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A non-sense mutation at Arg95 is predominant in complement 9 deficiency in Japanese
T Horiuchi1, H Nishizaka, T Kojima
1First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan. horiuchi@intmed1.med.kyushu-u.ac.jp
Insights
Deficiency of the ninth component of complement (C9D) is common in Japan. A novel mutation, R95X, was identified as the primary cause of C9D in most Japanese subjects, increasing meningococcal meningitis risk.
Area of Science:
- Immunogenetics
- Molecular Biology
- Human Genetics
Background:
- Deficiency of the ninth component of complement (C9D) is a prevalent genetic disorder in Japan, affecting 1 in 1000 individuals.
- While C9D individuals are typically asymptomatic, they exhibit a significantly elevated risk of developing meningococcal meningitis.
Observation:
- This study investigated the molecular basis of C9D in 10 unrelated Japanese subjects.
- Analysis of C9 gene exons 2-11 using PCR/single-strand conformation polymorphism revealed abnormalities in exon 4 in all C9D subjects.
- Direct sequencing identified a novel C to T transition (R95X) in exon 4 in 8 out of 10 subjects, resulting in a premature stop codon.
Findings:
- The novel R95X mutation was found to be homozygous in most Japanese C9D cases studied.
- Heterozygous R95X mutations were observed in two cases, with one also carrying a second mutation (C507Y).
- The genetic basis for C9D in one subject remains undetermined, indicating potential allelic heterogeneity.
Implications:
- The R95X mutation is identified as the predominant cause of C9D in the Japanese population.
- Understanding the molecular basis of C9D is crucial for assessing meningococcal meningitis risk in affected individuals.
- Further research may elucidate the genetic defect in remaining C9D cases and explore genotype-phenotype correlations.
Abstract:
Deficiency of the ninth component of complement (C9D) is one of the most common genetic abnormalities in Japan, with an incidence of one homozygote in 1000. Although C9D individuals are usually healthy, it has been shown that they have an significantly increased risk of developing meningococcal meningitis. In the present study we report the molecular bases for C9D in 10 unrelated Japanese subjects. As a screening step for mutations, exons 2 to 11 of the C9 gene were analyzed using exon-specific PCR/single-strand conformation polymorphism analysis, which demonstrated aberrantly migrating DNA bands in exon 4 in all the C9D subjects. Subsequent direct sequencing of exon 4 of the C9D subjects revealed that eight of the 10 C9D subjects were homozygous for a C to T transition at nucleotide 343, the first nucleotide of the codon CGA for Arg95, leading to a TGA stop codon (R95X). R95X is a novel mutation different from those recently identified in a Swiss family with C9D. Cases 6 and 7 were heterozygous for the R95X mutation. Family study in case 10 confirmed the genetic nature of the defect. In case 6, the second mutation for C9D of the C9 gene was identified to be the substitution of Cys to Tyr at amino acid residue 507 (C507Y), while the genetic defect(s) in the other allele in case 7 remains unknown. Our results indicate that a novel mutation, R95X, is present in most cases of C9D in Japan.