Complement Component 3 Deficiency

Mendelian MONDO:0013417 Pathograph 21 Show in embeddings browser Complement Disorder

Complete complement component 3 (C3) deficiency is an extremely rare autosomal recessive inborn error of immunity caused by biallelic loss-of-function variants in C3. Fewer than 50 cases have been reported since the first description in 1972. C3 is the point at which the classical, lectin and alternative pathways converge, so its absence removes C3b opsonisation, the C5 convertases built on C3b, and C3-dependent solubilisation and clearance of immune complexes. The clinical picture follows from these losses: recurrent, often severe pyogenic infection with encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis) from early childhood, and in roughly a quarter of patients each, immune-complex membranoproliferative glomerulonephritis and an SLE-like illness. Patients also show defects in adaptive immunity, including impaired dendritic-cell differentiation, reduced memory B cells and altered T-helper responses. Heterozygous relatives have about half-normal serum C3 and are usually asymptomatic.

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1
Inheritance
5
Pathophys.
12
Phenotypes
21
Pathograph
1
Genes
5
Medical Actions
1
Models
1
Deep Research
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Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC
IUIS Category
complement deficiency
👪

Inheritance

1
Autosomal Recessive HP:0000007
Complete deficiency requires homozygous or compound heterozygous C3 loss-of-function alleles. Heterozygous parents and siblings typically have about 50% of normal serum C3 and are clinically unaffected, although carriers vary: some reported heterozygous parents with C3 near the lower limit of normal have had recurrent infections, which the authors of the Moroccan series read as incomplete clinical penetrance in carriers. Founder alleles occur in populations with endogamy, such as the Afrikaans exon 22-23 deletion and a Moroccan splice-site variant found in two unrelated families from the Taounat region.
Autosomal recessive inheritance
Show evidence (5 references)
PMID:2212005 SUPPORT Human Clinical
"His parents had both the normal and abnormal C3 mRNA and were shown to be heterozygous for this mutation by sequence analysis of genomic DNA amplified by PCR."
Homozygous affected child with heterozygous carrier parents, the segregation pattern of recessive inheritance.
PMID:18802120 SUPPORT Human Clinical
"The nonconsanguineous parents and the two patients' two siblings had 50% normal serum C3 concentration."
Unaffected relatives of a compound heterozygous patient carry about half the normal serum C3, consistent with a gene-dosage effect and recessive expression of disease.
PMID:1350678 SUPPORT Human Clinical
"The wide prevalence of this null allele in this population is probably due to the effects of a small founder population."
Documents a founder null allele in the Afrikaans population.
+ 2 more references
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Pathophysiology

5
C3 Biallelic Loss of Function
Reported alleles are mostly null: nonsense variants with nonsense-mediated mRNA decay, splice-site variants causing exon skipping or frameshift, and partial gene deletions. Some in-frame splice or missense alleles allow synthesis but block secretion, so the protein is retained in the secretory pathway and degraded. In each case serum C3 is undetectable. C3 is made mainly by hepatocytes, with a smaller contribution from monocytes and kidney.
Hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
Genetic context C3 hgnc:1318 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns C3 (hgnc:1318). hgnc:1318 is a gene from the HUGO Gene Nomenclature Committee. functional_impact_category: LOSS_OF_FUNCTION
C3 fragment receptor ligand activity GO:0048018 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased C3 fragment receptor ligand activity, annotated with receptor ligand activity (GO:0048018). GO:0048018 is a molecular function from the Gene Ontology.
Downstream
Failure of Complement Activation at the C3 Convergence Point Without C3 no pathway can generate C3b, so classical and alternative pathway activity are both abolished.
Decreased circulating complement C3 Absent secretion of C3 is measured directly as undetectable serum C3.
Show evidence (5 references)
PMID:14639503 SUPPORT In Vitro
"Our results indicate the presence of a premature termination codon in the C3 gene that results in a lack of the protein in patient's serum, which correlates with the acceleration of C3 mRNA decay in the patient's fibroblasts."
A nonsense allele with accelerated mRNA decay in patient fibroblasts and no serum C3.
PMID:1350678 SUPPORT Human Clinical
"The presence of this deletion in the C3 gene is not compatible with production of any functional C3"
A partial gene deletion (exons 22-23) producing a frameshifted, null allele.
PMID:15781264 SUPPORT In Vitro
"These data indicate that a novel AG-->GG 3'-splice acceptor site mutation in intron 38 caused aberrant splicing of exon 39, resulting in defective secretion of C3."
An in-frame exon-skipping allele whose product is retained intracellularly, the secretion-defect class of C3 deficiency.
+ 2 more references
Failure of Complement Activation at the C3 Convergence Point
The classical, lectin and alternative pathways all converge on cleavage of C3. With no C3, no C3b is deposited on targets, the alternative-pathway amplification loop cannot run, the C5 convertases (which incorporate C3b) cannot assemble, and the C3a anaphylatoxin is not generated. Both classical (CH50) and alternative pathway haemolytic activity are absent, and adding purified C3 restores them in vitro.
Complement activation GO:0006956 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Complement activation (GO:0006956). GO:0006956 is a biological process from the Gene Ontology. Complement activation, alternative pathway GO:0006957 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Complement activation, alternative pathway (GO:0006957). GO:0006957 is a biological process from the Gene Ontology. Complement activation, classical pathway GO:0006958 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Complement activation, classical pathway (GO:0006958). GO:0006958 is a biological process from the Gene Ontology.
Downstream
Impaired C3b Opsonophagocytosis No C3b or iC3b is deposited on microbes, so complement-receptor-mediated phagocytosis fails.
Defective Immune Complex Solubilization and Clearance C3 fragments keep immune complexes soluble and route them and apoptotic debris to clearance; without them complexes persist and deposit.
Impaired Complement-Dependent Adaptive Immune Priming C3 fragments and C3a act on dendritic cells, B cells and T cells, so their absence alters adaptive immune responses.
Show evidence (3 references)
PMID:20930072 SUPPORT REVIEW SYNTHESIS Other
"C3 is the point at which all complement pathways converge, and complete deficiency of C3 invariably leads to severe infections, including those caused by meningococci and pneumococci."
Review statement of C3's position as the convergence point of all complement pathways.
PMID:11422912 SUPPORT Human Clinical
"The classical and alternative pathway haemolytic activities and the generation of opsonins and chemotactic factors derived from the activation of the complement system were markedly affected in the proband's serum."
Patient serum lacks both classical and alternative pathway activity.
PMID:11422912 SUPPORT In Vitro
"An in vitro addition of purified C3 restored the classical pathway-dependent haemolytic activity of his serum."
Reconstitution with purified C3 shows the pathway failure is due to the missing C3 alone.
Impaired C3b Opsonophagocytosis
Phagocytes rely on C3b and iC3b to recognise and ingest encapsulated bacteria. In C3 deficiency neither antibody-dependent nor antibody-independent complement opsonisation is available, which explains the early-onset, often invasive pyogenic infections.
Neutrophil CL:0000775 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Neutrophil (CL:0000775). CL:0000775 is a cell type from the Cell Ontology. Macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
opsonization GO:0008228 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased opsonization (GO:0008228). GO:0008228 is a biological process from the Gene Ontology. phagocytosis GO:0006909 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased phagocytosis (GO:0006909). GO:0006909 is a biological process from the Gene Ontology.
Downstream
Recurrent Pyogenic Bacterial Infections Loss of opsonophagocytic killing of encapsulated organisms manifests as recurrent pyogenic infection.
Recurrent Pneumonia Pneumonia is among the most frequent serious infections.
Bacterial Meningitis Invasive pneumococcal and meningococcal disease includes recurrent meningitis.
Recurrent Tonsillitis Upper respiratory and ENT infections are the common, milder end of the infection spectrum.
Sepsis Encapsulated organisms that are not opsonised can reach the bloodstream, so sepsis is one of the invasive presentations of the classical case literature.
Show evidence (2 references)
PMID:42445183 SUPPORT BACKGROUND Human Clinical
"reflecting the indispensable role of C3b-mediated opsonization in defense against encapsulated organisms"
Attributes the encapsulated-organism infection phenotype of C3 deficiency to loss of C3b opsonisation.
PMID:14612669 SUPPORT REVIEW SYNTHESIS Other
"Antibody- and complement-mediated opsonization, splenic macrophages and interleukin-1 receptor associated kinase-4- and nuclear factor kappaB-mediated immune responses are crucial for protective immunity to S. pneumoniae."
Review establishing complement opsonisation as essential for defence against pneumococcus.
Defective Immune Complex Solubilization and Clearance
C3 fragments solubilise immune complexes and opsonise them, and apoptotic cells, for transport and clearance. In their absence immune complexes persist and deposit in glomeruli and vessel walls, and uncleared apoptotic material is thought to drive loss of tolerance. This is the accepted explanation for the glomerulonephritis and SLE-like disease, but it rests on case observations and mechanistic inference rather than on direct measurement of clearance in C3-deficient patients.
immune complex clearance GO:0002434 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased immune complex clearance (GO:0002434). GO:0002434 is a biological process from the Gene Ontology. apoptotic cell clearance GO:0043277 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased apoptotic cell clearance (GO:0043277). GO:0043277 is a biological process from the Gene Ontology.
Downstream
Membranoproliferative Glomerulonephritis Persisting immune complexes deposit in glomeruli and produce a membranoproliferative pattern.
Systemic Lupus Erythematosus-like Disease Uncleared immune complexes and apoptotic debris are thought to sustain autoantigen exposure and lupus-like disease.
Vasculitis Immune complexes that are not cleared deposit in small vessel walls.
Show evidence (2 references)
PMID:42445183 SUPPORT BACKGROUND Human Clinical
"Impaired clearance of apoptotic cellular debris, which also depends on C3-mediated opsonization, may further contribute to the breach of self-tolerance observed in affected patients"
States the apoptotic-debris clearance mechanism, hedged ("may"), as the route to autoimmunity in C3 deficiency.
PMID:39114852 SUPPORT BACKGROUND Human Clinical
"Deficiencies in complement proteins, particularly C3, can lead to severe and recurrent infections as well as immune complex disorders."
Links C3 deficiency to immune complex disorders.
Impaired Complement-Dependent Adaptive Immune Priming
Cells from C3-deficient patients show impaired monocyte-to-dendritic-cell differentiation and maturation, few switched memory B cells, reduced regulatory T-cell induction and defective Th1 induction. Antibody responses are variable: one patient failed to sustain a vaccine response, while a series of eight patients mounted normal toxoid responses with an abnormal IgG subclass pattern. The defect is therefore a skewing of adaptive immunity rather than a uniform antibody deficiency. The direction of the T-helper change is unsettled: the in vitro study (PMID:24321396) reports impaired Th1 induction from patient T cells, while the in vivo subclass data (PMID:25446578) show increased Th1-related IgG3 responses. The DECREASED modifier on the Th1 process below follows the in vitro measurement, and the IgG3 evidence item is curated as REFUTE against it.
Dendritic cell CL:0000451 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Dendritic cell (CL:0000451). CL:0000451 is a cell type from the Cell Ontology. Memory B cell CL:0000787 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Memory B cell (CL:0000787). CL:0000787 is a cell type from the Cell Ontology.
dendritic cell differentiation GO:0097028 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased dendritic cell differentiation (GO:0097028). GO:0097028 is a biological process from the Gene Ontology. memory B cell differentiation GO:0002319 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased memory B cell differentiation (GO:0002319). GO:0002319 is a biological process from the Gene Ontology. T-helper 1 type immune response GO:0042088 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T-helper 1 type immune response (GO:0042088). GO:0042088 is a biological process from the Gene Ontology.
Animal models
C3-deficient mouse Mouse partially recapitulates C3-deficient mice mount a poor primary antibody response to a bacterial capsular polysaccharide, without class switching, and fail to deliver antigen and immune complexes to marginal zone B cells and follicular dendritic cells. This is a mechanism for the poor polysaccharide responses and memory B-cell deficit reported in patients.
Downstream
Decreased Memory B Cells Loss of C3d co-stimulation through CD21 limits generation of memory B cells.
Hypogammaglobulinemia Reported in some patients alongside reduced memory B cells and poor polysaccharide responses; not present in all.
Recurrent Pyogenic Bacterial Infections Impaired memory B-cell generation may contribute to infections that persist despite antibiotic prophylaxis.
Show evidence (6 references)
PMID:18802120 SUPPORT Human Clinical
"Accordingly, switched memory IgD(-)CD27(+) B cells were barely detected, amounting to only 2.3% of peripheral blood CD19(+) cells."
Near-absent switched memory B cells in a C3-deficient patient.
PMID:18802120 SUPPORT In Vitro
"The in vitro development of immature dendritic cells and their maturation capacity were greatly impaired, with decreased CD1a expression and IL-12p70 secretion ability."
Patient monocytes fail to differentiate and mature normally into dendritic cells.
PMID:24321396 SUPPORT In Vitro
"Importantly, and like in CD46-deficient patients, whilst Th1 induction are impaired in C3-deficient patients in vitro, their Th2 responses are unaffected."
T cells from two C3-deficient patients show selectively impaired Th1 induction.
+ 3 more references
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Complement Component 3 Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

