The molecular basis of C6 deficiency in the western Cape, South Africa

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.