C8B – Type II Complement Component 8 Deficiency

C8B encodes the β-chain of complement component C8, a critical terminal complement protein. Biallelic loss-of-function variants in C8B cause autosomal recessive type II complement component 8 deficiency, characterized by absence of C8β and recurrent Neisseria infections (PMID:8098723).

Extensive genetic studies have identified 47 unrelated probands from 34 families with C8β deficiency, including a recurrent C→T transition in exon 9 (c.1282C>T (p.Arg428Ter)) as the major allele and multiple novel frameshift and stop-gain variants such as c.271C>T (p.Gln91Ter) (PMID:7594510; PMID:19434484). Segregation analysis across 12 additional affected relatives confirms autosomal recessive inheritance.

The variant spectrum is dominated by null alleles: 86% are C→T transitions generating premature stop codons, while the remainder include single-base deletions (e.g., c.429del (p.Asp143GlufsTer?) and c.667del (p.Thr223fs)) and small duplications (e.g., c.1047_1053dup (p.Leu350fsTer?)) (PMID:7594510).

Functional assays consistently demonstrate absent hemolytic activity (CH50 and APH50) and lack of C8β on Western blot in patient sera. Reconstitution with purified C8 restores membrane attack complex formation and bactericidal function (PMID:9476133; PMID:19434484).

No conflicting evidence has been reported. The concordance of genetic and functional data across diverse cohorts supports a strong gene-disease relationship.

Key take-home: Autosomal recessive C8B deficiency is a clinically actionable disorder; genetic and functional testing enables definitive diagnosis, guiding prophylaxis and vaccination strategies against Neisserial infections.

References

• Journal of immunology • 1993 • Genetic basis of human complement C8 beta deficiency. PMID:8098723
• Journal of immunology • 1995 • Delineation of additional genetic bases for C8 beta deficiency. PMID:7594510
• Journal of clinical immunology • 2009 • A novel mutation in a patient with a deficiency of the eighth component of complement associated with recurrent meningococcal meningitis. PMID:19434484
• Immunopharmacology • 1997 • Molecular, genetic, and functional analysis of homozygous C8 beta-chain deficiency in two siblings. PMID:9476133
• Orphanet journal of rare diseases • 2016 • Invasive meningococcal disease in three siblings with hereditary deficiency of the 8(th) component of complement: evidence for the importance of an early diagnosis. PMID:27183977

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