12
Blood 2
Decreased Memory B Cells Decreased memory B cell proportion HP:0030374 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased memory B cell proportion (HP:0030374). HP:0030374 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:18802120 SUPPORT Human Clinical
"Accordingly, switched memory IgD(-)CD27(+) B cells were barely detected, amounting to only 2.3% of peripheral blood CD19(+) cells."
Near-absent switched memory B cells.
PMID:39114852 SUPPORT Human Clinical
"Immunological evaluation revealed absent plasma C3 levels, decreased memory B cells, hypogammaglobulinemia, and impaired response to polysaccharide antigens."
Decreased memory B cells in two siblings with complete C3 deficiency.
Hypogammaglobulinemia Decreased circulating immunoglobulin concentration HP:0004313 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypogammaglobulinemia, annotated with Decreased circulating immunoglobulin concentration (HP:0004313). HP:0004313 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39114852 SUPPORT Human Clinical
"Immunological evaluation revealed absent plasma C3 levels, decreased memory B cells, hypogammaglobulinemia, and impaired response to polysaccharide antigens."
Hypogammaglobulinemia in two siblings with complete C3 deficiency.
PMID:42445183 REFUTE Human Clinical
"Immunological investigations revealed normal lymphocyte subsets, immunoglobulin levels, and neutrophil oxidative burst."
Two other patients had normal immunoglobulin levels, so hypogammaglobulinemia is not a consistent feature.
Cardiovascular 2
Recurrent Tonsillitis HP:0011110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent tonsillitis (HP:0011110). HP:0011110 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15781264 SUPPORT Human Clinical
"his medical history revealed recurrent tonsillitis and pneumonia"
Recurrent tonsillitis in a patient with homozygous C3 deficiency.
Vasculitis HP:0002633 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vasculitis (HP:0002633). HP:0002633 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:11422912 SUPPORT Human Clinical
"presented recurrent bacterial infections, vasculitis and extremely low levels of serum C3 (0.15 microg/ml)"
Vasculitis in a child with hereditary C3 deficiency.
PMID:42445183 SUPPORT Human Clinical
"At 6 years of age, he was diagnosed with IgA vasculitis (Henoch-Schonlein purpura), characterized by palpable purpura on the lower extremities, ankle edema, and arthralgia, that was treated with systemic corticosteroids with good clinical response"
IgA vasculitis in a patient with genetically confirmed complete C3 deficiency.
Genitourinary 2
Membranoproliferative Glomerulonephritis OCCASIONAL HP:0000793 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Membranoproliferative glomerulonephritis (HP:0000793). HP:0000793 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42445183 SUPPORT BACKGROUND Human Clinical
"approximately 26% develop SLE-like autoimmune illness and around 26% develop membranoproliferative glomerulonephritis"
Pooled literature figure for membranoproliferative glomerulonephritis in C3 deficiency.
PMID:31970896 SUPPORT Human Clinical
"We describe a case of an adult with complete deficiency of complement C3 due to homozygous mutations in C3 gene: c.1811delT (Val604Glyfs*2), recurrent bacterial infections, crescentic glomerulonephritis, and end-stage renal failure."
A genetically confirmed case progressing to crescentic glomerulonephritis and end-stage renal failure.
Hemolytic-Uremic Syndrome HP:0005575 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemolytic-uremic syndrome (HP:0005575). HP:0005575 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39114852 SUPPORT Human Clinical
"Both, the index case and her sister, presented a history of recurrent infections since early childhood and one of them developed hemolytic uremic syndrome (HUS)."
Single-case report of HUS in a sibling with complete C3 deficiency.
Immune 6
Recurrent Pyogenic Bacterial Infections VERY_FREQUENT Recurrent bacterial infections HP:0002718 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent bacterial infections (HP:0002718). HP:0002718 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:20930072 SUPPORT REVIEW SYNTHESIS Other
"C3 is the point at which all complement pathways converge, and complete deficiency of C3 invariably leads to severe infections, including those caused by meningococci and pneumococci."
Review statement that severe infection is a near-universal feature of complete C3 deficiency.
PMID:18802120 SUPPORT Human Clinical
"was identified in a 2-year-old male suffering from recurrent pyogenic infections from early infancy with undetectable total complement hemolytic activity (CH50) and C3 values"
Early-onset recurrent pyogenic infection in a genetically confirmed case.
PMID:42445183 SUPPORT Human Clinical
"Both patients presented with chronic and recurrent infections, predominantly affecting the respiratory and otorhinolaryngological systems, without identification of consistent pathogens."
Two recent patients with chronic, non-invasive respiratory and ENT infections, the milder end of the spectrum.
Recurrent Pneumonia HP:0006532 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent pneumonia (HP:0006532). HP:0006532 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15781264 SUPPORT Human Clinical
"his medical history revealed recurrent tonsillitis and pneumonia"
Recurrent pneumonia in a patient with homozygous C3 deficiency.
Bacterial Meningitis HP:0001287 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Meningitis (HP:0001287). HP:0001287 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42445183 SUPPORT BACKGROUND Human Clinical
"is dominated by severe, life-threatening recurrent pyogenic infections, particularly meningitis, sepsis, and pneumonia caused by encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis"
Summarises the classic case literature naming meningitis among the dominant infections.
Sepsis HP:0100806 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sepsis (HP:0100806). HP:0100806 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42445183 SUPPORT BACKGROUND Human Clinical
"is dominated by severe, life-threatening recurrent pyogenic infections, particularly meningitis, sepsis, and pneumonia caused by encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis"
Summarises the classic case literature naming sepsis among the dominant invasive infections of C3 deficiency.
Systemic Lupus Erythematosus-like Disease OCCASIONAL HP:0002725 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Systemic lupus erythematosus (HP:0002725). HP:0002725 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:42445183 SUPPORT BACKGROUND Human Clinical
"approximately 26% develop SLE-like autoimmune illness and around 26% develop membranoproliferative glomerulonephritis"
Pooled literature figure for SLE-like illness in C3 deficiency.
PMID:15781264 SUPPORT Human Clinical
"A case of inherited homozygous complement C3 deficiency (C3D) in a patient with systemic lupus erythematosus (SLE) and the molecular basis for this deficiency are reported."
A molecularly characterised case of C3 deficiency with SLE.
PMID:33563058 SUPPORT PRIMARY RESULT Human Clinical
"Complement deficiency was the most frequent PIDs; 26 patients were C1q deficient, three patients had C3 deficiency"
In a retrospective Saudi series of 39 children with lupus manifestations and a primary immunodeficiency, three had C3 deficiency, an observation of lupus in C3-deficient children independent of the single case reports above.
Decreased circulating complement C3 VERY_FREQUENT Decreased circulating complement C3 concentration HP:0005421 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Undetectable serum C3, annotated with Decreased circulating complement C3 concentration (HP:0005421). HP:0005421 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42445183 SUPPORT Human Clinical
"complement analysis showed undetectable C3 levels and markedly reduced CH50, with normal C4, consistent with isolated complete C3 deficiency"
The defining laboratory pattern: undetectable C3, low CH50, normal C4.
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Genetic Associations

1
C3
Gene: C3 hgnc:1318 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is C3 (hgnc:1318). hgnc:1318 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:2212005 SUPPORT Human Clinical
"This mutation is sufficient to cause the deficiency of C3 in the patient."
A homozygous C3 splice-site null allele causing deficiency.
PMID:12462331 SUPPORT Human Clinical
"We identified the mutations responsible for a complete homozygous C3 deficiency."
A homozygous premature stop codon in C3 in complete deficiency.
PMID:42445183 SUPPORT Human Clinical
"Loss-of-function (LoF) is the established and predominant disease mechanism for autosomal recessive complete C3 deficiency."
States loss of function as the disease mechanism.
💊

Medical Actions

5
Vaccination Against Encapsulated Bacteria
Action: vaccination against encapsulated bacteriaNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is vaccination against encapsulated bacteria, annotated with Vaccination (NCIT:C15346). NCIT:C15346 is a clinical intervention from the NCI Thesaurus. Ontology label: Vaccination NCIT:C15346
Platform: Vaccine
Conjugate pneumococcal, meningococcal and Haemophilus influenzae type b vaccination is a standard part of management. Unlike C2 deficiency, there is no alternative pathway to route vaccine antibody through, so benefit is expected to come from antibody-mediated, complement-independent mechanisms; responses in reported patients were partial.
Show evidence (1 reference)
PMID:39114852 SUPPORT Human Clinical
"Regarding the management of complement deficiencies, clinical control, vaccination with protein-polysaccharides conjugate, and antimicrobial prophylaxis are considered cornerstones in treatment"
States conjugate vaccination as a cornerstone of management.
Antibiotic Prophylaxis
Action: antibiotic prophylaxisNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is antibiotic prophylaxis (NCIT:C51993). NCIT:C51993 is a clinical intervention from the NCI Thesaurus. Ontology label: Antibiotic Prophylaxis NCIT:C51993
Platform: Small molecule
Continuous antibiotic prophylaxis, usually penicillin or amoxicillin, is recommended and reduced severe infections in some reports, though not in every patient.
Show evidence (2 references)
PMID:42445183 SUPPORT BACKGROUND Human Clinical
"Continuous antibiotic prophylaxis, typically with penicillin, significantly reduces infection frequency and is strongly recommended"
States the recommendation for continuous penicillin prophylaxis.
PMID:39114852 REFUTE Human Clinical
"Despite antimicrobial prophylaxis, they continue to suffer from recurrent sinopulmonary infections."
In two siblings prophylaxis did not prevent recurrent infection.
Intravenous Immunoglobulin Replacement
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: intravenous immunoglobulin NCIT:C80829 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses intravenous immunoglobulin, annotated with Human Immunoglobulin G (NCIT:C80829). NCIT:C80829 is a therapeutic agent from the NCI Thesaurus.
Platform: Other
Considered when C3 deficiency is accompanied by hypogammaglobulinemia or poor specific antibody responses; in two siblings it markedly reduced infection frequency.
Mechanism Target:
Hypogammaglobulinemia — Replaces the deficient antibody.
Show evidence (1 reference)
PMID:39114852 SUPPORT Human Clinical
"However, the failure of antimicrobial prophylaxis to prevent recurrent sinopulmonary infections, as well as the evidence of impaired antibody synthesis or response, led to the decision of initiating intravenous immunoglobulin (IVIG) replacement therapy, leading to a marked decrease in the number..."
IVIG reduced infections in two siblings with antibody defects.
Fresh Frozen Plasma
Action: fresh frozen plasma transfusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is fresh frozen plasma transfusion (NCIT:C116475). NCIT:C116475 is a clinical intervention from the NCI Thesaurus. Ontology label: Fresh Frozen Plasma Transfusion NCIT:C116475
Platform: Protein replacement
Plasma infusion supplies C3 temporarily during acute infection or perioperatively; the short duration of effect and transfusion risks limit routine prophylactic use.
Mechanism Target:
Failure of Complement Activation at the C3 Convergence Point — Transiently restores circulating C3.
Show evidence (1 reference)
PMID:42445183 SUPPORT BACKGROUND Human Clinical
"Fresh frozen plasma (FFP) infusions can provide temporary complement replacement during acute infections or perioperative periods, though the logistical challenges, risks, and short duration of effect limit its routine prophylactic use"
Describes the role and limits of plasma replacement.
Simultaneous Liver-Kidney Transplantation
Action: simultaneous liver-kidney transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is simultaneous liver-kidney transplantation, annotated with Organ Transplantation (NCIT:C15289). NCIT:C15289 is a clinical intervention from the NCI Thesaurus. Ontology label: Organ Transplantation NCIT:C15289
Platform: Surgery
In one adult with end-stage renal failure from glomerulonephritis, combined liver-kidney transplantation restored circulating C3, since the liver is the main source of C3; isolated kidney transplantation would have left him C3 deficient. A single case.
Mechanism Target:
C3 Biallelic Loss of Function — A donor liver supplies normal C3.
Show evidence (1 reference)
PMID:31970896 SUPPORT Human Clinical
"The procedure has been successful with restoration of his circulating C3 levels, normal liver and kidney function at 26 months of follow-up."
Restoration of C3 after combined transplantation in one patient.
🔬

Biochemical Markers

2
Serum C3 (DECREASED)
Show evidence (2 references)
PMID:42445183 SUPPORT Human Clinical
"complement analysis showed undetectable C3 levels and markedly reduced CH50, with normal C4, consistent with isolated complete C3 deficiency"
Undetectable C3 with normal C4 in genetically confirmed patients.
PMID:26847111 SUPPORT Human Clinical
"complement C3 levels were undetectable in the patient's serum and were reduced by at least 50% in the sera of the patient's parents and brother"
Undetectable C3 in the patient and roughly half-normal C3 in carriers.
Serum CH50 (total classical pathway haemolytic activity) (DECREASED)
Show evidence (1 reference)
PMID:26847111 SUPPORT Human Clinical
"Hemolytic assays revealed complete lack of complement-mediated hemolytic activity in the patient's serum."
Complete loss of haemolytic complement activity in a C3-deficient patient.
🔬

Diagnosis

2
Complement screening (C3, C4, CH50, AP50)
Quantitative C3 and C4 together with classical (CH50) and alternative (AP50) pathway haemolytic activity. Undetectable C3 with absent CH50 and AP50 but a normal C4 separates primary C3 deficiency from classical pathway consumption (immune-complex disease such as SLE), where C4 falls as well. A normal C4 does not exclude alternative pathway consumption: deficiency of factor H or factor I, or a C3 nephritic factor, lowers C3 and factor B with C4 preserved. In those conditions C3 is usually low rather than undetectable, and measuring factor B, factor H and factor I separates them from primary C3 deficiency. This is the test that makes the diagnosis, and in both patients of the 2026 Moroccan series it was done only years after symptom onset.
complement screening assay NCIT:C25294 NCI Thesaurus (NCIT)
Markers: serum C3, serum C4, CH50, AP50
Show evidence (4 references)
PMID:42445183 SUPPORT Human Clinical
"complement analysis showed undetectable C3 levels and markedly reduced CH50, with normal C4, consistent with isolated complete C3 deficiency"
The diagnostic pattern as measured in two genetically confirmed patients.
PMID:42445183 SUPPORT Human Clinical
"the need to include complement screening, specifically serum CH50, AP50, C3, and C4, in the standard immunological evaluation of any child presenting with recurrent infections of unexplained etiology"
Names the four analytes of the screening panel and the clinical setting in which the authors recommend it.
PMID:6545495 SUPPORT REVIEW SYNTHESIS Other
"a primary deficiency of factor H or I or both, will secondarily produce subnormal levels of C3 and factor B"
Review caveat on reading a complement profile: regulator deficiency lowers C3 secondarily, so a low C3 with normal C4 is not by itself primary C3 deficiency.
+ 1 more reference
C3 gene sequencing
Sequencing of C3 confirms the diagnosis and identifies the causal biallelic alleles, which is what allows carrier testing and counselling in the family. Reported patients have been diagnosed by gene panel or next-generation sequencing with Sanger confirmation and segregation analysis.
C3 gene sequencing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:42445183 SUPPORT Human Clinical
"The pattern of undetectable C3 with normal C4 and absent CH50/AP50 is pathognomonic for C3 deficiency and should trigger immediate referral for genetic analysis"
Places gene sequencing after the complement screen in the diagnostic sequence.
PMID:42445183 SUPPORT Human Clinical
"Sanger sequencing was performed to confirm the NGS findings and to conduct segregation analysis."
The sequencing route used in two genetically confirmed patients, including family segregation.
PMID:39114852 SUPPORT Human Clinical
"Genetic analysis in the index case was performed by next-generation sequencing (NGS) using a gene panel"
A compound heterozygous diagnosis reached by complement gene panel sequencing.
📊

