
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]
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]
Kirschfink, M., Petry, F., Khirwadkar, K., Wigand, R., Kaltwasser, J. P., Loos, M. Complete functional C1q deficiency associated with systemic lupus erythematosus (SLE). Clin. Exp. Immun. 94: 267-272, 1993. [PubMed: 7900940] [Full Text: https://doi.org/10.1111/j.1365-2249.1993.tb03442.x]
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]
Lopez-Lera, A., Torres-Canizales, J. M., Garrido, S., Morales, A., Lopez-Trascasa, M. Rothmund-Thomson syndrome and glomerulonephritis in a homozygous C1q-deficient patient due to a gly164ser C1qC mutation. (Letter) J. Invest. Derm. 134: 1152-1154, 2014. [PubMed: 24157463] [Full Text: https://doi.org/10.1038/jid.2013.444]
Mampaso, F., Ecija, J., Fogue, L., Moneo, I., Gallego, N., Leyva-Cobian, F. Familial C1q deficiency in 3 siblings with glomerulonephritis and Rothmund-Thomson syndrome. Nephron 28: 179-185, 1981. [PubMed: 7029321] [Full Text: https://doi.org/10.1159/000182170]
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]
Slingsby, J. H., Norsworthy, P., Pearce, G., Vaishnaw, A. K., Issler, H., Morley, B. J., Walport, M. J. Homozygous hereditary C1q deficiency and systemic lupus erythematosus: a new family and the molecular basis of C1q deficiency in three families. Arthritis Rheum. 39: 663-670, 1996. [PubMed: 8630118] [Full Text: https://doi.org/10.1002/art.1780390419]