C2 – Complement component 2 deficiency

Complement component 2 (C2) deficiency is an autosomal recessive disorder characterized by impaired classical complement pathway activation leading to recurrent bacterial infections and increased risk of autoimmunity. Biallelic loss-of-function in C2 abolishes or markedly reduces C2 protein secretion, compromising C3 convertase formation and pathogen clearance.

Genetically, two major molecular classes exist. Type I deficiency is caused by a 28-bp genomic deletion in exon 6 that leads to skipping of exon 6 and a premature termination codon (PMID:1577763). Type II alleles result from missense substitutions at highly conserved residues that block C2 secretion without affecting transcript levels.

A case report described a 9-year-old African-American male with severe recurrent pyogenic infections who was compound heterozygous for the common type I deletion and a novel type II allele. Functional assays demonstrated that expression of alleles such as c.626C>T (p.Ser209Phe) and c.1390G>A (p.Gly464Arg) in cell models caused intracellular retention and minimal secretion of C2 (PMID:8621452; PMID:9670930).

A multi-patient study reported five individuals from two unrelated families with homozygous type I C2 deficiency. Three symptomatic patients had additional immunoglobulin defects (IgG2 or IgA deficiency) and defective alternative pathway hemolytic activity, highlighting modifying factors in clinical expressivity (PMID:8645999).

Mechanistic studies confirm that type I deletions eliminate C2 production, whereas type II missense mutations disrupt folding or secretion in the endoplasmic reticulum. Recombinant human C2 expressed in mammalian cells restores classical pathway activity and hemolytic function in deficient serum, supporting protein replacement as a potential therapy (PMID:20727163).

Integration of genetic and functional data across unrelated families establishes a strong gene–disease association. Clinical testing for the common 28-bp deletion and known missense alleles enables definitive diagnosis, informs genetic counseling, and may guide emerging complement replacement strategies.

Key take-home: Biallelic C2 loss-of-function causes a clinically actionable autosomal recessive immunodeficiency amenable to molecular diagnosis and potential protein therapy.

References

• Journal of immunology • 1998 • A novel type II complement C2 deficiency allele in an African-American family. PMID:9670930
• International archives of allergy and immunology • 1996 • Homozygous C2 deficiency: association with defective alternative pathway function and immunoglobulin deficiency. PMID:8645999
• The Journal of biological chemistry • 1996 • Type II human complement C2 deficiency. Allele-specific amino acid substitutions (Ser189 --> Phe; Gly444 --> Arg) cause impaired C2 secretion. PMID:8621452
• The Journal of biological chemistry • 1992 • Type I human complement C2 deficiency. A 28-base pair gene deletion causes skipping of exon 6 during RNA splicing. PMID:1577763
• BMC immunology • 2010 • Recombinant human complement component C2 produced in a human cell line restores the classical complement pathway activity in-vitro: an alternative treatment for C2 deficiency diseases. PMID:20727163

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