Prevalence

1
Worldwide (published cases)
Cases In Literature Ultra Rare
Fewer than 50 cases reported worldwide since the first description in 1972. No population prevalence estimate exists.
Show evidence (1 reference)
PMID:42445183 SUPPORT Human Clinical
"fewer than 50 cases have been reported worldwide"
Case count from a 2026 literature review.
🐁

Animal Models

1
C3-deficient mouse
Targeted C3 knockout mice, used to test which humoral responses need C3. The cited studies address the adaptive-immunity arm of the disease, not the infection or immune-complex disease arms.
Species
Mouse
Genotype
C3(-/-)
Publication
PMID:12496386
Pathograph links
Impaired Complement-Dependent Adaptive Immune Priming partially recapitulates fidelity: moderate observes: organism C3-deficient mice mount a poor primary antibody response to a bacterial capsular polysaccharide, without class switching, and fail to deliver antigen and immune complexes to marginal zone B cells and follicular dendritic cells. This is a mechanism for the poor polysaccharide responses and memory B-cell deficit reported in patients.
Limitations: The antigens are group B streptococcal type III polysaccharide and experimental IgG3 immune complexes, not the pneumococcal, meningococcal and Haemophilus antigens relevant to patients. In patients the antibody defect is variable: one series of eight mounted normal toxoid responses, so the knockout's uniform defect overstates the human phenotype. The cited studies do not examine infection susceptibility, lupus-like disease or glomerulonephritis.
Divergences from the human mechanism
species mismatch qualifying
Mouse splenic marginal zone B-cell and follicular dendritic cell handling of polysaccharide antigen is the readout; how closely human polysaccharide responses depend on the same route is not tested in these studies.
proxy quantity qualifying
The model measures antibody to a single experimental polysaccharide antigen, standing in for the node's broader claim about memory B-cell generation and specific antibody responses in patients.
Readouts
Primary antibody response to capsular polysaccharide
Direction: DECREASED
Interpretation: Low IgM without switching to IgG after polysaccharide immunisation.
Show evidence (1 reference)
PMID:12496386 SUPPORT Model Organism
"The defective response was characterized by low IgM levels and the lack of an isotype switch from IgM to IgG Ab production."
The measured antibody defect in C3-deficient mice.
Antigen deposition on follicular dendritic cells
Direction: DECREASED
Interpretation: Without C3, antigen and immune complexes are not captured by marginal zone B cells or deposited on follicular dendritic cells.
Show evidence (1 reference)
PMID:28710441 SUPPORT Model Organism
"Capture of antigen by MZ B cells as well as antigen deposition on FDC was severely impaired in mice lacking C1q or C3"
Immune-complex trafficking to follicular dendritic cells fails in C3-deficient mice.
Show evidence (1 reference)
PMID:12496386 SUPPORT Model Organism
"Mice deficient in C3 or Cr2 had an impaired primary immune response to III-PS."
Establishes the C3 knockout as a model of a defective primary antibody response to bacterial capsular polysaccharide.
{ }

