C9 – Complement Component 9 Deficiency

Complement component 9 (C9) is the terminal protein of the membrane attack complex (MAC), essential for complement-mediated lysis of pathogens. Autosomal recessive loss-of-function variants in C9 ablate MAC formation, leading to increased susceptibility to Neisseria infections. In a Swiss family, two unrelated probands were found to harbor compound heterozygous stop-gain mutations, c.166C>A (p.Pro56Thr) and c.464C>T (p.Thr155Ile), each generating premature TGA codons and segregating with C9 deficiency in three first-degree relatives (2 probands)PMID:9144525.

In Japan, four unrelated C9-deficient patients with meningococcal meningitis were homozygous for a nonsense mutation at codon 95, c.346C>T (p.Arg116Ter), indicating a shared allele and autosomal recessive inheritance (4 probands)PMID:9703418. Population screening of 145 640 healthy Japanese donors identified 138 individuals with C9 deficiency, confirming the high prevalence of null alleles in East Asians (138/145 640)PMID:10072634.

Haplotype analyses demonstrated a founder effect for the c.346C>T (p.Arg116Ter) variant in Japanese (carrier frequency 6.7%) and lower frequencies in Koreans (2.0%) and Chinese (1.0%), consistent with an ancient East Asian origin (6.7% carriers)PMID:12596049. To date, over 20 distinct pathogenic C9 variants have been described, including nonsense, frameshift, splice-site, and small indel alleles distributed across exons 2–11.

Functional assays confirm that null alleles abrogate MAC assembly and haemolytic activity. A C9 knockout mouse model (mC9–/–) demonstrated attenuated antibody-mediated hemolysis and lipopolysaccharide-induced shock, recapitulating human deficiency and linking C9 loss to impaired inflammasome activation (mouse model)PMID:27444648.

Together, genetic and experimental evidence establish C9 deficiency as a definitive autosomal recessive disorder. C9 genetic testing enables diagnosis of patients with recurrent meningococcal infections and guides prophylactic antibiotic and vaccine strategies. This gene–disease pair has robust clinical validity and supports utility in diagnostic decision-making and future therapeutic development.

Key Take-home: Autosomal recessive C9 deficiency due to diverse loss-of-function alleles causes impaired MAC formation and recurrent neisserial infections, warranting genetic testing in at-risk individuals.

References

• Journal of immunology • 1997 • The human complement C9 gene: identification of two mutations causing deficiency and revision of the gene structure. PMID:9144525
• Human genetics • 1998 • Nonsense mutation in exon 4 of human complement C9 gene is the major cause of Japanese complement C9 deficiency. PMID:9703418
• Experimental and clinical immunogenetics • 1998 • Terminal complement component deficiencies in Japan. PMID:10072634
• Human genetics • 2003 • Founder effect of the C9 R95X mutation in Orientals. PMID:12596049
• Scientific reports • 2016 • Target deletion of complement component 9 attenuates antibody-mediated hemolysis and lipopolysaccharide (LPS)-induced acute shock in mice. PMID:27444648

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