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The molecular basis of C6 deficiency in the western Cape, South Africa
M J Hobart1, B A Fernie, K A Fijen
1Molecular Immunopathology Unit, Medical Research Council Centre, Cambridge, UK. mhobart@dmu.ac.uk
Insights
Three genetic defects cause total complement component 6 (C6) deficiency in South Africa, with a novel 879delG mutation being most common. These findings explain C6 deficiency in 38 individuals and suggest distinct origins for some mutations.
Area of Science:
- Immunogenetics
- Molecular Biology
- Human Genetics
Background:
- Total deficiency of the sixth component of human complement (C6) is rare and linked to recurrent infections.
- C6 deficiency is prevalent in families from the western Cape, South Africa, often identified due to meningococcal disease.
Purpose of the Study:
- To identify the molecular basis of total C6 deficiency (C6Q0) in South African populations.
- To investigate the origins and prevalence of specific C6 gene mutations in the western Cape.
Main Methods:
- Sequencing of expressed exons of the C6 gene in individuals with C6 deficiency.
- Analysis of C6/C7 region DNA marker haplotypes to trace mutation origins.
- Comparison of identified mutations and haplotypes with previously reported cases.
Main Results:
- Three molecular defects causing C6Q0 were identified: 879delG (novel, common in the Cape), 1195delC, and 1936delG (previously reported in African-Americans).
- The 879delG and 1195delC mutations were associated with specific DNA haplotypes, indicating common ancestry.
- These three defects explain C6Q0 in all 38 unrelated individuals studied from the Cape; 879delG was also found in Dutch kindreds.
Conclusions:
- The identified molecular defects, particularly 879delG, account for total C6 deficiency in the western Cape population.
- Haplotype analysis suggests distinct origins for some C6 deficiency mutations, with the Cape's 879delG likely not originating from the Netherlands.
- Understanding these genetic defects is crucial for managing C6-deficient individuals, especially in regions with endemic meningococcal disease.
Abstract:
Deficiency of the sixth component of human complement (C6) has been reported in a number of families from the western Cape, South Africa. Meningococcal disease is endemic in the Cape and almost all pedigrees of total C6 deficiency (C6Q0) have been ascertained because of recurrent disease. We have sequenced the expressed exons of the C6 gene from selected cases and have found three molecular defects leading to total deficiency: 879delG, which is the common defect in the Cape and hitherto unreported, and 1195delC and 1936delG, which have been previously reported in African-Americans. We also show that the 879delG and 1195delC defects are associated with characteristic C6/C7 region DNA marker haplotypes, although small variations were observed. The 1936delG defect was observed only once in the Cape, but its associated haplotype could be deduced. The data from the haplotypes indicate that these three molecular defects account for the defects in all the 38 unrelated C6Q0 individuals we have studied from the Cape. We have also observed the 879delG defect in two Dutch C6-deficient kindreds, but the 879delG defect in the Cape probably did not come from The Netherlands.