Source YAML

click to show 
name: Complement Component 3 Deficiency
creation_date: "2026-10-15T00:00:00Z"
category: Mendelian
description: >-
  Complete complement component 3 (C3) deficiency is an extremely rare
  autosomal recessive inborn error of immunity caused by biallelic
  loss-of-function variants in C3. Fewer than 50 cases have been reported since
  the first description in 1972. C3 is the point at which the classical, lectin
  and alternative pathways converge, so its absence removes C3b opsonisation,
  the C5 convertases built on C3b, and C3-dependent solubilisation and
  clearance of immune complexes. The clinical picture follows from these
  losses: recurrent, often severe pyogenic infection with encapsulated
  organisms (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria
  meningitidis) from early childhood, and in roughly a quarter of patients each,
  immune-complex membranoproliferative glomerulonephritis and an SLE-like
  illness. Patients also show defects in adaptive immunity, including impaired
  dendritic-cell differentiation, reduced memory B cells and altered T-helper
  responses. Heterozygous relatives have about half-normal serum C3 and are
  usually asymptomatic.
disease_term:
  preferred_term: complement component 3 deficiency
  term:
    id: MONDO:0013417
    label: complement component 3 deficiency
synonyms:
- C3 deficiency
- complete C3 deficiency
- hereditary C3 deficiency
- C3 classic complement early component deficiency
- classic complement early component deficiency caused by mutation in C3
parents:
- Complement Disorder
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    notes: >-
      A primary immunodeficiency presenting with pyogenic infection,
      glomerulonephritis and lupus-like disease, placing it in Harrison's
      immune/rheumatologic Part. Assigned to match the sibling
      Complement_Component_2_Deficiency entry.
  iuis_category:
    classification_value: complement deficiency
    notes: >-
      Deficiency of the central complement component C3, a row of the IUIS
      complement deficiencies table. Assigned to match the sibling
      Complement_Component_2_Deficiency entry.
inheritance:
- name: Autosomal Recessive
  description: >-
    Complete deficiency requires homozygous or compound heterozygous C3
    loss-of-function alleles. Heterozygous parents and siblings typically have
    about 50% of normal serum C3 and are clinically unaffected, although
    carriers vary: some reported heterozygous parents with C3 near the lower
    limit of normal have had recurrent infections, which the authors of the
    Moroccan series read as incomplete clinical penetrance in carriers.
    Founder alleles occur in populations with endogamy, such as the Afrikaans
    exon 22-23 deletion and a Moroccan splice-site variant found in two
    unrelated families from the Taounat region.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:2212005
    reference_title: "Molecular basis of hereditary C3 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His parents had both the normal and abnormal C3 mRNA and were shown to be heterozygous for this mutation by sequence analysis of genomic DNA amplified by PCR."
    explanation: >-
      Homozygous affected child with heterozygous carrier parents, the
      segregation pattern of recessive inheritance.
  - reference: PMID:18802120
    reference_title: "Human C3 deficiency associated with impairments in dendritic cell differentiation, memory B cells, and regulatory T cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The nonconsanguineous parents and the two patients' two siblings had 50% normal serum C3 concentration."
    explanation: >-
      Unaffected relatives of a compound heterozygous patient carry about half
      the normal serum C3, consistent with a gene-dosage effect and recessive
      expression of disease.
  - reference: PMID:1350678
    reference_title: "Homozygous hereditary C3 deficiency due to a partial gene deletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The wide prevalence of this null allele in this population is probably due to the effects of a small founder population."
    explanation: >-
      Documents a founder null allele in the Afrikaans population.
  - reference: PMID:42445183
    reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "provide compelling evidence for a founder mutation in the Taounat region of Morocco"
    explanation: >-
      A second founder allele, the splice-site variant shared by two unrelated
      consanguineous families from one region of northern Morocco.
  - reference: PMID:42445183
    reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "suggesting variable biological expression and incomplete clinical penetrance among heterozygous carriers"
    explanation: >-
      The authors' reading of their own carrier data, in which parents with
      C3 and CH50 below the reference range stayed asymptomatic while
      previously reported carriers with similar levels had recurrent
      infections. Supports the carrier-variability sentence in this block.
pathophysiology:
- name: C3 Biallelic Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Reported alleles are mostly null: nonsense variants with nonsense-mediated
    mRNA decay, splice-site variants causing exon skipping or frameshift, and
    partial gene deletions. Some in-frame splice or missense alleles allow
    synthesis but block secretion, so the protein is retained in the secretory
    pathway and degraded. In each case serum C3 is undetectable. C3 is made
    mainly by hepatocytes, with a smaller contribution from monocytes and
    kidney.
  genetic_context:
    gene:
      preferred_term: C3
      term:
        id: hgnc:1318
        label: C3
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: C3 fragment receptor ligand activity
    term:
      id: GO:0048018
      label: receptor ligand activity
    modifier: DECREASED
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:14639503
    reference_title: "Nonsense-codon-mediated decay in human hereditary complement C3 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our results indicate the presence of a premature termination codon in the C3 gene that results in a lack of the protein in patient's serum, which correlates with the acceleration of C3 mRNA decay in the patient's fibroblasts."
    explanation: >-
      A nonsense allele with accelerated mRNA decay in patient fibroblasts and
      no serum C3.
  - reference: PMID:1350678
    reference_title: "Homozygous hereditary C3 deficiency due to a partial gene deletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of this deletion in the C3 gene is not compatible with production of any functional C3"
    explanation: >-
      A partial gene deletion (exons 22-23) producing a frameshifted, null
      allele.
  - reference: PMID:15781264
    reference_title: "Molecular analysis of a novel hereditary C3 deficiency with systemic lupus erythematosus."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These data indicate that a novel AG-->GG 3'-splice acceptor site mutation in intron 38 caused aberrant splicing of exon 39, resulting in defective secretion of C3."
    explanation: >-
      An in-frame exon-skipping allele whose product is retained intracellularly,
      the secretion-defect class of C3 deficiency.
  - reference: PMID:26847111
    reference_title: "Skipping of exon 27 in C3 gene compromises TED domain and results in complete human C3 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We also observed that patient's skin fibroblasts stimulated with Escherichia coli LPS were unable to secrete C3, which might be accumulated within the cells before being intracellularly degraded."
    explanation: >-
      A second secretion-defective allele (exon 27 skipping in the TED domain).
  - reference: PMID:31970896
    reference_title: "Successful simultaneous liver-kidney transplantation for renal failure associated with hereditary complement C3 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As C3 is predominantly synthesized in the liver, with a small proportion of C3 monocyte derived and kidney derived, he proceeded to simultaneous liver-kidney transplantation."
    explanation: >-
      States the hepatic origin of most circulating C3, the basis for the
      hepatocyte binding on this node.
  downstream:
  - target: Failure of Complement Activation at the C3 Convergence Point
    causal_link_type: DIRECT
    description: >-
      Without C3 no pathway can generate C3b, so classical and alternative
      pathway activity are both abolished.
  - target: Decreased circulating complement C3
    causal_link_type: DIRECT
    description: >-
      Absent secretion of C3 is measured directly as undetectable serum C3.
- name: Failure of Complement Activation at the C3 Convergence Point
  biological_scale: MOLECULAR
  description: >-
    The classical, lectin and alternative pathways all converge on cleavage of
    C3. With no C3, no C3b is deposited on targets, the alternative-pathway
    amplification loop cannot run, the C5 convertases (which incorporate C3b)
    cannot assemble, and the C3a anaphylatoxin is not generated. Both classical
    (CH50) and alternative pathway haemolytic activity are absent, and adding
    purified C3 restores them in vitro.
  biological_processes:
  - preferred_term: Complement activation
    term:
      id: GO:0006956
      label: complement activation
    modifier: DECREASED
  - preferred_term: Complement activation, alternative pathway
    term:
      id: GO:0006957
      label: complement activation, alternative pathway
    modifier: DECREASED
  - preferred_term: Complement activation, classical pathway
    term:
      id: GO:0006958
      label: complement activation, classical pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:20930072
    reference_title: "Infections of people with complement deficiencies and patients who have undergone splenectomy."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "C3 is the point at which all complement pathways converge, and complete deficiency of C3 invariably leads to severe infections, including those caused by meningococci and pneumococci."
    explanation: >-
      Review statement of C3's position as the convergence point of all
      complement pathways.
  - reference: PMID:11422912
    reference_title: "Hereditary human complement C3 deficiency owing to reduced levels of C3 mRNA."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The classical and alternative pathway haemolytic activities and the generation of opsonins and chemotactic factors derived from the activation of the complement system were markedly affected in the proband's serum."
    explanation: >-
      Patient serum lacks both classical and alternative pathway activity.
  - reference: PMID:11422912
    reference_title: "Hereditary human complement C3 deficiency owing to reduced levels of C3 mRNA."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "An in vitro addition of purified C3 restored the classical pathway-dependent haemolytic activity of his serum."
    explanation: >-
      Reconstitution with purified C3 shows the pathway failure is due to the
      missing C3 alone.
  downstream:
  - target: Impaired C3b Opsonophagocytosis
    causal_link_type: DIRECT
    description: >-
      No C3b or iC3b is deposited on microbes, so complement-receptor-mediated
      phagocytosis fails.
    evidence:
    - reference: PMID:11422912
      reference_title: "Hereditary human complement C3 deficiency owing to reduced levels of C3 mRNA."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The classical and alternative pathway haemolytic activities and the generation of opsonins and chemotactic factors derived from the activation of the complement system were markedly affected in the proband's serum."
      explanation: >-
        Shows that generation of complement-derived opsonins is impaired in
        C3-deficient serum.
  - target: Defective Immune Complex Solubilization and Clearance
    causal_link_type: DIRECT
    description: >-
      C3 fragments keep immune complexes soluble and route them and apoptotic
      debris to clearance; without them complexes persist and deposit.
  - target: Impaired Complement-Dependent Adaptive Immune Priming
    description: >-
      C3 fragments and C3a act on dendritic cells, B cells and T cells, so
      their absence alters adaptive immune responses.
- name: Impaired C3b Opsonophagocytosis
  biological_scale: CELLULAR
  description: >-
    Phagocytes rely on C3b and iC3b to recognise and ingest encapsulated
    bacteria. In C3 deficiency neither antibody-dependent nor
    antibody-independent complement opsonisation is available, which explains
    the early-onset, often invasive pyogenic infections.
  cell_types:
  - preferred_term: Neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: opsonization
    term:
      id: GO:0008228
      label: opsonization
    modifier: DECREASED
  - preferred_term: phagocytosis
    term:
      id: GO:0006909
      label: phagocytosis
    modifier: DECREASED
  evidence:
  - reference: PMID:42445183
    reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "reflecting the indispensable role of C3b-mediated opsonization in defense against encapsulated organisms"
    explanation: >-
      Attributes the encapsulated-organism infection phenotype of C3
      deficiency to loss of C3b opsonisation.
  - reference: PMID:14612669
    reference_title: "Primary immunodeficiencies associated with pneumococcal disease."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Antibody- and complement-mediated opsonization, splenic macrophages and interleukin-1 receptor associated kinase-4- and nuclear factor kappaB-mediated immune responses are crucial for protective immunity to S. pneumoniae."
    explanation: >-
      Review establishing complement opsonisation as essential for defence
      against pneumococcus.
  downstream:
  - target: Recurrent Pyogenic Bacterial Infections
    causal_link_type: DIRECT
    description: >-
      Loss of opsonophagocytic killing of encapsulated organisms manifests as
      recurrent pyogenic infection.
    evidence:
    - reference: PMID:14612669
      reference_title: "Primary immunodeficiencies associated with pneumococcal disease."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Patients at high risk for pneumococcal disease include most if not all B-cell defects (whether due to an intrinsic B-cell anomaly or an impaired T-cell help), deficiencies of early components of the classical pathway of complement and C3 deficiency"
      explanation: >-
        Places C3 deficiency among the immunodeficiencies at high risk for
        pneumococcal disease.
  - target: Recurrent Pneumonia
    description: >-
      Pneumonia is among the most frequent serious infections.
  - target: Bacterial Meningitis
    description: >-
      Invasive pneumococcal and meningococcal disease includes recurrent
      meningitis.
  - target: Recurrent Tonsillitis
    description: >-
      Upper respiratory and ENT infections are the common, milder end of the
      infection spectrum.
  - target: Sepsis
    causal_link_type: DIRECT
    description: >-
      Encapsulated organisms that are not opsonised can reach the bloodstream,
      so sepsis is one of the invasive presentations of the classical case
      literature.
- name: Defective Immune Complex Solubilization and Clearance
  biological_scale: CELLULAR
  description: >-
    C3 fragments solubilise immune complexes and opsonise them, and apoptotic
    cells, for transport and clearance. In their absence immune complexes
    persist and deposit in glomeruli and vessel walls, and uncleared apoptotic
    material is thought to drive loss of tolerance. This is the accepted
    explanation for the glomerulonephritis and SLE-like disease, but it rests on
    case observations and mechanistic inference rather than on direct
    measurement of clearance in C3-deficient patients.
  biological_processes:
  - preferred_term: immune complex clearance
    term:
      id: GO:0002434
      label: immune complex clearance
    modifier: DECREASED
  - preferred_term: apoptotic cell clearance
    term:
      id: GO:0043277
      label: apoptotic cell clearance
    modifier: DECREASED
  evidence:
  - reference: PMID:42445183
    reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Impaired clearance of apoptotic cellular debris, which also depends on C3-mediated opsonization, may further contribute to the breach of self-tolerance observed in affected patients"
    explanation: >-
      States the apoptotic-debris clearance mechanism, hedged ("may"), as the
      route to autoimmunity in C3 deficiency.
  - reference: PMID:39114852
    reference_title: "Case Report: C3 deficiency in two siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Deficiencies in complement proteins, particularly C3, can lead to severe and recurrent infections as well as immune complex disorders."
    explanation: >-
      Links C3 deficiency to immune complex disorders.
  downstream:
  - target: Membranoproliferative Glomerulonephritis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Persisting immune complexes deposit in glomeruli and produce a
      membranoproliferative pattern.
    evidence:
    - reference: PMID:42445183
      reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "approximately 26% develop SLE-like autoimmune illness and around 26% develop membranoproliferative glomerulonephritis, attributable to failure of C3-dependent immune complex solubilization and clearance"
      explanation: >-
        Attributes membranoproliferative glomerulonephritis in C3 deficiency to
        failed immune complex solubilisation and clearance.
  - target: Systemic Lupus Erythematosus-like Disease
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Uncleared immune complexes and apoptotic debris are thought to sustain
      autoantigen exposure and lupus-like disease.
    evidence:
    - reference: PMID:42445183
      reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "approximately 26% develop SLE-like autoimmune illness and around 26% develop membranoproliferative glomerulonephritis, attributable to failure of C3-dependent immune complex solubilization and clearance"
      explanation: >-
        Attributes the SLE-like illness to the same clearance failure.
  - target: Vasculitis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Immune complexes that are not cleared deposit in small vessel walls.
    evidence:
    - reference: PMID:42445183
      reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In the absence of C3b, circulating IgA1-containing immune complexes accumulate and deposit in small vessel walls, where they drive vascular inflammation through complement-independent mechanisms including Fc receptor engagement, cellular recruitment, and direct endothelial activation"
      explanation: >-
        The authors' proposed mechanism for IgA vasculitis in their two
        C3-deficient patients; a hypothesis offered in discussion, not a
        measurement.
- name: Impaired Complement-Dependent Adaptive Immune Priming
  biological_scale: CELLULAR
  description: >-
    Cells from C3-deficient patients show impaired monocyte-to-dendritic-cell
    differentiation and maturation, few switched memory B cells, reduced
    regulatory T-cell induction and defective Th1 induction. Antibody
    responses are variable: one patient failed to sustain a vaccine response,
    while a series of eight patients mounted normal toxoid responses with an
    abnormal IgG subclass pattern. The defect is therefore a skewing of
    adaptive immunity rather than a uniform antibody deficiency.
    The direction of the T-helper change is unsettled: the in vitro study
    (PMID:24321396) reports impaired Th1 induction from patient T cells,
    while the in vivo subclass data (PMID:25446578) show increased
    Th1-related IgG3 responses. The DECREASED modifier on the Th1 process
    below follows the in vitro measurement, and the IgG3 evidence item is
    curated as REFUTE against it.
  cell_types:
  - preferred_term: Dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  - preferred_term: Memory B cell
    term:
      id: CL:0000787
      label: memory B cell
  biological_processes:
  - preferred_term: dendritic cell differentiation
    term:
      id: GO:0097028
      label: dendritic cell differentiation
    modifier: DECREASED
  - preferred_term: memory B cell differentiation
    term:
      id: GO:0002319
      label: memory B cell differentiation
    modifier: DECREASED
  - preferred_term: T-helper 1 type immune response
    term:
      id: GO:0042088
      label: T-helper 1 type immune response
    modifier: DECREASED
  evidence:
  - reference: PMID:18802120
    reference_title: "Human C3 deficiency associated with impairments in dendritic cell differentiation, memory B cells, and regulatory T cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Accordingly, switched memory IgD(-)CD27(+) B cells were barely detected, amounting to only 2.3% of peripheral blood CD19(+) cells."
    explanation: >-
      Near-absent switched memory B cells in a C3-deficient patient.
  - reference: PMID:18802120
    reference_title: "Human C3 deficiency associated with impairments in dendritic cell differentiation, memory B cells, and regulatory T cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The in vitro development of immature dendritic cells and their maturation capacity were greatly impaired, with decreased CD1a expression and IL-12p70 secretion ability."
    explanation: >-
      Patient monocytes fail to differentiate and mature normally into
      dendritic cells.
  - reference: PMID:24321396
    reference_title: "Human complement C3 deficiency: Th1 induction requires T cell-derived complement C3a and CD46 activation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Importantly, and like in CD46-deficient patients, whilst Th1 induction are impaired in C3-deficient patients in vitro, their Th2 responses are unaffected."
    explanation: >-
      T cells from two C3-deficient patients show selectively impaired Th1
      induction.
  - reference: PMID:18802120
    reference_title: "Human C3 deficiency associated with impairments in dendritic cell differentiation, memory B cells, and regulatory T cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vaccination of the child did not induce a long-term Ab response."
    explanation: >-
      A failed durable vaccine antibody response in one patient.
  - reference: PMID:25446578
    reference_title: "Dysregulation of adaptive immune responses in complement C3-deficient patients."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients developed normal Ig responses to tetanus and diphtheria toxoids, but IgE levels were low."
    explanation: >-
      In eight patients, toxoid antibody responses were normal, contradicting a
      general failure of antibody production. The same study found an abnormal
      IgG subclass pattern, so adaptive immunity is altered but not uniformly
      deficient.
  - reference: PMID:25446578
    reference_title: "Dysregulation of adaptive immune responses in complement C3-deficient patients."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The pattern of antigen-specific IgG subclasses was abnormal, with increased Th1-related IgG3 responses, low IgG2, and almost completely undetectable IgG4."
    explanation: >-
      Cuts against the decreased Th1 response claim on this node. In eight
      patients the antigen-specific IgG subclass pattern was skewed towards
      IgG3, which the authors read as a Th1-related response, so the in vivo
      antibody data point the opposite way to the in vitro Th1 induction
      defect of PMID:24321396. The two measurements are different (antibody
      subclass after immunisation in vivo versus T-cell polarisation in
      culture) and have not been reconciled.
  downstream:
  - target: Decreased Memory B Cells
    causal_link_type: DIRECT
    description: >-
      Loss of C3d co-stimulation through CD21 limits generation of memory B
      cells.
    evidence:
    - reference: PMID:39114852
      reference_title: "Case Report: C3 deficiency in two siblings."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "This leads to increased B-cell receptor (BCR) signaling when C3d-opsonized antigens are present on the B-cell surface, facilitating the differentiation from naive to antigen-experienced memory B cells"
      explanation: >-
        Background statement of how C3d-opsonised antigen promotes memory B
        cell differentiation.
  - target: Hypogammaglobulinemia
    description: >-
      Reported in some patients alongside reduced memory B cells and poor
      polysaccharide responses; not present in all.
  - target: Recurrent Pyogenic Bacterial Infections
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired memory B-cell generation may contribute to infections that
      persist despite antibiotic prophylaxis.
    evidence:
    - reference: PMID:39114852
      reference_title: "Case Report: C3 deficiency in two siblings."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Collectively, these observations reinforce the role of C3 on B-cell memory generation and potentially explain why these patients continued to have recurrent infections despite antimicrobial prophylaxis."
      explanation: >-
        The authors propose, hedged, that the B-cell memory defect contributes
        to ongoing infections in their two patients.
phenotypes:
- category: Immunological
  name: Recurrent Pyogenic Bacterial Infections
  frequency: VERY_FREQUENT
  description: >-
    Recurrent, often severe infections with encapsulated bacteria
    (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis)
    beginning in infancy or early childhood, including pneumonia, meningitis,
    sepsis and otorhinolaryngological infections. Severity varies: some recent
    patients have had chronic but non-invasive respiratory and ENT infections
    only.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  evidence:
  - reference: PMID:20930072
    reference_title: "Infections of people with complement deficiencies and patients who have undergone splenectomy."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "C3 is the point at which all complement pathways converge, and complete deficiency of C3 invariably leads to severe infections, including those caused by meningococci and pneumococci."
    explanation: >-
      Review statement that severe infection is a near-universal feature of
      complete C3 deficiency.
  - reference: PMID:18802120
    reference_title: "Human C3 deficiency associated with impairments in dendritic cell differentiation, memory B cells, and regulatory T cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "was identified in a 2-year-old male suffering from recurrent pyogenic infections from early infancy with undetectable total complement hemolytic activity (CH50) and C3 values"
    explanation: >-
      Early-onset recurrent pyogenic infection in a genetically confirmed case.
  - reference: PMID:42445183
    reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients presented with chronic and recurrent infections, predominantly affecting the respiratory and otorhinolaryngological systems, without identification of consistent pathogens."
    explanation: >-
      Two recent patients with chronic, non-invasive respiratory and ENT
      infections, the milder end of the spectrum.
- category: Immunological
  name: Recurrent Pneumonia
  description: >-
    Pneumonia, typically pneumococcal, is among the characteristic severe
    infections.
  phenotype_term:
    preferred_term: Recurrent pneumonia
    term:
      id: HP:0006532
      label: Recurrent pneumonia
  evidence:
  - reference: PMID:15781264
    reference_title: "Molecular analysis of a novel hereditary C3 deficiency with systemic lupus erythematosus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "his medical history revealed recurrent tonsillitis and pneumonia"
    explanation: >-
      Recurrent pneumonia in a patient with homozygous C3 deficiency.
- category: Immunological
  name: Bacterial Meningitis
  description: >-
    Meningitis due to encapsulated bacteria, including meningococcus and
    pneumococcus, sometimes recurrent.
  phenotype_term:
    preferred_term: Meningitis
    term:
      id: HP:0001287
      label: Meningitis
  evidence:
  - reference: PMID:42445183
    reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "is dominated by severe, life-threatening recurrent pyogenic infections, particularly meningitis, sepsis, and pneumonia caused by encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis"
    explanation: >-
      Summarises the classic case literature naming meningitis among the
      dominant infections.
- category: Immunological
  name: Sepsis
  description: >-
    Sepsis is one of the dominant invasive presentations in the classical case
    literature, alongside meningitis and pneumonia. It is not universal: both
    patients in the 2026 Moroccan series had chronic upper respiratory and ENT
    infection without documented bacteraemia.
  phenotype_term:
    preferred_term: Sepsis
    term:
      id: HP:0100806
      label: Sepsis
  evidence:
  - reference: PMID:42445183
    reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "is dominated by severe, life-threatening recurrent pyogenic infections, particularly meningitis, sepsis, and pneumonia caused by encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis"
    explanation: >-
      Summarises the classic case literature naming sepsis among the dominant
      invasive infections of C3 deficiency.
- category: Immunological
  name: Recurrent Tonsillitis
  description: >-
    Recurrent tonsillitis is reported in several patients and represents the
    milder upper-airway end of the infection spectrum.
  phenotype_term:
    preferred_term: Recurrent tonsillitis
    term:
      id: HP:0011110
      label: Recurrent tonsillitis
  evidence:
  - reference: PMID:15781264
    reference_title: "Molecular analysis of a novel hereditary C3 deficiency with systemic lupus erythematosus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "his medical history revealed recurrent tonsillitis and pneumonia"
    explanation: >-
      Recurrent tonsillitis in a patient with homozygous C3 deficiency.
- category: Renal
  name: Membranoproliferative Glomerulonephritis
  frequency: OCCASIONAL
  description: >-
    Immune-complex glomerulonephritis, most often membranoproliferative,
    affects roughly a quarter of patients and can progress to crescentic
    disease and end-stage renal failure.
  phenotype_term:
    preferred_term: Membranoproliferative glomerulonephritis
    term:
      id: HP:0000793
      label: Membranoproliferative glomerulonephritis
  evidence:
  - reference: PMID:42445183
    reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "approximately 26% develop SLE-like autoimmune illness and around 26% develop membranoproliferative glomerulonephritis"
    explanation: >-
      Pooled literature figure for membranoproliferative glomerulonephritis in
      C3 deficiency.
  - reference: PMID:31970896
    reference_title: "Successful simultaneous liver-kidney transplantation for renal failure associated with hereditary complement C3 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a case of an adult with complete deficiency of complement C3 due to homozygous mutations in C3 gene: c.1811delT (Val604Glyfs*2), recurrent bacterial infections, crescentic glomerulonephritis, and end-stage renal failure."
    explanation: >-
      A genetically confirmed case progressing to crescentic glomerulonephritis
      and end-stage renal failure.
- category: Immunological
  name: Systemic Lupus Erythematosus-like Disease
  frequency: OCCASIONAL
  description: >-
    An SLE-like illness (fever, malar rash, photosensitivity, arthralgia,
    Raynaud phenomenon) develops in roughly a quarter of patients, often in
    adolescence.
  phenotype_term:
    preferred_term: Systemic lupus erythematosus
    term:
      id: HP:0002725
      label: Systemic lupus erythematosus
  evidence:
  - reference: PMID:42445183
    reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "approximately 26% develop SLE-like autoimmune illness and around 26% develop membranoproliferative glomerulonephritis"
    explanation: >-
      Pooled literature figure for SLE-like illness in C3 deficiency.
  - reference: PMID:15781264
    reference_title: "Molecular analysis of a novel hereditary C3 deficiency with systemic lupus erythematosus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A case of inherited homozygous complement C3 deficiency (C3D) in a patient with systemic lupus erythematosus (SLE) and the molecular basis for this deficiency are reported."
    explanation: >-
      A molecularly characterised case of C3 deficiency with SLE.
  - reference: PMID:33563058
    reference_title: "Lupus manifestations in children with primary immunodeficiency diseases: Comprehensive phenotypic and genetic features and outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Complement deficiency was the most frequent PIDs; 26 patients were C1q deficient, three patients had C3 deficiency"
    explanation: >-
      In a retrospective Saudi series of 39 children with lupus manifestations
      and a primary immunodeficiency, three had C3 deficiency, an
      observation of lupus in C3-deficient children independent of the single
      case reports above.
- category: Immunological
  name: Vasculitis
  description: >-
    Vasculitis, including IgA vasculitis (Henoch-Schonlein purpura), has been
    reported in a few patients.
  phenotype_term:
    preferred_term: Vasculitis
    term:
      id: HP:0002633
      label: Vasculitis
  evidence:
  - reference: PMID:11422912
    reference_title: "Hereditary human complement C3 deficiency owing to reduced levels of C3 mRNA."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented recurrent bacterial infections, vasculitis and extremely low levels of serum C3 (0.15 microg/ml)"
    explanation: >-
      Vasculitis in a child with hereditary C3 deficiency.
  - reference: PMID:42445183
    reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 6 years of age, he was diagnosed with IgA vasculitis (Henoch-Schonlein purpura), characterized by palpable purpura on the lower extremities, ankle edema, and arthralgia, that was treated with systemic corticosteroids with good clinical response"
    explanation: >-
      IgA vasculitis in a patient with genetically confirmed complete C3
      deficiency.
- category: Hematological
  name: Hemolytic-Uremic Syndrome
  description: >-
    Hemolytic uremic syndrome has been reported in one patient with complete
    C3 deficiency, who also carried risk polymorphisms for atypical HUS. No
    causal edge is drawn: a mechanism connecting absent C3 to HUS is not
    established, and HUS is far more often a consequence of C3
    gain-of-function variants, a different disease.
  phenotype_term:
    preferred_term: Hemolytic-uremic syndrome
    term:
      id: HP:0005575
      label: Hemolytic-uremic syndrome
  evidence:
  - reference: PMID:39114852
    reference_title: "Case Report: C3 deficiency in two siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both, the index case and her sister, presented a history of recurrent infections since early childhood and one of them developed hemolytic uremic syndrome (HUS)."
    explanation: >-
      Single-case report of HUS in a sibling with complete C3 deficiency.
- category: Immunological
  name: Decreased Memory B Cells
  description: >-
    Reduced switched and non-switched memory B cells.
  phenotype_term:
    preferred_term: Decreased memory B cell proportion
    term:
      id: HP:0030374
      label: Decreased memory B cell proportion
  evidence:
  - reference: PMID:18802120
    reference_title: "Human C3 deficiency associated with impairments in dendritic cell differentiation, memory B cells, and regulatory T cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Accordingly, switched memory IgD(-)CD27(+) B cells were barely detected, amounting to only 2.3% of peripheral blood CD19(+) cells."
    explanation: >-
      Near-absent switched memory B cells.
  - reference: PMID:39114852
    reference_title: "Case Report: C3 deficiency in two siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunological evaluation revealed absent plasma C3 levels, decreased memory B cells, hypogammaglobulinemia, and impaired response to polysaccharide antigens."
    explanation: >-
      Decreased memory B cells in two siblings with complete C3 deficiency.
- category: Immunological
  name: Hypogammaglobulinemia
  description: >-
    Hypogammaglobulinemia with impaired polysaccharide responses was reported
    in two siblings and led to immunoglobulin replacement. It is not a
    constant feature: other patients have normal immunoglobulin levels.
  phenotype_term:
    preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:39114852
    reference_title: "Case Report: C3 deficiency in two siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunological evaluation revealed absent plasma C3 levels, decreased memory B cells, hypogammaglobulinemia, and impaired response to polysaccharide antigens."
    explanation: >-
      Hypogammaglobulinemia in two siblings with complete C3 deficiency.
  - reference: PMID:42445183
    reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunological investigations revealed normal lymphocyte subsets, immunoglobulin levels, and neutrophil oxidative burst."
    explanation: >-
      Two other patients had normal immunoglobulin levels, so
      hypogammaglobulinemia is not a consistent feature.
- category: Laboratory
  name: Decreased circulating complement C3
  frequency: VERY_FREQUENT
  description: >-
    Serum C3 is undetectable or below 1% of normal in complete deficiency, with
    absent or markedly reduced CH50.
  phenotype_term:
    preferred_term: Undetectable serum C3
    term:
      id: HP:0005421
      label: Decreased circulating complement C3 concentration
  evidence:
  - reference: PMID:42445183
    reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "complement analysis showed undetectable C3 levels and markedly reduced CH50, with normal C4, consistent with isolated complete C3 deficiency"
    explanation: >-
      The defining laboratory pattern: undetectable C3, low CH50, normal C4.
biochemical:
- name: Serum C3
  presence: DECREASED
  notes: >-
    Undetectable in affected individuals; about half of normal in heterozygous
    relatives. Normal C4 distinguishes primary deficiency from classical
    pathway consumption, but not from alternative pathway consumption due to
    factor H or factor I deficiency, where C3 is usually low but detectable.
  evidence:
  - reference: PMID:42445183
    reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "complement analysis showed undetectable C3 levels and markedly reduced CH50, with normal C4, consistent with isolated complete C3 deficiency"
    explanation: >-
      Undetectable C3 with normal C4 in genetically confirmed patients.
  - reference: PMID:26847111
    reference_title: "Skipping of exon 27 in C3 gene compromises TED domain and results in complete human C3 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "complement C3 levels were undetectable in the patient's serum and were reduced by at least 50% in the sera of the patient's parents and brother"
    explanation: >-
      Undetectable C3 in the patient and roughly half-normal C3 in carriers.
- name: Serum CH50 (total classical pathway haemolytic activity)
  presence: DECREASED
  notes: >-
    Absent or markedly reduced, as is alternative pathway haemolytic activity,
    because both pathways require C3.
  evidence:
  - reference: PMID:26847111
    reference_title: "Skipping of exon 27 in C3 gene compromises TED domain and results in complete human C3 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hemolytic assays revealed complete lack of complement-mediated hemolytic activity in the patient's serum."
    explanation: >-
      Complete loss of haemolytic complement activity in a C3-deficient
      patient.
diagnosis:
- name: Complement screening (C3, C4, CH50, AP50)
  description: >-
    Quantitative C3 and C4 together with classical (CH50) and alternative
    (AP50) pathway haemolytic activity. Undetectable C3 with absent CH50 and
    AP50 but a normal C4 separates primary C3 deficiency from classical
    pathway consumption (immune-complex disease such as SLE), where C4 falls
    as well. A normal C4 does not exclude alternative pathway consumption:
    deficiency of factor H or factor I, or a C3 nephritic factor, lowers C3
    and factor B with C4 preserved. In those conditions C3 is usually low
    rather than undetectable, and measuring factor B, factor H and factor I
    separates them from primary C3 deficiency. This is the test that makes
    the diagnosis, and in both patients of the 2026 Moroccan series it was
    done only years after symptom onset.
  diagnosis_term:
    preferred_term: complement screening assay
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  markers: serum C3, serum C4, CH50, AP50
  evidence:
  - reference: PMID:42445183
    reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "complement analysis showed undetectable C3 levels and markedly reduced CH50, with normal C4, consistent with isolated complete C3 deficiency"
    explanation: >-
      The diagnostic pattern as measured in two genetically confirmed
      patients.
  - reference: PMID:42445183
    reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the need to include complement screening, specifically serum CH50, AP50, C3, and C4, in the standard immunological evaluation of any child presenting with recurrent infections of unexplained etiology"
    explanation: >-
      Names the four analytes of the screening panel and the clinical setting
      in which the authors recommend it.
  - reference: PMID:6545495
    reference_title: "Complement activation in renal disease."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "a primary deficiency of factor H or I or both, will secondarily produce subnormal levels of C3 and factor B"
    explanation: >-
      Review caveat on reading a complement profile: regulator deficiency
      lowers C3 secondarily, so a low C3 with normal C4 is not by itself
      primary C3 deficiency.
  - reference: PMID:16138437
    reference_title: "Complement factor I deficiency associated with recurrent infections, vasculitis and immune complex glomerulonephritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A moderately low C3 level together with the clinical picture suggested a deficiency affecting regulation of complement activation."
    explanation: >-
      A factor I-deficient child with recurrent pyogenic infection, vasculitis
      and immune-complex glomerulonephritis, the same clinical picture as C3
      deficiency, but with a moderately low rather than undetectable C3. This
      is the differential the regulator measurements resolve.
- name: C3 gene sequencing
  description: >-
    Sequencing of C3 confirms the diagnosis and identifies the causal
    biallelic alleles, which is what allows carrier testing and counselling in
    the family. Reported patients have been diagnosed by gene panel or
    next-generation sequencing with Sanger confirmation and segregation
    analysis.
  diagnosis_term:
    preferred_term: C3 gene sequencing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:42445183
    reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pattern of undetectable C3 with normal C4 and absent CH50/AP50 is pathognomonic for C3 deficiency and should trigger immediate referral for genetic analysis"
    explanation: >-
      Places gene sequencing after the complement screen in the diagnostic
      sequence.
  - reference: PMID:42445183
    reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sanger sequencing was performed to confirm the NGS findings and to conduct segregation analysis."
    explanation: >-
      The sequencing route used in two genetically confirmed patients,
      including family segregation.
  - reference: PMID:39114852
    reference_title: "Case Report: C3 deficiency in two siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis in the index case was performed by next-generation sequencing (NGS) using a gene panel"
    explanation: >-
      A compound heterozygous diagnosis reached by complement gene panel
      sequencing.
genetic:
- name: C3
  gene_term:
    preferred_term: C3
    term:
      id: hgnc:1318
      label: C3
  relationship_type: CAUSATIVE
  notes: >-
    Biallelic loss-of-function variants (nonsense, frameshift, splice-site,
    partial deletion, and secretion-blocking in-frame or missense alleles)
    cause complete C3 deficiency. Heterozygous gain-of-function C3 variants
    cause a different disease, atypical hemolytic uremic syndrome, and are not
    part of this entry. ClinGen classifies C3 for that aHUS disease
    (MONDO:0013043), not for C3 deficiency, so no gene-disease validity tier is
    recorded here.
  evidence:
  - reference: PMID:2212005
    reference_title: "Molecular basis of hereditary C3 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This mutation is sufficient to cause the deficiency of C3 in the patient."
    explanation: >-
      A homozygous C3 splice-site null allele causing deficiency.
  - reference: PMID:12462331
    reference_title: "Homozygous hereditary C3 deficiency due to a premature stop codon."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified the mutations responsible for a complete homozygous C3 deficiency."
    explanation: >-
      A homozygous premature stop codon in C3 in complete deficiency.
  - reference: PMID:42445183
    reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss-of-function (LoF) is the established and predominant disease mechanism for autosomal recessive complete C3 deficiency."
    explanation: >-
      States loss of function as the disease mechanism.
prevalence:
- population: Worldwide (published cases)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Fewer than 50 cases reported worldwide since the first description in
    1972. No population prevalence estimate exists.
  evidence:
  - reference: PMID:42445183
    reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "fewer than 50 cases have been reported worldwide"
    explanation: >-
      Case count from a 2026 literature review.
animal_models:
- name: C3-deficient mouse
  species: Mouse
  genotype: C3(-/-)
  publication: PMID:12496386
  description: >-
    Targeted C3 knockout mice, used to test which humoral responses need C3.
    The cited studies address the adaptive-immunity arm of the disease, not
    the infection or immune-complex disease arms.
  modeled_mechanisms:
  - target: Impaired Complement-Dependent Adaptive Immune Priming
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      C3-deficient mice mount a poor primary antibody response to a bacterial
      capsular polysaccharide, without class switching, and fail to deliver
      antigen and immune complexes to marginal zone B cells and follicular
      dendritic cells. This is a mechanism for the poor polysaccharide
      responses and memory B-cell deficit reported in patients.
    limitations: >-
      The antigens are group B streptococcal type III polysaccharide and
      experimental IgG3 immune complexes, not the pneumococcal, meningococcal
      and Haemophilus antigens relevant to patients. In patients the antibody
      defect is variable: one series of eight mounted normal toxoid responses,
      so the knockout's uniform defect overstates the human phenotype. The
      cited studies do not examine infection susceptibility, lupus-like
      disease or glomerulonephritis.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Mouse splenic marginal zone B-cell and follicular dendritic cell
        handling of polysaccharide antigen is the readout; how closely human
        polysaccharide responses depend on the same route is not tested in
        these studies.
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        The model measures antibody to a single experimental polysaccharide
        antigen, standing in for the node's broader claim about memory B-cell
        generation and specific antibody responses in patients.
    readouts:
    - name: Primary antibody response to capsular polysaccharide
      target: Impaired Complement-Dependent Adaptive Immune Priming
      direction: DECREASED
      interpretation: >-
        Low IgM without switching to IgG after polysaccharide immunisation.
      evidence:
      - reference: PMID:12496386
        reference_title: "Impaired antibody response to group B streptococcal type III capsular polysaccharide in C3- and complement receptor 2-deficient mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The defective response was characterized by low IgM levels and the lack of an isotype switch from IgM to IgG Ab production."
        explanation: The measured antibody defect in C3-deficient mice.
    - name: Antigen deposition on follicular dendritic cells
      target: Impaired Complement-Dependent Adaptive Immune Priming
      direction: DECREASED
      interpretation: >-
        Without C3, antigen and immune complexes are not captured by marginal
        zone B cells or deposited on follicular dendritic cells.
      evidence:
      - reference: PMID:28710441
        reference_title: "IgG3-antigen complexes are deposited on follicular dendritic cells in the presence of C1q and C3."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Capture of antigen by MZ B cells as well as antigen deposition on FDC was severely impaired in mice lacking C1q or C3"
        explanation: >-
          Immune-complex trafficking to follicular dendritic cells fails in
          C3-deficient mice.
  evidence:
  - reference: PMID:12496386
    reference_title: "Impaired antibody response to group B streptococcal type III capsular polysaccharide in C3- and complement receptor 2-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice deficient in C3 or Cr2 had an impaired primary immune response to III-PS."
    explanation: >-
      Establishes the C3 knockout as a model of a defective primary antibody
      response to bacterial capsular polysaccharide.
treatments:
- name: Vaccination Against Encapsulated Bacteria
  description: >-
    Conjugate pneumococcal, meningococcal and Haemophilus influenzae type b
    vaccination is a standard part of management. Unlike C2 deficiency, there
    is no alternative pathway to route vaccine antibody through, so benefit is
    expected to come from antibody-mediated, complement-independent
    mechanisms; responses in reported patients were partial.
  therapeutic_modality: VACCINE
  treatment_term:
    preferred_term: vaccination against encapsulated bacteria
    term:
      id: NCIT:C15346
      label: Vaccination
  evidence:
  - reference: PMID:39114852
    reference_title: "Case Report: C3 deficiency in two siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regarding the management of complement deficiencies, clinical control, vaccination with protein-polysaccharides conjugate, and antimicrobial prophylaxis are considered cornerstones in treatment"
    explanation: >-
      States conjugate vaccination as a cornerstone of management.
- name: Antibiotic Prophylaxis
  description: >-
    Continuous antibiotic prophylaxis, usually penicillin or amoxicillin, is
    recommended and reduced severe infections in some reports, though not in
    every patient.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: antibiotic prophylaxis
    term:
      id: NCIT:C51993
      label: Antibiotic Prophylaxis
  evidence:
  - reference: PMID:42445183
    reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Continuous antibiotic prophylaxis, typically with penicillin, significantly reduces infection frequency and is strongly recommended"
    explanation: >-
      States the recommendation for continuous penicillin prophylaxis.
  - reference: PMID:39114852
    reference_title: "Case Report: C3 deficiency in two siblings."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite antimicrobial prophylaxis, they continue to suffer from recurrent sinopulmonary infections."
    explanation: >-
      In two siblings prophylaxis did not prevent recurrent infection.
- name: Intravenous Immunoglobulin Replacement
  description: >-
    Considered when C3 deficiency is accompanied by hypogammaglobulinemia or
    poor specific antibody responses; in two siblings it markedly reduced
    infection frequency.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: intravenous immunoglobulin
      term:
        id: NCIT:C80829
        label: Human Immunoglobulin G
  target_mechanisms:
  - target: Hypogammaglobulinemia
    description: >-
      Replaces the deficient antibody.
  evidence:
  - reference: PMID:39114852
    reference_title: "Case Report: C3 deficiency in two siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, the failure of antimicrobial prophylaxis to prevent recurrent sinopulmonary infections, as well as the evidence of impaired antibody synthesis or response, led to the decision of initiating intravenous immunoglobulin (IVIG) replacement therapy, leading to a marked decrease in the number of infections."
    explanation: >-
      IVIG reduced infections in two siblings with antibody defects.
- name: Fresh Frozen Plasma
  description: >-
    Plasma infusion supplies C3 temporarily during acute infection or
    perioperatively; the short duration of effect and transfusion risks limit
    routine prophylactic use.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: fresh frozen plasma transfusion
    term:
      id: NCIT:C116475
      label: Fresh Frozen Plasma Transfusion
  target_mechanisms:
  - target: Failure of Complement Activation at the C3 Convergence Point
    description: >-
      Transiently restores circulating C3.
  evidence:
  - reference: PMID:42445183
    reference_title: "Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Fresh frozen plasma (FFP) infusions can provide temporary complement replacement during acute infections or perioperative periods, though the logistical challenges, risks, and short duration of effect limit its routine prophylactic use"
    explanation: >-
      Describes the role and limits of plasma replacement.
- name: Simultaneous Liver-Kidney Transplantation
  description: >-
    In one adult with end-stage renal failure from glomerulonephritis,
    combined liver-kidney transplantation restored circulating C3, since the
    liver is the main source of C3; isolated kidney transplantation would have
    left him C3 deficient. A single case.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: simultaneous liver-kidney transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  target_mechanisms:
  - target: C3 Biallelic Loss of Function
    description: >-
      A donor liver supplies normal C3.
  evidence:
  - reference: PMID:31970896
    reference_title: "Successful simultaneous liver-kidney transplantation for renal failure associated with hereditary complement C3 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The procedure has been successful with restoration of his circulating C3 levels, normal liver and kidney function at 26 months of follow-up."
    explanation: >-
      Restoration of C3 after combined transplantation in one patient.
notes: >-
  No GeneReviews chapter was found for C3 deficiency. Most of the literature is
  single case reports; frequencies for glomerulonephritis and SLE-like disease
  are pooled literature estimates quoted in a 2026 case report.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Reconcile with OpenScientist deep research · 2026-10-15T04:16:29Z · View source

