Alternative titles; symbols
HGNC Approved Gene Symbol: C1S
Cytogenetic location: 12p13.31 Genomic coordinates (GRCh38): 12:7,060,718-7,071,032 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p13.31 | C1s deficiency | 613783 | 3 | |
| Ehlers-Danlos syndrome, periodontal type, 2 | 617174 | Autosomal dominant | 3 |
MacKinnon et al. (1987) derived the complete amino acid sequence of C1s from molecular cloning of cDNA. Tosi et al. (1987) presented the complete cDNA sequence of C1s. Kusumoto et al. (1988) found that the amino acid sequence of C1s was 40.5% identical to that of C1r (216950), with excellent matches of tentative disulfide bond locations conserving the overall domain structure of C1r.
By means of a cDNA in somatic cell hybrids, Cohen-Haguenauer et al. (1986) assigned the C1S and C1R (216950) genes to chromosome 12.
Leppert et al. (1987) found a maximum lod score of 5.99 at theta = 0.038 for linkage between C1S and one of the PRP loci (see 168710); the maximum lod score between C1R and another PRP locus was 4.21 at theta = 0.001. Although C1r and C1s are structurally and functionally similar, with a significant degree of sequence homology suggesting origin by gene duplication, cDNA probes for human C1r and C1s do not cross-hybridize even at mild stringency conditions and are therefore gene-specific.
Using a panel of human-rodent cell hybrids, Nguyen et al. (1988) independently assigned the C1r and C1s genes to chromosome 12. In situ hybridization confirmed these assignments and localized the genes to 12p13.
By hybridization of C1r and C1s probes to restriction endonuclease fragments of genomic DNA, Tosi et al. (1987) demonstrated close physical linkage of the genes. This finding was consistent with their evolution through tandem gene duplication and was also consistent with the previously observed combined hereditary deficiencies of C1r and C1s (see 216950). Their coordinate expression may depend on the close linkage. The 2 genes lie in a DNA stretch not longer than 50 kb.
By DNA blotting and sequencing analyses of genomic DNA and of an isolated genomic DNA clone, Kusumoto et al. (1988) showed that the C1r and C1s genes are closely located in a 'tail-to-tail' arrangement at a distance of about 9.5 kb.
Complement Component C1s Deficiency
Inoue et al. (1998) reported a patient with systemic lupus erythematosus-like syndrome and chronic glomerulonephritis who had selective C1s deficiency (613783) resulting from a homozygous mutation in the C1S gene (120580.0001).
In a 27-month-old girl with multiple autoimmune diseases, Dragon-Durey et al. (2001) detected selective C1S deficiency (613783) resulting from a homozygous nonsense mutation in exon 12 of the C1S gene (120580.0002).
Ehlers-Danlos Syndrome, Periodontal Type, 2
In 2 unrelated families with the periodontal type of Ehlers-Danlos syndrome (EDSPD2; 617174), Kapferer-Seebacher et al. (2016) identified heterozygosity for a missense mutation and an in-frame deletion in the C1S gene (120580.0003 and 120580.0004). The mutations segregated with disease in the families and neither was found in the ExAC, 1000 Genomes Project, ClinVar, or dbSNP (March 2016) databases. The authors stated that the mutations appeared to have gain-of-function effects.
In a patient with systemic lupus erythematosus-like syndrome and chronic glomerulonephritis, Inoue et al. (1998) reported the molecular basis of selective C1s deficiency (613783). No C1s protein was detectable by immunoblot. By Northern blot and RT-PCR analysis, C1s mRNA was of appropriate size, but only 10% of the level detected in HCS2/8, a human chondrosarcoma cell line. Levels of beta-actin and C1r mRNA were similar to levels detected in HCS2/8. The patient was homozygous for a 4-bp deletion in exon 10 of the C1S gene, 1087-1090delTTTG. This deletion resulted in a premature termination codon 94 bp downstream.
In a 27-month-old girl with multiple autoimmune diseases, Dragon-Durey et al. (2001) determined that an absence of plasma C1s (613783) accounted for a lack of classic complement (CH50) pathway activity. Microsatellite and sequence analyses revealed a C-to-T transition in codon 534 in exon 12 of the C1S gene, resulting in an arg-to-ter substitution and premature termination. DNA analysis indicated that both parents were heterozygous for the mutation. Restriction enzyme analysis showed that the propositus was homozygous for the mutation, while a paternal grandmother, maternal grandfather, and aunts on both sides of the family were heterozygous. The mutation was not detected in systemic lupus erythematosus (152700) patients or unrelated Caucasian controls, including some from the same geographic region. At age 5, the child was alive and well while receiving immunosuppressive drugs daily and penicillin.
