HGNC Approved Gene Symbol: C9
Cytogenetic location: 5p13.1 Genomic coordinates (GRCh38): 5:39,284,140-39,364,495 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5p13.1 | {Macular degeneration, age-related, 15, susceptibility to} | 615591 | Autosomal dominant | 3 |
| C9 deficiency | 613825 | 3 |
Activation of the complement system results in formation of the membrane attack complex (MAC) on the membranes of target cells. The complex is assembled by sequential addition of 1 molecule each of C5b (120900), C6 (217050), C7 (217070), and C8 (see 120950) and 6 to 16 molecules of the ninth component, C9. MAC assembly results in membrane disruption, leading to death of the target cell (summary by DiScipio et al., 1984).
DiScipio et al. (1984) screened a human liver cDNA library by the colony-hybridization technique using 2 radiolabelled oligonucleotide probes corresponding to regions of the C9 amino acid sequence. The cDNA coding for C9 was sequenced. The derived protein consists of 537 amino acids in a single polypeptide chain. The N-terminal half of C9 is predominantly hydrophilic, whereas the C-terminal half is more hydrophobic. The amphipathic organization of the primary structure is consistent with the potential of polymerized C9 to penetrate lipid bilayers and cause the formation of transmembrane channels as part of the lytic action of MAC.
Marazziti et al. (1988) compared the protein structure of C9 with that of low density lipoprotein receptor (LDLR; 606945).
Marazziti et al. (1988) compared the gene structure of C9 with that of LDLR (606945). The C9 gene contains 11 exons with lengths of 100 to 250 bp, except for exon 11, which includes the 3-prime UTR and extends over more than 1 kb. Witzel-Schlomp et al. (1997) gave revised information on the structure of the C9 gene, especially the exon-intron boundaries.
By hybridizing a cloned cDNA coding for human complement factor C9 to hybrid cells containing subsets of human chromosomes on a rodent background, Rogne et al. (1989) localized the gene for C9 to chromosome 5. Abbott et al. (1989) used a novel application of PCR to amplify specifically the human C9 gene on a background of rodent DNA in somatic cell hybrids. The assignment of the gene to 5p13 was confirmed and regionalized by in situ hybridization.
Coto et al. (1991) identified RFLPs for the C6, C7, and C9 loci and showed that these 3 loci are tightly linked. When examining the haplotypes of unrelated parents in their family study, they found significant linkage disequilibrium between C6 and C7 and between C7 and C9. Thus, the so-called terminal complement components are encoded by a cluster of genes. Coto et al. (1991) suggested that this cluster be referred to as MACII, MACI being the C8A (120950) and C8B (120960) cluster. Rogne et al. (1991) used DNA polymorphism of C9 and protein variants of C6 to show that the 2 genes are closely linked (maximum lod = 9.28 at theta = 0.00). They found no indication of allelic association. Setien et al. (1993) found that although the C6 and C7 genes are contained in the same NotI fragment of 500 kb, no evidence of physical linkage between C9 and C6 or C7 could be found in a range 50 kb to 2.5 Mb.
C9 Deficiency
In members of a Swiss family with C9 deficiency (C9D; 613825), originally reported by Zoppi et al. (1990), Witzel-Schlomp et al. (1997) identified compound heterozygous mutations in the C9 gene (C33X, 120940.0002 and R133X, 120940.0007).
Horiuchi et al. (1998) reported the molecular basis for C9 deficiency in 10 unrelated Japanese individuals. By use of exon-specific PCR/single-strand conformation polymorphism analysis, they demonstrated aberrantly migrating DNA bands in all 10 individuals. Subsequent direct sequencing of exon 4 revealed that 8 of the 10 were homozygous for an arg95-to-ter (R95X; 120940.0001) substitution in the C9 gene. Family study for 1 of these individuals confirmed the genetic nature of the defect. The remaining 2 individuals with C9 deficiency were heterozygous for the R95X mutation; one of these individuals also carried a cys507-to-tyr (C507Y; 120940.0005) mutation, whereas the genetic defect in the other allele of the other individual was not identified.
Witzel-Schlomp et al. (1998) studied the genetic basis of inherited C9 deficiency in an adult of Irish origin reported previously by Hobart et al. (1997) and in an unrelated Irish family in which 1 member had died at the age of 22 years of meningitis, probably meningococcal. In the first patient, heterozygosity for C6, C7, and C9 DNA markers was found, indicating probable compound heterozygosity of the C9 mutations. Two previously identified C9 mutations were found: C33X and R95X. Two novel C9 mutations were detected in the second Irish family: C98G (120940.0003) and S406X (120940.0004)
Ichikawa et al. (2001) reported a 28-year-old Japanese woman with C9 deficiency and dermatomyositis. DNA sequence analysis revealed the R95X mutation of the C9 gene. This case demonstrated that the muscle lesions of dermatomyositis can occur in the presence of a complement defect that would prevent the formation of the C5b-9 membrane attack complex.