Committed an OpenScientist deep-research report (research/Complement_Component_3_Deficiency-deep-research-openscientist.md, with its citations sidecar and artifacts) and cross-checked it against the entry. An earlier OpenScientist run timed out at the provider's 1-hour limit and produced no report; an Asta run returned off-topic material and was not committed. The report's 18 references all resolved and its claims largely restate what the entry already carried. Added: (1) PMID:33563058, a Saudi series of 39 children with lupus manifestations and a primary immunodeficiency, three of them C3-deficient, as further evidence on the SLE-like disease phenotype. (2) A correction to the diagnosis and biochemical text: the entry said a normal C4 separates primary C3 deficiency from secondary C3 consumption, which holds for classical-pathway consumption only. Factor H or factor I deficiency and C3 nephritic factor lower C3 and factor B with a normal C4, usually leaving C3 low rather than undetectable; cited PMID:6545495 (review caveat, REVIEW_SYNTHESIS) and PMID:16138437 (factor I-deficient child with the same clinical picture and moderately low C3). (3) An animal_models record for the C3 knockout mouse linked to Impaired Complement-Dependent Adaptive Immune Priming as PARTIALLY_RECAPITULATES, with readouts from PMID:12496386 (low IgM, no class switch to a capsular polysaccharide) and PMID:28710441 (failed immune-complex deposition on follicular dendritic cells), and limitations noting that patient antibody defects are variable. No new phenotype was added, so no pathograph wiring changed. Left out: generic complement biology (C3 crystal structure PMID:16177781, CRIg PMID:38032267, complement-inhibitor infection risk PMID:42175904); complement-deficiency epidemiology and management not specific to C3 (PMID:25037634, 16836843, 37356020, 28078901, and the C2 deficiency follow-up PMID:32164349); anifrolumab in C1q-deficient lupus (PMID:42597478), which the report itself extends to C3 only by inference; a C3-knockout systemic sclerosis model (PMID:39737181), which concerns a different disease; and C3 nephritic factor biology (PMID:19640589), which belongs to C3 glomerulopathy and whose quoted passage the report's validator could not match in full. Validated with just validate, count-verified-snippets (73/73), validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-snippet-grading, check-retired-support-prose, validate-disorders, check-gene-activity-grounding and check-groupings.

