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Complement component 3 (C3) is the central effector of all complement activation pathways. Biallelic loss-of-function variants in C3 cause a rare autosomal recessive complement component 3 deficiency (MONDO:0013417), marked by absent C3 protein, recurrent severe pyogenic infections, hypogammaglobulinemia, and immune complex–mediated sequelae such as hemolytic-uremic syndrome (HUS) (HP:0002729, HP:0004313, HP:0005575).
The association is classified as Strong. Over 20 unrelated individuals with biallelic C3 variants have been reported across multiple families, including consanguineous kindreds and sibling pairs, with clear autosomal recessive segregation and concordant functional impairment in patient cells ([PMID:8340676]; [PMID:14639503]).
Inheritance is autosomal recessive. Segregation studies include affected siblings in at least one family (n = 2) and multiple consanguineous kindreds demonstrating cosegregation of LoF alleles with disease ([PMID:39114852]). Case series encompass >23 probands harboring nonsense, frameshift, and splice-site variants leading to absent or truncated C3. A representative variant is c.1602C>A (p.Tyr534Ter), observed homozygously in an affected subject with complete C3 deficiency ([PMID:14639503]).
Mechanism is loss of C3 due to nonsense-mediated mRNA decay and failure of secretion. Patient fibroblasts show accelerated C3 mRNA decay and intracellular retention of mutant proC3, with severely reduced complement hemolytic activity and absent serum C3 ([PMID:14639503]; [PMID:12462331]). Animal and cellular models confirm that C3 loss abrogates opsonization and convertase function, leading to infection susceptibility and immune complex disease ([PMID:8340676]).
No studies have reported unaffected individuals with biallelic LoF variants or alternative phenotypes, and no functional assays dispute the pathogenic mechanism.
Collectively, genetic and functional data provide robust evidence that biallelic LoF C3 variants cause autosomal recessive complement component 3 deficiency. This supports clinical genetic testing for C3 in patients with recurrent encapsulated bacterial infections, HUS, or unexplained hypogammaglobulinemia. Key take-home: identification of C3 deficiency enables targeted immunological management, including vaccination strategies and immunoglobulin replacement.
Gene–Disease AssociationStrong23 probands across multiple families, AR segregation, concordant functional data Genetic EvidenceStrong23 biallelic LoF variants in C3 in unrelated cases; AR inheritance; segregation in sib pair Functional EvidenceModeratemRNA decay and secretion assays in patient fibroblasts; complement activity models demonstrate LoF |