In 5 affected members of a 3-generation family (family 16) with the periodontal type of Ehlers-Danlos syndrome (EDSPD2; 617174), Kapferer-Seebacher et al. (2016) identified heterozygosity for a c.880T-C transition (c.880T-C, NM_201442.2) in the C1S gene, resulting in a cys294-to-arg substitution (cys279-to-arg (C279R) in the mature protein) within the Sushi CCP1. The mutation segregated with disease in the family and was not found in the ExAC, 1000 Genomes Project, ClinVar, or dbSNP (March 2016) databases.
In 4 affected members of a large 5-generation family (family 17) with the periodontal type of Ehlers-Danlos syndrome (EDSPD2; 617174), Kapferer-Seebacher et al. (2016) identified heterozygosity for an in-frame 3-bp deletion (c.945_947del, NM_201442.2) in the C1S gene, resulting in deletion of an amino acid residue (Val316del, or Val301 in the mature protein). The mutation was not found in the ExAC, 1000 Genomes Project, ClinVar, or dbSNP (March 2016) databases.
Cohen-Haguenauer, O., Serero, S., Tosi, M., Van Cong, N., Stubnicer, A.-C., de Tand, M.-F., Meo, T., Frezal, J. Chromosomal assignment of human C1R, C1S genes on chromosome 12 and C1 inhibitor gene on chromosome 11. (Abstract) 7th International Congress of Human Genetics, Berlin 1986. P. 617.
Dragon-Durey, M.-A., Quartier, P., Fremeaux-Bacchi, V., Blouin, J., de Barace, C., Prieur, A.-M., Weiss, L., Fridman, W.-H. Molecular basis of a selective C1s deficiency associated with early onset multiple autoimmune diseases. J. Immun. 166: 7612-7616, 2001. [PubMed: 11390518] [Full Text: https://doi.org/10.4049/jimmunol.166.12.7612]
Inoue, N., Saito, T., Masuda, R., Suzuki, Y., Ohtomi, M., Sakiyama, H. Selective complement C1s deficiency caused by homozygous four-base deletion in the C1s gene. Hum. Genet. 103: 415-418, 1998. [PubMed: 9856483] [Full Text: https://doi.org/10.1007/s004390050843]
Kapferer-Seebacher, I., Pepin, M., Werner, R., Aitman, T. J., Nordgren, A., Stoiber, H., Thielens, N., Gaboriaud, C., Amberger, A., Schossig, A., Gruber, R., Giunta, C., and 28 others. Periodontal Ehlers-Danlos syndrome is caused by mutations in C1R and C1S, which encode subcomponents C1r and C1s of complement. Am. J. Hum. Genet. 99: 1005-1014, 2016. [PubMed: 27745832] [Full Text: https://doi.org/10.1016/j.ajhg.2016.08.019]
Kusumoto, H., Hirosawa, S., Salier, J. P., Hagen, F. S., Kurachi, K. Human genes for complement components C1r and C1s in a close tail-to-tail arrangement. Proc. Nat. Acad. Sci. 85: 7307-7311, 1988. [PubMed: 2459702] [Full Text: https://doi.org/10.1073/pnas.85.19.7307]
Leppert, M., Ferrell, R., Kamboh, M. I., Beasley, J., O'Connell, P., Lathrop, M., Lalouel, J. M., White, R. Linkage of the polymorphic protein markers F13B, C1S, C1R, and blood group antigen Kidd in CEPH reference families. (Abstract) Cytogenet. Cell Genet. 46: 647 only, 1987.
MacKinnon, C. M., Carter, P. E., Smyth, S. J., Dunbar, B., Fothergill, J. E. Molecular cloning of cDNA for human complement component C1s: the complete amino acid sequence. Europ. J. Biochem. 169: 547-553, 1987. [PubMed: 3500856] [Full Text: https://doi.org/10.1111/j.1432-1033.1987.tb13644.x]
Nguyen, V. C., Tosi, M., Gross, M. S., Cohen-Haguenauer, O., Jegou-Foubert, C., de Tand, M. F., Meo, T., Frezal, J. Assignment of the complement serine protease genes C1r and C1s to chromosome 12 region 12p13. Hum. Genet. 78: 363-368, 1988. [PubMed: 2834284] [Full Text: https://doi.org/10.1007/BF00291737]
Tosi, M., Duponchel, C., Meo, T., Julier, C. Complete cDNA sequence of human complement C1s and close physical linkage of the homologous genes C1s and C1r. Biochemistry 26: 8516-8524, 1987. [PubMed: 2831944] [Full Text: https://doi.org/10.1021/bi00400a004]