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A novel mutation in a patient with a deficiency of the eighth component of complement associated with recurrent
D F Arnold1, A G Roberts, A Thomas
1Department of Clinical Immunology, Nuffield Department of Medicine, University of Oxford and Oxford Radcliffe Hospitals, John Radcliffe Hospital, Oxford OX3 9DU, UK.
Introduction:
Complement component C8 is one of the five terminal complement components required for the formation of the membrane attack complex. Complete absence of C8 results in increased susceptibility to gram-negative bacteria such as Neisseria species.
Materials And Methods:
Two functionally distinct C8 deficiency states have been described: C8 alpha-gamma deficiency has been predominantly reported amongst Afro-Caribbeans, Hispanics, and Japanese and C8beta mainly in Caucasians.
Results:
We report a case of functional and immunochemical deficiency of the complement component C8, diagnosed in a Caucasian adult following three episodes of meningitis. Western blotting and hemolytic assay demonstrated absence of C8beta. In genetic studies, the common exon 9 C > T transition responsible for 85% of C8beta deficiencies was not found. Two mutations were identified: a novel duplication mutation, c.1047_1053 dupGGCTGTG in exon 7 that introduces a frame shift, resulting in the addition of seven novel amino acid residues and a premature stop codon, and a previously reported mutation, c.271C > T in exon 3. The parents each expressed one of these mutations, confirming compound heterozygosity.
Discussion:
This is the first report of a duplication mutation in C8beta deficiency and extends the molecular heterogeneity of the disorder.
Insights
A novel duplication mutation in complement component 8 beta (C8β) deficiency was identified in a Caucasian patient with recurrent meningitis. This finding expands the known genetic causes of C8β deficiency.
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- Complement component 8 (C8) is crucial for the membrane attack complex formation.
- Complete C8 deficiency increases susceptibility to Neisseria infections.
- C8 deficiency presents as C8 alpha-gamma or C8beta deficiency, with distinct ethnic distributions.
Observation:
- A Caucasian adult with recurrent meningitis was diagnosed with functional and immunochemical C8 deficiency.
- Absence of C8beta was confirmed via Western blotting and hemolytic assay.
- Genetic analysis excluded the common C8beta deficiency mutation.
Findings:
- A novel duplication mutation (c.1047_1053 dupGGCTGTG) in exon 7 of C8beta was identified, causing a frameshift and premature stop codon.
- A previously reported mutation (c.271C > T) in exon 3 was also found.
- Compound heterozygosity for these two mutations was confirmed in the patient.
Implications:
- This study reports the first duplication mutation associated with C8beta deficiency.
- The findings highlight the molecular heterogeneity of C8beta deficiency.
- Understanding novel mutations is key to diagnosing and managing complement deficiencies.
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