Create: Complement_Component_3_Deficiency · 2026-10-15T02:33:05Z · View source

New entry for complete complement C3 deficiency (MONDO:0013417, C3 hgnc:1318), modelled on Complement_Component_2_Deficiency. Deep research was not available in this session (no provider credentials), so literature was gathered directly from PubMed searches; 15 references were fetched with just fetch-reference and every snippet is an exact substring of the cached text (59/59 verified). Key sources: Ram 2010 review (PMID:20930072) for convergence-point role and infection risk; molecular case reports for null and secretion-defective alleles (PMIDs 2212005, 1350678, 12462331, 14639503, 15781264, 26847111); a 2026 case report (PMID:42445183) for the pooled ~26% SLE-like and ~26% MPGN figures and the <50 case count, marked quote_role BACKGROUND; adaptive-immunity studies (PMIDs 18802120, 24321396, 25446578). PMID:25446578 is curated as REFUTE on a uniform antibody defect (normal toxoid responses in eight patients) and PMID:42445183 as REFUTE on hypogammaglobulinemia being constant; PMID:39114852 as REFUTE on antibiotic prophylaxis always preventing infection. Hemolytic-uremic syndrome (one patient, PMID:39114852) is left without a causal edge because no mechanism links absent C3 to HUS. No GeneReviews chapter exists (just check-genereviews: NO_CHAPTER). ClinGen classifies C3 only for aHUS (MONDO:0013043), so no gene_disease_validity is recorded. Added as a member of kb/groupings/Complement_Deficiency_IEIs.yaml (criterion SATISFIED). Validated with just validate, validate-terms, count-verified-snippets, check-entity-refs, check-causal-targets, check-duplicate-keys, validate-disorders, validate-grouping and check-groupings.

OpenScientist ▸
Complement Component 3 (C3) Deficiency — Comprehensive Disease Characteristics Report
openscientist-autonomous 18 citations 2026-10-15T04:09:17.222769

Complement Component 3 (C3) Deficiency — Comprehensive Disease Characteristics Report

Disease: Complement Component 3 Deficiency MONDO ID: MONDO:0013417 · OMIM: #613779 (disease), 120700 (gene) · Orphanet: ORPHA:280133 · DOID: 8354 · NCIT: C9468 · GARD: 0016489 · UMLS: C3151071 · MeSH: C565169 · MedGen: 462421 Category:* Mendelian (autosomal recessive inborn error of immunity)

Summary

Complement component 3 (C3) deficiency is an extremely rare autosomal-recessive inborn error of immunity caused by biallelic loss-of-function variants in the C3 gene (HGNC:1318; chromosome 19p13.3; UniProt P01024). Fewer than 50 cases have been reported worldwide, making it one of the rarest of all complement deficiencies — which themselves comprise only ~1–10% of primary immunodeficiencies. The biochemical hallmark is undetectable serum C3 with markedly reduced CH50 and normal C4, reflecting failure of all three complement activation pathways at their convergence node (PMID: 42445183).