Age-Related Macular Degeneration 15
Seddon et al. (2013) sequenced the exons of 681 genes within all reported age-related macular degeneration (ARMD) loci and related pathways in 2,493 cases. They genotyped 5,115 independent samples and confirmed association with ARMD (ARMD15; 615591) of an allele in the C9 gene encoding a pro167-to-ser variant (P167S; 120940.0006).
In 4 affected individuals from a family with ARMD, Ratnapriya et al. (2020) identified heterozygosity for the previously reported P167S mutation in the C9 gene. A metaanalysis of rare variants in 3,519 ARMD patients and 3,754 controls suggested a burden of rare variants in the C9 gene (p = 0.024).
Horiuchi et al. (1998) found that 8 of 10 unrelated Japanese subjects with C9 deficiency (C9D; 613825) were homozygous for a C-to-T transition at nucleotide 343, which converted codon 95 from CGA (arg) to TGA (stop). Two other patients were heterozygous for the R95X mutation; one of these had a C507Y (120940.0005) substitution, while the genetic defect in the other allele of the other patient remained unknown.
Kira et al. (1998) likewise found that all 4 Japanese C9-deficient patients who had suffered from meningococcal meningitis had this CGA (arg)-to-TGA (stop) mutation.
Ichikawa et al. (2001) found this mutation in a 28-year-old Japanese woman with C9 deficiency and dermatomyositis. Whereas levels of serum hemolytic complement (CH50) are characteristically normal or elevated in patients with dermatomyositis, this patient showed markedly depressed levels of CH50. This case demonstrated that the muscle lesions of dermatomyositis can occur in the presence of a complement defect that would prevent the formation of the C5b-9 membrane attack complex.
The R95X mutation is responsible for most Japanese C9 deficiency cases, with a carrier frequency of 6.7%. Khajoee et al. (2003) showed that in Koreans and Chinese, the R95X carrier frequencies were 2.0% and 1.0%, respectively. The founder effect found in East Asians (Japanese, Koreans, and Chinese) but not in Caucasians, as well as the haplotype sharing in only a small chromosomal region, suggested that the R95X mutation is ancient and occurred after the divergence of East Asians and Caucasians, and before migration of the Yayoi people to Japan. Because the mortality of meningococcal infections in complement-deficient patients is lower than that in normal individuals, a founder effect and a selective advantage in isolation might be the main reasons for the high frequency of the R95X mutation in Japan.
In affected members of a Swiss family with C9 deficiency (C9D; 613825), originally reported by Zoppi et al. (1990), Witzel-Schlomp et al. (1997) found compound heterozygosity for mutations in the C9 gene: a 166C-A transversion in exon 2, resulting in a cys33-to-ter (C33X) substitution, and a 464T-C transition in exon 4, resulting in an arg133-to-ter (R133X; 120940.0007) substitution.
In an adult of Irish origin with C9 deficiency, originally reported by Hobart et al. (1997), Witzel-Schlomp et al. (1998) identified compound heterozygosity for the C33X mutation and the R95X mutation (120940.0001) in the C9 gene.
In an Irish family (family Y) with C9 deficiency (C9D; 613825), Witzel-Schlomp et al. (1998) found compound heterozygosity for mutations in the C9 gene: a 359T-G transversion in exon 4, resulting in a cys98-to-gly (C98G) substitution, and a 1284C-G transversion in exon 9, resulting in a ser406-to-ter (S406X; 120940.0004) substitution.
For discussion of the ser406-to-ter (S406X) mutation in the C9 gene that was found in compound heterozygous state in patients with C9 deficiency (C9D; 613825) by Witzel-Schlomp et al. (1998), see 120940.0003.
For discussion of the cys507-to-tyr (C507Y) mutation in the C9 gene that was found in compound heterozygous state in a patient with C9 deficiency (C9D; 613825) by Horiuchi et al. (1998), see 120940.0001.
Seddon et al. (2013) found an increased risk of age-related macular degeneration (ARMD15; 615591) among individuals carrying a pro167-to-ser (P167S) mutation in the C9 gene (rs34882957), with a joint p value of 6.5 x 10(-7) and an odds ratio of 2.2.
In 3 affected sisters and the affected daughter of 1 of the sisters from a family (W11-4035) with ARMD, Ratnapriya et al. (2020) identified heterozygosity for a c.499C-T transition in exon 5 of the C9 gene, resulting in the P167S substitution. The variant was present at low minor allele frequency (0.0066) in the ExAC database. Familial segregation was not reported.
For discussion of the arg133-to-ter (R133X) mutation in the C9 gene that was found in compound heterozygous state in patients with C9 deficiency (C9D; 613825) by Witzel-Schlomp et al. (1997), see 120940.0002.
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