Alternative titles; symbols
HGNC Approved Gene Symbol: C8B
Cytogenetic location: 1p32.2 Genomic coordinates (GRCh38): 1:56,929,207-56,966,015 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p32.2 | C8 deficiency, type II | 613789 | Autosomal recessive | 3 |
The eighth component of complement (C8) belongs to the late-acting complement proteins (C5-C9) forming the membrane attack complex. C8 is a serum protein that consists of 3 nonidentical subunits arranged asymmetrically as a disulfide-linked alpha-gamma dimer (C8A, 120950; C8G, 120930) and a noncovalently associated beta chain (C8B). Each component is encoded by a different gene (Ng et al., 1987; Kaufmann et al., 1993).
Herrmann et al. (1989) estimated the size of the C8B gene to be 32 to 36 kb.
By using PCR primers located in the adjacent intron sequences of C8B, Kaufmann et al. (1993) could amplify all 12 exons of the C8B gene from genomic DNA. These analyses and the insert sizes of the genomic lambda clones indicated that the C8B gene has a total size of approximately 40 kb.
The C8A and C8B genes are closely linked on chromosome 1p (Rogde et al., 1986).
Bahary et al. (1991) mapped the murine homolog of C8B to chromosome 4.
By direct sequence analysis of all exon-specific PCR products from normal and C8B-deficient persons, Kaufmann et al. (1993) found a single C-T change in exon 9 of the C8B gene, leading to a stop codon (R428X; 120960.0001). An allele-specific PCR system was designed to detect the normal and the deficiency allele simultaneously. Using this approach as well as PCR typing of the TaqI polymorphism located in intron 11, 5 families with 7 C8B-deficient members were investigated. The mutant allele was observed in all families investigated and could therefore be regarded as a major cause of C8B deficiency (C8D2; 613789) in Caucasians. In 2 C8B-deficient patients, only 1 chromosome carried the C-T change; the molecular nature of the other allele had not been determined.
In a study of 34 unrelated families with C8B deficiency from the U.S. and the former U.S.S.R., Saucedo et al. (1995) found that 59 (86%) of 69 null alleles were due to the C-to-T transition in exon 9. An additional 6 null alleles were caused by C-to-T transitions in exons 3 (120960.0003 and 120960.0004) and 6 (120960.0002). Two null alleles were caused by cytosine deletions in exons 3 (120960.0005) and 5 (120960.0006). Of the null alleles, 97% were C-to-T transitions in which an arg (64 alleles) or gln (1 allele) was replaced by a stop codon.
C8B Mutation Nomenclature
Using current recommendations for mutation nomenclature, Arnold et al. (2009) numbered nucleotides of the C8B gene starting at the A of the ATG translational start site of the coding reference sequence NM_000066. They noted that, traditionally, C8B nucleotides had been numbered starting at the 5-prime end of cDNA clone M16973. In their Table 2, Arnold et al. (2009) provided a comparison of the recommended mutation nomenclature used by them with the traditional mutation nomenclature used by others, including Kaufmann et al. (1993), Saucedo et al. (1995), and Rao et al. (2004), along with the corresponding protein changes.
In all 7 affected members of 5 Caucasian families segregating C8 deficiency (C8D2; 613789), Kaufmann et al. (1993) identified a C-to-T transition in exon 9 of the C8B gene, leading to the creation of a stop codon; CGA (arg) was changed to TGA (stop) at nucleotide position 1309. The codon involved was 374, according to Kaufmann (1993), resulting in an ARG374TER substitution. The authors noted that the mutation occurred at a CpG dinucleotide. Five patients were homozygous for the mutation; in 2 the mutation was found on only 1 chromosome and the other mutation was not identified.
In 2 patients with C8B deficiency from Switzerland and Poland, Rao et al. (2004) identified compound heterozygosity for the exon 9 C-T transition and another missense mutation in the C8B gene. The Swiss patient also had a 298C-T transition in exon 3 (Q91X; 120960.0004), and the Polish patient also had a 388C-T transition in exon 3 (R121X; 120960.0003).
In their Table 2, Arnold et al. (2009) reported that this mutation should be designated 1282C-T rather than 1309C-T. The correct amino acid substitution is arg428 to ter (R428X).
In a patient with C8 deficiency (C8D2; 613789), Saucedo et al. (1995) identified compound heterozygosity for the 1309C-T mutation (120960.0001) in exon 9 of the C8B gene and an 847C-T transition in exon 6.
In their Table 2, Arnold et al. (2009) reported that this mutation should be designated 820C-T rather than 847C-T. The resulting amino acid substitution is arg274 to ter (R274X).
Saucedo et al. (1995) identified 5 patients in 3 families with C8 deficiency (C8D2; 613789) who had a 388C-T transition in exon 3 of the C8B gene. The mutation was linked to a polymorphism at nucleotide 376 that accounts for an acidic allotype. Four of the patients were compound heterozygous for 388C-T and the 1309C-T mutation (120960.0001), and 1 patient was homozygous for 388C-T.