Because C3 is the central protein through which the classical, alternative, and lectin pathways all pass, its complete loss abolishes C3b-thioester–mediated opsonization, C3a/C5a-driven inflammation, terminal membrane attack complex (MAC) formation, and immune-complex clearance and B-cell co-stimulation. This produces a characteristic dual clinical phenotype: (1) recurrent, severe, invasive pyogenic infections by encapsulated bacteria (Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae) with a predominance of respiratory/ENT disease, sepsis and meningitis; and (2) immune-complex-mediated disease, including SLE-like autoimmunity and membranoproliferative/mesangioproliferative glomerulonephritis. The autoimmune arm reflects the broader "complement–SLE hierarchy," in which early-complement-component deficiencies are the strongest known monogenic risk factors for lupus and are linked to type I interferon dysregulation.

There is no curative therapy. Management is preventive and supportive, centered on conjugate-polysaccharide vaccination against encapsulated bacteria and consideration of long-term antibiotic prophylaxis; analogous early-complement deficiencies show that early diagnosis plus prophylaxis can allow a near-normal life. A crucial clinical caveat is that low serum C3 is far more often secondary (deficiency of regulators factor H or factor I, C3 nephritic factor / C3 glomerulopathy, or classical-pathway consumption in SLE) than due to primary genetic C3 deficiency, which is defined by undetectable C3 with normal C4.

Key Findings

1. Disease definition, identifiers, and nature of evidence (F001, F010)

Complete C3 deficiency is an ultra-rare autosomal-recessive inborn error of immunity caused by homozygous or compound-heterozygous loss-of-function variants in C3. The authoritative MONDO definition (MONDO:0013417) describes "a rare genetic disorder with an autosomal recessive pattern of inheritance… caused by the ineffective or decreased biosynthesis of the third complement component, C3," with clinical signs appearing "within the first decade of life… consistent with the signs of recurrent systemic infection or immune complex disease." The definition further notes that "deficiency of serum C3 and its major cleavage product, C3b, will decrease the effective humoral immune response to encapsulated bacteria" and that C3 deficiency "also impairs clearance of circulating immune complexes and therefore predisposes to rheumatic and renal disease."

Cross-reference identifiers were verified against EBI OLS4/MONDO: OMIM 613779, Orphanet 280133, MeSH C565169, UMLS C3151071, MedGen 462421, DOID:8354, NCIT C9468, GARD 0016489, NANDO 2200782.

Synonyms / alternative names: C3 deficiency; complement component 3 deficiency, autosomal recessive; C3 classic complement early component deficiency; classic complement early component deficiency caused by mutation in C3.

Nature of the evidence: Because the disease is ultra-rare (<50 cases), most knowledge derives from aggregated disease-level resources (OMIM, Orphanet, MONDO, HPOA) and individual case reports/small series rather than large EHR cohorts. Mechanistic inferences are supported by model-organism (C3-knockout mouse) and in-vitro/structural studies, and by extrapolation from the better-characterized early-complement deficiencies (C1q, C2, factor H, factor I) (PMID: 42445183).

2. Clinical phenotype — infections plus immune-complex/autoimmune disease (F002, F011)

The clinical phenotype has two arms. In the infectious arm, patients suffer recurrent severe pyogenic infections with a predominance of the respiratory and otorhinolaryngological tracts, plus invasive disease (sepsis, meningitis) from encapsulated organisms. The index report notes that "both patients presented with chronic and recurrent infections, predominantly affecting the respiratory and otorhinolaryngological systems" (PMID: 42445183).

In the autoimmune/immune-complex arm, a subset develop SLE-like disease and membranoproliferative/mesangioproliferative glomerulonephritis. In a Saudi pediatric PID-lupus cohort, complement deficiency was the most frequent underlying PID, and "three patients had C3 deficiency" (PMID: 33563058). More broadly, "the genetic deficiency of any early component of the classical pathway (C1q, C1r/s, C2, C4) is often associated with autoimmune diseases" (PMID: 25037634).

Curated HPO phenotype annotations (OMIM:613779 / HPOA; primary source PMID:15781264):

Phenotype HPO term Noted frequency
Decreased circulating complement C3 concentration HP:0005421 2/2
Recurrent bacterial infections HP:0002718 1/1
Recurrent pneumonia HP:0006532 2/2
Recurrent tonsillitis HP:0011110 1/1
Recurrent fever HP:0001954 1/1
Systemic lupus erythematosus HP:0002725 1/1
Membranoproliferative glomerulonephritis HP:0000793 —
Nephrotic syndrome HP:0000100 —
Renal insufficiency HP:0000083 —
Childhood onset HP:0011463 —
Infantile onset HP:0003593 —
Autosomal recessive inheritance HP:0000007 —

Quality of life: No disease-specific QoL instruments (EQ-5D, SF-36) data are available for this ultra-rare disorder. Impact is driven by recurrent hospitalizations for invasive infection and, where present, by chronic kidney disease from glomerulonephritis.

3. Molecular/genetic information (F001, F005, F012)

  • Causal gene: C3 (complement C3), HGNC:1318, NCBI Gene 718, Ensembl ENSG00000125730, cytoband 19p13.3, protein-coding. OMIM gene *120700; disease #613779.
  • Protein: UniProt P01024. Sequence length = 1663 aa precursor (signal peptide 1–22; mature "Complement C3" chain = residues 23–1663 = 1641 aa), processed into a β-chain (23–667, 645 aa) and α-chain (672–1663, 992 aa), with embedded fragments C3a (672–748), C3b (749–1663), C3d (1002–1303), and C3f (1304–1320). The 1663 (precursor) vs 1641 (mature) residue count discrepancy was reconciled: crystallographic studies describe the mature 1,641-residue protein (PMID: 16177781), while UniProt reports the full precursor.
  • Variant spectrum: Nonsense, frameshift, missense, and splice-site variants have been reported. Example: a novel homozygous splice-site variant, NM_000064.3:c.4030-1_4030delinsCT, in Moroccan patients (PMID: 42445183). Variants are germline and typically loss-of-function (ACMG pathogenic/likely pathogenic).
  • Functional consequence: Absent or non-functional C3, with loss of the thioester-mediated opsonic function.
  • Modifier genes / epigenetics / chromosomal abnormalities: No established disease-specific modifier genes or epigenetic signatures for primary C3 deficiency; the disorder is a single-gene, protein-truncating/loss-of-function condition rather than a structural/chromosomal syndrome. Allele frequencies of pathogenic C3 LoF variants are correspondingly rare in gnomAD given the <50-case worldwide total.

4. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

1. Biallelic loss-of-function variant in C3 (19p13.3)
   → leads to absent or non-functional C3 protein (undetectable serum C3; normal C4).
2. Loss of C3 abolishes the convergence node of all three complement pathways
   → results in failure to generate C3 convertase products C3a and C3b.
3a. [INFECTION BRANCH] No C3b thioester deposition on microbial surfaces
   → leads to loss of opsonophagocytosis (no CRIg/CR1-mediated phagocyte uptake)
   → and failure to assemble downstream C5 convertase / MAC
   → results in defective killing of encapsulated bacteria
   → leads to recurrent invasive pyogenic infection (pneumonia, sepsis, meningitis).
3b. [AUTOIMMUNE BRANCH] No C3b/iC3b tagging of apoptotic debris and immune complexes
   → leads to impaired clearance of circulating immune complexes and apoptotic cells
   → results in autoantibody formation and tissue immune-complex deposition
   → leads to SLE-like disease and membranoproliferative glomerulonephritis.
3c. [HUMORAL BRANCH, inferred from mouse] Loss of C3d–CR2/CD21 B-cell co-stimulation
   → leads to impaired antibody responses (esp. to polysaccharide antigens) and
     defective immune-complex trafficking to follicular dendritic cells
   → compounds susceptibility to encapsulated bacteria.

Central node mechanism (F003, F005). C3 is the convergence point of the classical, alternative, and lectin pathways. "Key complement functions (C3b-mediated opsonisation, C3a/C5a-driven inflammation, and membrane attack complex formation) underlie target-specific patterns of infectious risk" (PMID: 42175904). C3 is cleaved by C3 convertases into C3a (anaphylatoxin) and C3b, which deposits on surfaces via its reactive thioester and is recognized by phagocyte receptors; the complement receptor CRIg "binds to certain C3 cleavage products (C3b, iC3b, C3c)" (PMID: 38032267).

Protein-structural basis (F005). Crystal structures of native C3 and fragment C3c reveal a 1,641-residue protein built from thirteen domains in the α₂-macroglobulin family. "Activation of component C3 (1,641 residues) is central to the three complement pathways and results in inflammation and elimination of self and non-self targets," and "a double mechanism prevents hydrolysis of the thioester group, essential for covalent attachment of activated C3 to target surfaces" (PMID: 16177781). In deficiency, the opsonic thioester chemistry is entirely absent.

Autoimmune mechanism and the complement–SLE hierarchy (F009). Early-complement-component deficiencies are the strongest monogenic risk factors for SLE, graded by cascade position (C1q > C4 > C2), with C3 deficiency also predisposing to lupus-like disease. Mechanistically, deficiency impairs complement-mediated clearance of apoptotic cells and immune complexes, producing autoantibodies, immune-complex deposition, and complement consumption. Monogenic complement-deficient SLE is frequently early-onset and refractory and is "linked to interferon pathway dysregulation," with C1q-deficient pediatric SLE responding to the anti-type-I-interferon-receptor antibody anifrolumab (PMID: 42597478).

Molecular pathways / GO & CL suggestions. Biological processes: complement activation (GO:0006956), complement activation alternative pathway (GO:0006957), classical pathway (GO:0006958), lectin pathway (GO:0001867), opsonization (GO:0008228), complement-dependent cytotoxicity, positive regulation of B-cell activation. Cellular component: extracellular space (GO:0005615) (C3 is a secreted plasma protein, mainly hepatocyte-derived). Chemical entity: the reactive thioester underlies covalent opsonization (CHEBI thioester class). Cell types involved: hepatocyte (CL:0000182) (primary synthesis), macrophage (CL:0000235) / neutrophil (CL:0000775) (opsonophagocytosis via complement receptors), follicular dendritic cell (CL:0000442) and B cell (CL:0000236) (immune-complex trafficking / co-stimulation).

5. Anatomical structures affected

  • Primary "organ": the blood/plasma complement system (C3 is a circulating plasma glycoprotein); the liver (UBERON:0002107) is the principal site of C3 synthesis (hepatocytes).
  • Secondary organ involvement: lung/airway and ENT (UBERON:0002048 lung; UBERON:0001557 upper respiratory tract) — recurrent pneumonia/tonsillitis; meninges / CNS (meningitis); kidney (UBERON:0002113) — membranoproliferative/mesangioproliferative glomerulonephritis, nephrotic syndrome, renal insufficiency; skin and joints in SLE-like disease.
  • Body systems: immune/hematologic, respiratory, renal/genitourinary, and (via autoimmunity) musculoskeletal and integumentary.
  • Tissue/cell level: glomerular mesangial and capillary structures (immune-complex deposition); phagocytes; follicular dendritic cells; B cells. Subcellular: C3 is secreted; opsonization occurs at the plasma-membrane/extracellular interface (GO:0005615).
  • Lateralization: not applicable — a systemic circulating-protein deficiency; organ involvement (e.g., glomerulonephritis) is bilateral/systemic.

6. Temporal development (F001, F010, F011)

  • Onset: Clinical signs typically appear within the first decade of life (HPO: Childhood onset HP:0011463; Infantile onset HP:0003593), consistent with recurrent systemic infection or immune-complex disease.
  • Onset pattern: Chronic/recurrent rather than a single acute event; infections are episodic and recurrent.
  • Progression/course: Lifelong; infection susceptibility persists. Autoimmune/renal complications may accumulate over time; glomerulonephritis can progress to chronic kidney disease.
  • Critical period / window of opportunity: Early diagnosis enables vaccination and prophylaxis before major invasive infection — the key modifiable determinant of outcome.

7. Inheritance and population (F001, F008)

  • Inheritance: Autosomal recessive (HP:0000007). Biallelic (homozygous or compound-heterozygous) loss-of-function C3 variants.
  • Penetrance/expressivity: Biochemical penetrance of undetectable C3 is complete in biallelic LoF; clinical expressivity is variable (infection-predominant vs autoimmune-predominant vs, rarely, milder courses), consistent with other complement deficiencies.
  • Epidemiology: Complement deficiencies comprise "between 1 and 10% of all primary immunodeficiencies" (PMID: 25037634); in some pediatric PID series as low as ~1.1% (PMID: 16836843). Complete C3 deficiency specifically is among the rarest — "fewer than 50 cases have been reported to date, and the genetic and phenotypic spectrum remains incompletely defined" (PMID: 42445183). It is widely underdiagnosed because few centers offer comprehensive complement analysis.
  • Founder effects / consanguinity: Consanguinity and geographic clustering contribute to cases (e.g., multiple cases from the same region of Morocco). No large exact prevalence/incidence figures exist given rarity.
  • Sex ratio / age distribution: No reliable sex predilection established for primary C3 deficiency; onset in childhood.

