Alternative titles; symbols
HGNC Approved Gene Symbol: C1R
Cytogenetic location: 12p13.31 Genomic coordinates (GRCh38) : 12:7,080,219-7,092,445 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p13.31 | Ehlers-Danlos syndrome, periodontal type, 1 | 130080 | Autosomal dominant | 3 |
The complement system is a major mediator of innate immunity. The first enzymatic event in the cascade of the classical pathway of complement is the activation of its first component, C1. C1 is a multimolecular complex consisting of 2 loosely interacting entities: C1q (see 120550), the recognition subunit, and C1r(2)/C1s(2), the catalytic one. C1r(2)/C1s(2) is a tetrameric Ca(2+)-dependent complex of C1r and C1s (120580), 2 serine-proteinase zymogens. C1r acts by transforming the activation signal (the fixation of C1q on activating reagents, e.g., immune complexes) into an enzymic activity (summary by Journet and Tosi, 1986).
Leytus et al. (1986) reported the nucleotide sequence for cDNA coding for C1r. Journet and Tosi (1986) cloned and sequenced a full-length cDNA for the C1r precursor, which contains a 17-amino acid leader peptide, followed by a mature 688-amino acid protein.
By means of a cDNA in somatic cell hybrids, Cohen-Haguenauer et al. (1986) assigned the C1R and C1S 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.
In a study of 5 families heterozygous at both the C1R and the C1S locus, Lyons et al. (1989) found evidence consistent with, but not proving, linkage of the loci; maximum lod score = 1.505 at theta = 0.00.
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.
Kamboh and Ferrell (1986) demonstrated genetic polymorphism of C1R using the high-resolving power of isoelectric focusing in 6M urea followed by immunoblotting. Kamboh et al. (1988) described a new allele by isoelectric focusing and immunoblotting. Using the same methods, Kamboh et al. (1989) described 5 new alleles.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Ehlers-Danlos Syndrome, Periodontal Type, 1
In affected members of 15 unrelated families with the periodontal type of Ehlers-Danlos syndrome (EDSPD1; 130080), Kapferer-Seebacher et al. (2016) identified heterozygosity for missense or in-frame insertion/deletion mutations in the C1R gene (see, e.g., 613785.0001-613785.0007). The mutations segregated with disease in the families and none of the mutations were 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 large 5-generation Austrian family (family 1) with the periodontal type of Ehlers-Danlos syndrome (EDSPD1; 130080), Kapferer-Seebacher et al. (2016) identified heterozygosity for a c.149_150TC-AT change (c.149_150TC-AT, NM_001733.4) in the C1R gene, resulting in a val50-to-asp substitution (val32-to-asp (V32D) in the mature protein) at an evolutionarily conserved residue within the CUB1 collagen-binding domain. The mutation segregated fully with disease in the family, and was not found in the ExAC, 1000 Genomes Project, ClinVar, or dbSNP (March 2016) databases. Western blots of HEK293 cells and supernatants in which V50D had been overexpressed indicated that the abnormal C1R protein was retained in the cell but could undergo autoactivation that might lead to interaction with off-target substrates. In addition, mutation-transfected cells showed an increased proportion of dilated cisternae of the rough endoplasmic reticulum compared to controls. Kapferer-Seebacher et al. (2016) noted that unlike previously reported families with EDSPD, none of the affected individuals in this family exhibited pretibial discoloration.
In the proband from a family (family 11) with the periodontal type of Ehlers-Danlos syndrome (EDSPD1; 130080) that was originally reported by Stewart et al. (1977), Kapferer-Seebacher et al. (2016) identified heterozygosity for a c.1073G-T transversion (c.1073G-T, NM_001733.4) in the C1R gene, resulting in a cys358-to-phe substitution (cys340-to-phe (C340F) in the mature protein) within the Sushi CCP1 domain. The mutation was not found in the ExAC, 1000 Genomes Project, ClinVar, or dbSNP (March 2016) databases.
