Complement Component 9 Deficiency
A number sign (#) is used with this entry because complement component-9 deficiency (C9D) is caused by homozygous or compound heterozygous mutation in the C9 gene (120940) on chromosome 5p13.
Clinical FeaturesLint et al. (1980) reported C9 deficiency in a Caucasian family.
Kusaba et al. (1983) reported a large family with hereditary deficiency of C9. The proposita was a 64-year-old Japanese woman with gastric cancer. C9 was not detectable by either rocket immunoelectrophoresis or hemolytic assay. C9 was also undetectable in 2 healthy sisters. Levels presumably indicative of heterozygosity (22 to 46% of normal) were found in 8 males and 7 females from 3 generations of the family. One instance of male-to-male transmission was found, and all offspring of homozygotes tested had heterozygous levels. No liability to specific disease was detected in any. This appeared to be the ninth family with C9 deficiency reported from Japan.
Yonemura et al. (1990) found that deficiency of C9 tempered the clinical manifestations, specifically hemolysis, in a woman who also had paroxysmal nocturnal hemoglobinuria.
MappingC9 deficiency results from mutation in the C9 gene, which was mapped to chromosome 5p13 by Abbott et al. (1989).
Molecular GeneticsC9 Deficiency
Witzel-Schlomp et al. (1997) described 2 mutations of the C9 gene, present in compound heterozygote state, in members of a Swiss family with C9 deficiency reported by Zoppi et al. (1990).
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 a C-to-T transition at nucleotide 343 of the C9 gene, resulting in an arg95-to-ter (R95X; 120940.0001) substitution. 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 was compound heterozygous for R95X and a cys507-to-tyr (C507Y; 120940.0005) mutation, whereas the genetic defect(s) in the other allele in the second heterozygous 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 case, heterozygosity for C6, C7, and C9 DNA markers was found, indicating probable compound heterozygosity of the C9 mutations. One mutation was the same as one of those observed in the Swiss family of Zoppi et al. (1990) (120940.0002). The second C9 mutation, a C-to-T transition, was found in exon 4 at cDNA position 350, resulting in R95X. Two different mutations were detected in the second Irish family: a C-to-G transversion in exon 9 creating a TGA stop codon, located at cDNA nucleotide 1284 (S406X; 120940.0004), and a T-to-G change in exon 4, cDNA nucleotide 359, leading to a cys98-to-gly (C98G; 120940.0003) substitution.
Ichikawa et al. (2001) reported a 28-year-old Japanese woman with C9 deficiency and dermatomyositis. DNA sequence analysis revealed a nonsense mutation at arg95 of the C9 gene (R95X; 120940.0001). 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.
Carrier Detection
Alvarez et al. (1995) analyzed RFLPs at the closely linked C6 (217050), C7 (217070), and C9 loci in a family with brothers who had C9 deficiency and recurrent Neisseria meningitidis. The haplotype carrying the 'silent' C9 allele was defined, allowing for detection of carriers among asymptomatic relatives.
Population GeneticsDeficiency of C9 is one of the most common genetic abnormalities in Japan with an incidence of 1 homozygote in 1,000. Very few cases of C9 deficiency have been reported in Caucasians. Although affected individuals are usually healthy, it has been shown that they have a significantly increased risk of developing meningococcal meningitis (Nagata et al., 1989).
By screening for complement deficiencies in 145,640 blood donors from Osaka and combining their results with reports of 92,686 donors from throughout Japan, Fukumori and Horiuchi (1998) identified 5 individuals with C5 deficiency (609536), 6 individuals with C6 deficiency (612446), 17 individuals with C7 deficiency (610102), 5 individuals with C8 alpha/gamma deficiency (613790), and 439 individuals with C9 deficiency. A homozygous R95X (120940.0001) mutation in the C9 gene had been identified in 8 of 10 unrelated Japanese individuals with C9 deficiency by Horiuchi et al. (1998). The other 2 individuals were compound heterozygous for R95X and a second mutation. Fukumori and Horiuchi (1998) concluded that the R95X mutation is relatively common in all Asian populations, but not in European populations.
To determine the prevalence of heterozygous carriers of R95X in a Japanese population, Kira et al. (1999) collected DNA samples from 300 individuals in 2 of the 4 main islands of Japan. Twenty individuals were heterozygous; none was homozygous. The prevalence of carriers was placed at 6.7% (20/300). An estimated frequency (0.12%) of complete C9 deficiency due to homozygosity for this mutation was consistent with frequencies determined by serologic studies.