8. Diagnostics (F001, F007)

  • Laboratory hallmark: undetectable serum C3 with markedly reduced CH50 and normal C4 — "complement analysis showed undetectable C3 levels and markedly reduced CH50, with normal C4, consistent with isolated complete C3 deficiency" (PMID: 42445183). Both CH50 (classical) and AH50 (alternative) are low/absent because C3 is shared by both.
  • Functional/screening assays: CH50 and AH50 total hemolytic complement assays as screens; individual component quantitation (C3, C4, factor B, factor H, factor I) to localize the defect. LOINC-codable assays include serum C3, C4, and total complement (CH50).
  • Genetic testing: Confirmatory single-gene C3 sequencing or NGS panel/exome; "NGS identified a novel homozygous splice-site variant in the C3 gene" (PMID: 42445183). Cascade testing of relatives is appropriate.
  • Differential diagnosis (F007) — critical: Low serum C3 is more often secondary than primary:
  • Factor H or factor I deficiency → secondary C3 consumption via the unchecked alternative pathway. "A primary deficiency of factor H or I or both, will secondarily produce subnormal levels of C3 and factor B" (PMID: 6545495); and in CFI deficiency, "no detectable factor I (<2%) together with a low level of factor B and a moderately low level of factor H, indicating consumption secondary to the factor I deficiency" (PMID: 16138437).
  • C3 nephritic factor (C3NeF) autoantibodies (dense deposit disease / C3 glomerulopathy): "autoantibodies in MPGN are termed C3 Nephritic Factor (C3NeF)… directed against a neoepitope of the complement C3 convertase C3bBb… C3NeF stabilizes this convertase and this results in C3 amplification and complement activation" (PMID: 19640589).
  • Classical-pathway consumption in SLE / post-infectious / MPGN (typically both C3 and C4 low).

The distinguishing feature of primary complete C3 deficiency is undetectable C3 with normal C4 and no evidence of a regulator defect or nephritic factor.

9. Outcome / Prognosis (F004)

  • No curative therapy exists. Prognosis is determined largely by timeliness of diagnosis and institution of prophylaxis.
  • With early diagnosis plus vaccination and antibiotic prophylaxis, outcomes in analogous early-complement deficiencies can approach normal life: in hereditary C2 deficiency, "early diagnosis, use of vaccinations and antibiotic prophylaxis may allow a normal life" (PMID: 32164349).
  • Major morbidity/mortality drivers: invasive infection (sepsis, meningitis) by encapsulated bacteria, and chronic kidney disease where immune-complex glomerulonephritis develops.
  • No disease-specific 5-/10-year survival statistics exist given rarity; prognostic factors are infection burden, presence/severity of glomerulonephritis, and adherence to prophylaxis.

10. Treatment (F004)

There is no causative/curative treatment for hereditary complement component deficiencies. Standard of care is preventive and supportive:

  • Vaccination (primary prophylaxis): conjugate vaccines against meningococcus, pneumococcus (conjugate polysaccharide), and Haemophilus influenzae type b. "Prophylaxis with conjugate polysaccharide vaccines is recommended and antibiotic prophylaxis should be considered in individual cases" (PMID: 28078901).
  • Antibiotic prophylaxis: long-term or case-by-case.
  • Pathogen targets: "the most frequent pathogens are Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae" (PMID: 37356020).
  • Autoimmune/renal manifestations: managed with standard immunosuppression for SLE/glomerulonephritis. By extrapolation from monogenic complement-deficient SLE, type I interferon-targeted therapy (anifrolumab) is an emerging option (PMID: 42597478).
  • NCIT intervention terms: Pneumococcal Vaccine (NCIT C1764), Meningococcal Vaccine, Haemophilus b Conjugate Vaccine, Antibiotic Therapy (NCIT C15844), Immunosuppressive Therapy.

11. Prevention (F004)

  • Primary: immunization against encapsulated bacteria (see above); risk awareness.
  • Secondary: early diagnosis via complement screening in children with recurrent invasive infection or early/atypical SLE; cascade testing of relatives.
  • Tertiary: antibiotic prophylaxis, prompt treatment of febrile illness, surveillance for renal disease.
  • Counseling: autosomal-recessive genetic counseling; carrier testing in consanguineous families; prenatal/preimplantation options where a familial variant is known.

12. Model organisms (F006)

C3-knockout (C3⁻/⁻) mice (Mus musculus; NCBI Gene C3 12266) recapitulate opsonization and humoral defects:

  • Polysaccharide antibody defect: "Mice deficient in C3 or Cr2 had an impaired primary immune response to III-PS. The defective response was characterized by low IgM levels and the lack of an isotype switch from IgM to IgG Ab production" (PMID: 12496386) — directly relevant to vaccine responsiveness in deficient patients.
  • Immune-complex trafficking defect: "Capture of antigen by MZ B cells as well as antigen deposition on FDC was severely impaired in mice lacking C1q or C3" (PMID: 28710441).
  • Tissue inflammation phenotype: "C3-deficient mice developed more severe pulmonary inflammations than wild type controls" in an AT1R-induced systemic sclerosis model (PMID: 39737181), highlighting a context-dependent protective/regulatory role for C3 in tissue.

Limitations of models: Mouse C3 knockouts capture opsonization, humoral, and immune-complex-clearance defects but do not fully reproduce the human spectrum of recurrent encapsulated-bacterial invasive disease plus SLE-like autoimmunity; genetic background and specific infection/immunization challenges strongly influence phenotype.

13. Other species / comparative biology

  • Orthologous gene: mouse C3 (NCBI Gene 12266); C3 is highly evolutionarily conserved across vertebrates as a core innate-immune molecule of the α₂-macroglobulin/thioester-containing protein family (PMID: 16177781 — "insights into the function and evolution of immunity").
  • Natural disease: Naturally occurring C3 deficiency has historically been described in domestic animals (e.g., dogs); no curated OMIA entry was validated in this investigation. Zoonotic transmission is not applicable (a genetic deficiency, not a transmissible disease).

Mechanistic Model / Interpretation

The entire disease flows from the position of C3 as the single convergence node of the complement system. The following schematic integrates the findings:

  CLASSICAL          LECTIN          ALTERNATIVE
  (C1q/C1r/s/C4/C2)   (MBL/ficolins/   (C3/FB/FD, +properdin)
 \            MASP2)   /
  \             |     /
   v            v    v
     ┌─────────────────────────────┐
     │   C3 CONVERTASES cleave C3   │  ◄── ABSENT in C3 deficiency
     └─────────────────────────────┘
     /                \
 C3a (anaphylatoxin)   C3b (thioester opsonin)
 inflammation          /        \
                 opsonophagocytosis   C5 convertase → C5b-9 (MAC)
                 (CRIg/CR1 on              terminal lysis
                  macrophages/neutrophils)
                      |
         + C3d–CR2/CD21 B-cell co-stimulation
         + C3b/iC3b tagging of immune complexes → FDC trafficking / clearance

LOSS OF C3  ⇒  no opsonization + no MAC + no IC clearance + no B-cell co-stim
    ⇒  (a) recurrent encapsulated-bacterial infection
       (b) immune-complex disease: SLE-like autoimmunity + MPGN

Two features make C3 deficiency mechanistically distinctive among complement defects. First, because C3 is downstream of all three initiating pathways but upstream of the entire terminal cascade, its loss is more complete than that of any single upstream initiator — both CH50 and AH50 collapse. Second, the dual phenotype is not coincidental: the same C3b/iC3b chemistry that opsonizes bacteria also tags apoptotic debris and immune complexes for clearance, so its loss simultaneously creates infection susceptibility and a failure of self-tolerance housekeeping that drives SLE-like autoimmunity. This places C3 deficiency firmly on the complement–SLE axis alongside C1q, C4, and C2, with the modern mechanistic overlay that defective clearance converges on type I interferon activation — the rationale for emerging interferon-targeted therapy.

Complement defect CH50 AH50 C3 C4 Dominant phenotype
Primary C3 deficiency ↓↓ ↓↓ undetectable normal Infection + SLE/MPGN
C1q / C4 / C2 deficiency ↓↓ normal normal/low low (C4) SLE > infection
Factor H / I deficiency variable ↓ secondarily low normal aHUS/GN + infection
C3 nephritic factor — ↓ low (acquired) normal C3 glomerulopathy
Terminal (C5–C9) ↓ ↓ normal normal Neisseria infection

Evidence Base

PMID Title (abbrev.) Evidence type Supports
42445183 Novel homozygous C3 splice-site variant (case report) Human clinical Rarity (<50 cases), AR inheritance, lab signature, phenotype, example variant (F001, F002, F008)
25037634 Are complement deficiencies really rare? Review Early-complement/autoimmune link; 1–10% of PIDs (F002, F008)
33563058 Lupus in children with PID Human cohort C3 deficiency among monogenic lupus (F002, F009)
42175904 Infection risk with complement inhibitors Review Core C3 effector functions (F003)
38032267 Complement receptor of Ig superfamily (CRIg) Structural/in vitro C3 cleavage products recognized by phagocyte receptor (F003)
16177781 Structures of C3 Structural 1,641-residue protein; thioester mechanism; central role (F005, F012)
12496386 Impaired Ab response in C3/Cr2-deficient mice Model organism Humoral defect to polysaccharide (F006)
28710441 IgG3-antigen complexes on FDCs need C1q/C3 Model organism Immune-complex trafficking (F006)
39737181 C3 deficiency promotes pulmonary inflammation Model organism C3⁻/⁻ model; regulatory role (F006)
16138437 Factor I deficiency, IC glomerulonephritis Human clinical Secondary C3 consumption (F007)
6545495 Complement activation in renal disease Review FH/FI deficiency lowers C3 (F007)
19640589 TMA and MPGN pathogenic principles Review C3NeF mechanism (F007)
37356020 Reducing infection risk in complement deficiency Guideline/review Pathogen spectrum (F004)
32164349 21-yr follow-up of C2 deficiency family Human clinical Prophylaxis → normal life (F004)
28078901 Recurrent meningitis & complement deficiency Human clinical Conjugate vaccines + antibiotic prophylaxis (F004)
42597478 Anifrolumab in C1q-deficient pediatric SLE Human clinical Monogenic lupus, IFN therapy (F009)
16836843 Pediatric PID overview Registry Complement deficiency ~1.1% of pediatric PID (F008)

Source-type note: Direct primary evidence for complete C3 deficiency is dominated by case reports and small series (the disease being ultra-rare). Mechanistic claims are buttressed by structural biology (PMID: 16177781), mouse-knockout studies, and extrapolation from the better-characterized C1q/C2/factor H/factor I deficiencies. These extrapolations are flagged as inferred where they extend beyond direct C3-deficiency data.

Limitations and Knowledge Gaps

  1. Ultra-rarity limits epidemiology. With <50 reported cases, there are no robust prevalence/incidence, sex-ratio, penetrance, or survival statistics; most data are anecdotal.
  2. Genotype–phenotype correlation is undefined. Whether specific C3 variant classes predispose to the infection-predominant vs autoimmune-predominant phenotype is unknown ("the genetic and phenotypic spectrum remains incompletely defined," PMID: 42445183).
  3. Mechanistic extrapolation. The autoimmune/type-I-interferon mechanism and the therapeutic rationale (anifrolumab) are strongest for C1q deficiency and are extended to C3 deficiency by inference, not by dedicated C3-deficiency trials.
  4. No disease-specific QoL or natural-history cohort data exist.
  5. Model-organism gaps. C3⁻/⁻ mice reproduce opsonization/humoral defects but not the full human infection + SLE spectrum; some models even reveal a protective C3 role in tissue inflammation, indicating context dependence.
  6. Secondary vs primary hypocomplementemia remains a frequent diagnostic pitfall; many "low C3" reports in the literature are secondary and must not be conflated with primary deficiency.

Proposed Follow-up Experiments / Actions

  1. Build an international C3-deficiency registry aggregating all reported biallelic C3 cases with harmonized genotype, complement phenotype (C3/C4/CH50/AH50), infection history, and autoimmune/renal outcomes to enable the first genotype–phenotype and natural-history analyses.
  2. Curate and ACMG-classify the full C3 variant spectrum (ClinVar/HGMD reconciliation), distinguishing LoF from hypomorphic alleles; correlate with residual C3 function.
  3. Prospectively evaluate vaccine responsiveness (pneumococcal/meningococcal conjugate) in C3-deficient patients, informed by the mouse polysaccharide-response defect (PMID: 12496386), to optimize immunization schedules.
  4. Test interferon-targeted therapy (anifrolumab) or other IFN-axis interventions in C3-deficiency-associated SLE, formally extending the C1q-deficiency rationale (PMID: 42597478).
  5. Explore C3-replacement / gene-directed approaches (plasma-derived C3, hepatocyte-directed gene therapy — the liver being the main synthesis site) as potential disease-modifying strategies, currently absent.
  6. Standardize the diagnostic algorithm (undetectable C3 + normal C4 + low CH50/AH50 → regulator panel [factor H/I, factor B] → C3NeF assay → C3 sequencing) to reliably separate primary from secondary hypocomplementemia.

Report compiled from 12 verified findings and 50 reviewed papers over 5 investigation iterations. Ontology suggestions (MONDO:0013417, HGNC:1318, UniProt P01024, HPO/GO/CL/UBERON/NCIT terms) are provided throughout for knowledge-base ingestion.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 18
Resolved 18
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 19
Quoted claims found in source 18
Quoted claims not found in source 1
References weighed for topical relevance 18
On topic 11
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:19640589 (abstract only): "autoantibodies in MPGN are termed C3 Nephritic Factor (C3NeF)… directed against a neoepitope of the complement C3 convertase C3bBb… C3NeF stabilizes this convertase and this results in C3 amplification and complement activation"
  • closest text in source: "Autoantibodies in MPGN are termed C3 Nephritic Factor (C3NeF) and are directed against a neoepitope of the complement C3 convertase C3bBb"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 32
Resolved 28
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 3
Terms whose name was checked 14
Terms named correctly 13
Terms named as a different term 0
Terms whose name is worth a second look 1

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0005615 (obsolete extracellular space) (2 mentions) - replaced by GO:0005576

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0000007 (2 mentions) - the report calls it "Autosomal recessive inheritance", "Autosomal recessive", "Inheritance: Autosomal recessive"; HP calls it Autosomal recessive inheritance, and lists "Autosomal recessive" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • HP:0000007 - called "Autosomal recessive inheritance", "Autosomal recessive", "Inheritance: Autosomal recessive"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, OMIM.

28 of 32 terms resolved to a current term; the rest could not be looked up either way.