In the probands from 2 unrelated families (families 8 and 9) with the periodontal type of Ehlers-Danlos syndrome (EDSPD1; 130080), 1 of which was previously reported by Hartsfield and Kousseff (1990), Kapferer-Seebacher et al. (2016) identified heterozygosity for a c.927C-G transversion (c.927C-G, NM_001733.4) in the C1R gene, resulting in a cys309-to-trp substitution (cys291-to-trp (C291W) in the mature protein) within the Sushi CCP1 domain. The mutation segregated with disease in the family for which DNA was available from family members and was not found in the ExAC, 1000 Genomes Project, ClinVar, or dbSNP (March 2016) databases. Western blots of HEK293 cells and supernatants in which C309W had been overexpressed indicated that the abnormal C1R protein was retained in the cell but could undergo autoactivation that might lead to interaction with off-target substrates. In addition, mutation-transfected cells showed an increased proportion of dilated cisternae of the rough endoplasmic reticulum compared to controls.
In the proband from a 5-generation Swedish family (family 5) with the periodontal type of Ehlers-Danlos syndrome (EDSPD1; 130080), previously studied by Rahman et al. (2003), Kapferer-Seebacher et al. (2016) identified heterozygosity for a c.902G-C transversion (c.902G-C, NM_001733.4) in the C1R gene, resulting in an arg301-to-pro substitution (arg283-to-pr0 (R301P) in the mature protein) at an evolutionarily conserved residue within the CUB2 domain. The mutation was not found in the ExAC, 1000 Genomes Project, ClinVar, or dbSNP (March 2016) databases.
In a 7-year-old girl, her father, and paternal grandfather (family 4), who had the periodontal type of Ehlers-Danlos syndrome (EDSPD1; 130080) and were previously studied by Reinstein et al. (2013), Kapferer-Seebacher et al. (2016) identified heterozygosity for a c.899T-C transition (c.899 T-C, NM_001733.4) in the C1R gene, resulting in a leu300-to-pro substitution (leu282-to-pro (L300P) in the mature protein) at an evolutionarily conserved residue within the CUB2 domain. The mutation, which was not found in the ExAC, 1000 Genomes Project, ClinVar, or dbSNP (March 2016) databases, was also not detected in the paternal great-grandfather, who exhibited the dental features of periodontal EDS but no skin or joint findings; Kapferer-Seebacher et al. (2016) concluded that the mutation occurred de novo in the grandfather or was mosaic in the great-grandfather.
In a 42-year-old woman (family 7) with the periodontal type of Ehlers-Danlos syndrome (EDSPD1; 130080), previously reported by Cikla et al. (2014), Kapferer-Seebacher et al. (2016) identified heterozygosity for an in-frame deletion/insertion mutation (c.917_927delinsGGACA, NM_001733.4) in the C1R gene, predicted to result in an Ile306_Cys309del/insArgArg change (Ile288_Cys291del/insArgArg in the mature protein) within the Sushi CCP1 domain. The mutation was not found in the ExAC, 1000 Genomes Project, ClinVar, or dbSNP (March 2016) databases. The proband died of cerebral hemorrhage from an aneurysm of the left middle cerebral artery.
In a 33-year-old woman (family 2) with the periodontal type of Ehlers-Danlos syndrome (EDSPD1; 130080), previously reported by George et al. (2016), Kapferer-Seebacher et al. (2016) identified heterozygosity for a c.869A-G transition (c.869A-G, NM_001733.4) in the C1R gene, resulting in an asp290-to-gly substitution (asp272-gly (D272G) in the mature protein) within the C1q binding site. The mutation was not found in the ExAC, 1000 Genomes Project, ClinVar, or dbSNP (March 2016) databases. The patient exhibited an acrogeric facial appearance and had chronic hoarseness due to cricoarytenoid fibrosis.
Cikla, U., Sadighi, A., Bauer, A., Baskaya, M. K. Fatal ruptured blood blister-like aneurysm of middle cerebral artery associated with Ehlers-Danlos syndrome type VIII (periodontitis type). J. Neurol. Surg. Rep. 75: e210-e213, 2014. Note: Electronic Article. [PubMed: 25485215] [Full Text: https://doi.org/10.1055/s-0034-1387185]
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.