In a Polish patient with C8B deficiency, Rao et al. (2004) identified compound heterozygosity for the exon 9 C-T transition and the 388C-T transition in exon 3 of the C8B gene.
In their Table 2, Arnold et al. (2009) reported that this mutation should be designated 361C-T rather than 388C-T. The resulting amino acid substitution is arg121 to ter (R121X).
Saucedo et al. (1995) identified 4 sibs with C8 deficiency (C8D2; 613789) who were compound heterozygous for a 298C-T transition in exon 3 of the C8B gene and the 1309C-T mutation (120960.0001). In a Swiss patient with C8B deficiency, Rao et al. (2004) identified compound heterozygosity for the exon 9 C-T transition and a 298C-T transition in exon 3 of the C8B gene.
In their Table 2, Arnold et al. (2009) reported that this mutation should be designated 271C-T rather than 298C-T. The resulting amino acid substitution is gln91 to ter (Q121X).
In a British male with recurrent meningococcal disease and C8B deficiency, Arnold et al. (2009) identified compound heterozygosity for the 271C-T mutation and a duplication of nucleotides 1047 to 1053 (GGCTGTG) in exon 7 (120960.0007) of the C8B gene.
Saucedo et al. (1995) identified 2 sibs with C8 deficiency (C8D2; 613789) who were compound heterozygous for 2 frameshift mutations in the C8B gene: a cytosine deletion at nucleotide 363 in exon 3 and a cytosine deletion at nucleotide 632 in exon 5 (120960.0006). Both mutations resulted in premature protein termination.
In their Table 2, Arnold et al. (2009) reported that these cytosine deletions should be designated as occurring at nucleotides 336 and 605 rather than at nucleotides 363 and 632, respectively.
For discussion of the 1-bp deletion in the C8B gene (605delC) that was found in compound heterozygous state in patients with C8 deficiency (C8D2; 613789) by Saucedo et al. (1995), see 120960.0005.
In a British male with recurrent meningococcal disease and C8B deficiency (C8D2; 613789), Arnold et al. (2009) identified a duplication of nucleotides 1047 to 1053 (GGCTGTG) in exon 7 of the C8B gene. The mutation introduced a frameshift that resulted in premature termination. The patient was compound heterozygous for the 271C-T mutation (Q91X; 120960.0004) in C8B.
Arnold, D. F., Roberts, A. G., Thomas, A., Ferry, B., Morgan, B. P., Chapel, H. A novel mutation in a patient with a deficiency of the eighth component of complement associated with recurrent meningococcal meningitis. J. Clin. Immun. 29: 691-695, 2009. [PubMed: 19434484] [Full Text: https://doi.org/10.1007/s10875-009-9295-7]
Bahary, N., Zorich, G., Pachter, J. E., Leibel, R. L., Friedman, J. M. Molecular genetic linkage maps of mouse chromosomes 4 and 6. Genomics 11: 33-47, 1991. [PubMed: 1684952] [Full Text: https://doi.org/10.1016/0888-7543(91)90099-z]
Herrmann, D., Sodetz, J. M., Rittner, C., Schneider, P. M. DNA polymorphism of the human complement C8B gene: formal genetics and intragenic localization. Immunogenetics 30: 291-295, 1989. [PubMed: 2571588] [Full Text: https://doi.org/10.1007/BF02421333]
Kaufmann, T., Hansch, G., Rittner, C., Spath, P., Tedesco, F., Schneider, P. M. Genetic basis of human complement C8-beta deficiency. J. Immun. 150: 4943-4947, 1993. [PubMed: 8098723]
Kaufmann, T., Rittner, C., Schneider, P. M. The human complement component C8B gene: structure and phylogenetic relationship. Hum. Genet. 92: 69-75, 1993. [PubMed: 8365729] [Full Text: https://doi.org/10.1007/BF00216147]
Kaufmann, T. Personal Communication. Mainz, Germany 7/14/1993.
Ng, S. C., Rao, A. G., Howard, O. M. Z., Sodetz, J. M. The eighth component of human complement: evidence that it is an oligomeric serum protein assembled from products of three different genes. Biochemistry 26: 5229-5233, 1987. [PubMed: 3676249] [Full Text: https://doi.org/10.1021/bi00391a003]
Rao, L., Li, Y., Chen, G., Zhou, B., Schneider, P. M., Zhang, L. Further study on heterogeneic basis of complement C8-beta deficiency. Chin. J. Med. Genet. 21: 10-13, 2004.
Rogde, S., Olaisen, B., Gedde-Dahl, T., Jr., Teisberg, P. The C8A and C8B loci are closely linked on chromosome 1. Ann. Hum. Genet. 50: 139-144, 1986. [PubMed: 3435043] [Full Text: https://doi.org/10.1111/j.1469-1809.1986.tb01032.x]
Saucedo, L., Ackermann, L., Platonov, A. E., Gewurz, A., Rakita, R. M., Densen, P. Delineation of additional genetic bases for C8-beta deficiency: prevalence of null alleles and predominance of C-to-T transition in their genesis. J. Immun. 155: 5022-5028, 1995. [PubMed: 7594510]