George, S. M. C., Vandersteen, A., Nigar, E., Ferguson, D. J. P., Topham, E. J., Pope, F. M. Two patients with Ehlers-Danlos syndrome type VIII with unexpected hoarseness. Clin. Exp. Derm. 41: 771-774, 2016. [PubMed: 27663155] [Full Text: https://doi.org/10.1111/ced.12911]
Hartsfield, J. K., Jr., Kousseff, B. G. Phenotypic overlap of Ehlers-Danlos syndrome types IV and VIII. Am. J. Med. Genet. 37: 465-470, 1990. [PubMed: 2260589] [Full Text: https://doi.org/10.1002/ajmg.1320370408]
Journet, A., Tosi, M. Cloning and sequencing of full-length cDNA encoding the precursor of human complement component C1r. Biochem. J. 240: 783-787, 1986. [PubMed: 3030286] [Full Text: https://doi.org/10.1042/bj2400783]
Kamboh, M. I., Ferrell, R. E. Genetic studies of low abundance human plasma proteins. III. Polymorphism of the C1R subcomponent of the first complement component. Am. J. Hum. Genet. 39: 826-831, 1986. [PubMed: 3026176]
Kamboh, M. I., Lyons, L. A., Ferrell, R. E. Genetic studies of low-abundance human plasma proteins. XIII. Population genetics of C1R complement subcomponent and description of new variants. Am. J. Hum. Genet. 44: 148-153, 1989. [PubMed: 2535773]
Kamboh, M. I., Lyons, L., Ferrell, R. E. Genetic studies of low-abundance human plasma proteins. IX. A new allele at the complement subcomponent C1R structural locus. Hum. Genet. 81: 93-94, 1988. [PubMed: 3198132] [Full Text: https://doi.org/10.1007/BF00283738]
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.
Leytus, S. P., Kurachi, K., Sakariassen, K. S., Davie, E. W. Nucleotide sequence of the cDNA coding for human complement C1r. Biochemistry 25: 4855-4863, 1986. [PubMed: 3021205] [Full Text: https://doi.org/10.1021/bi00365a020]
Lyons, L. A., Kamboh, M. I., Ferrell, R. E. Genetic studies of low-abundance human plasma proteins. XI. Linkage analysis and population genetics of the C1S subcomponent of the first complement component. Complement Inflamm. 6: 81-87, 1989. [PubMed: 2541966] [Full Text: https://doi.org/10.1159/000463078]
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]
Rahman, N., Dunstan, M., Teare, M. D., Hanks, S., Douglas, J., Coleman, K., Bottomly, W. E., Campbell, M. E., Berglund, B., Nordenskjold, M., Forssell, B., Burrows, N., Lunt, P., Young, I., Williams, N., Bignell, G. R., Futreal, P. A., Pope, F. M. Ehlers-Danlos syndrome with severe early-onset periodontal disease (EDS-VIII) is a distinct, heterogeneous disorder with one predisposition gene at chromosome 12p13. Am. J. Hum. Genet. 73: 198-204, 2003. [PubMed: 12776252] [Full Text: https://doi.org/10.1086/376416]
Reinstein, E., DeLozier, C. D., Simon, Z., Bannykh, S., Rimoin, D. L., Curry, C. J. Ehlers-Danlos syndrome type VIII is clinically heterogeneous disorder associated primarily with periodontal disease, and variable connective tissue features. Europ. J. Hum. Genet. 21: 233-236, 2013. [PubMed: 22739343] [Full Text: https://doi.org/10.1038/ejhg.2012.132]
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
Stewart, R. E., Hollister, D. W., Rimoin, D. L. A new variant of Ehlers-Danlos syndrome: an autosomal dominant disorder of fragile skin, abnormal scarring, and generalized periodontosis. Birth Defects Orig. Art. Ser. XIII(3B): 85-93, 1977. [PubMed: 890102]
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]