Disease-associated inherited deficiencies of complement

Protein	Gene	Inheritance	Gene OMIM	Laboratory features	Diseases
Classical pathway
C1q	C1QA	AR	120550	CH50 = 0; CP defective activation; Inefficient clearance apoptotic cells	SLE; infections with encapsulated organisms
	C1QB	AR	120570
	C1QC	AR	120575
C1r	C1R	AR	613785	CH50 = 0; CP defective activation	SLE; infections with encapsulated organisms; Ehlers-Danlos phenotype
C1r	C1R	AD GOF	613785	Normal CH50	Hyperpigmentation; skin fragility
C1s	C1S	AR	120580	CH50 = 0; CP defective activation	SLE; infection with encapsulated organisms; Ehlers-Danlos phenotype
C1s	C1S	AD GOF	120580	Normal CH50	Hyperpigmentation; skin fragility
C2	C2	AR	217000	CH50 = 0; CP defective activation	SLE; infections with encapsulated organisms; atherosclerosis; AMD
C4	C4A + C4B	AR	120810 + 120820	CH50 = 0; CP defective activation; biallelic mutations, deletions, or conversions of both C4A and C4B	SLE; infections with encapsulated organisms; partial or complete C4A deficiency predisposes to SLE
C3*	C3	AR LOF	120700	Both CH50 and AH50 = 0; Defective opsonization and humoral immune response	Infections; glomerulonephritis
C3*	C3	AD GOF	120700	Increased complement activation	aHUS; AMD
Lectin pathway
MBL	MBL2	AD	154545	LP defective activation	Increased susceptibility to bacterial infection
MASP-2	MASP2	AR	605102	LP defective activation	Pyogenic infections; inflammatory lung disease; autoimmunity
MASP-3	MASP1^¶	AR	600521	LP defective activation	3MC1
Collectin (CL-L1; CL-K1)	COLEC11	AR	612502	LP defective activation	3MC2
Ficolin 3	FCN3	AR	604973	LP defective activation	Respiratory infections; abscesses
Alternative pathway
Factor B	CFB	AD GOF	138470	AH50 = normal	aHUS; AMD
Factor B	CFB	AR	138470	AH50 = 0	Infections with encapsulated bacteria
Factor D	CFD	AR	134350	AH50 = 0	Neisserial infections
Properdin	CFP	XLR	300383	AH50 = 0; need to employ assay that would require properdin	Neisserial infections
Membrane attack complex
C5	C5	AR	120900	CH50 and AH50 = 0; defective bactericidal activity	Neisserial infections
C6	C6	AR	217050	CH50 and AH50 = 0; defective bactericidal activity
C7	C7	AR	217070
C8-alpha	C8A	AR	120950
C8-beta	C8B	AR	120960
C8-gamma	C8G	AR	120930
C9	C9	AR	120940	Reduced CH50 and AH50; deficient bactericidal activity	Mild susceptibility to Neisserial infections
Regulators and receptors
C1 inhibitor	SERPING1	AD	606860	Spontaneous activation of complement; consumption of C4/C2; spontaneous activation contact system; generation of bradykinin from high molecular weight kininogen	Hereditary angioedema
Factor I	CFI	AD	217030	AP activation; C3 consumption	AMD; aHUS; preeclampsia
Factor I	CFI	AR	217030	AP activation; C3 consumption	Neisserial infections
Factor H	CFH	AD	134370	AP activation; C3 consumption	AMD; aHUS; preeclampsia
Factor H	CFH	AR	134370	AP activation; C3 consumption	Neisserial infections
CD46 (membrane cofactor protein)	MCP	AD LOF	120920	Excessive AP activation; half normal (approximately 75% of cases) to normal levels on PBC via flow cytometry; decreased C3b/C4b binding	aHUS; HELLP syndrome; C3G
CD46 (membrane cofactor protein)	MCP	AR	120920	Excessive AP activation; CD46 levels absent	CVID
CD55	CD55	AR	125240	Hyperactivation of complement on endothelium	CHAPLE disease = protein-losing enteropathy; thrombosis
CD59	CD59	AR	107271	Erythrocytes highly susceptible to complement-mediated lysis	PNH-like, hemolytic anemia; polyneuropathy
Factor H-related protein deficiencies	CFHR1	AR or AD	134371	Normal CH50 and AH50; autoantibodies to factor H; linked deletions of one or more CFHR genes leads to susceptibility to autoantibody-mediated aHUS	Older onset aHUS; Neisserial infections
	CFHR2		600889
	CFHR3		605336
	CFHR4		605337
	CFHR5		608593
Receptors
CR2	CR2	AR	120650		CVID
CR3 (CD11b/CD18)	ITGAM + ITGB2	AR	120980	Low levels of CD11/CD18 (LFA-1 or leukocyte function antigen-1) glycoprotein	LAD I
CR4 (CD11c/CD18)	ITGAX + ITGB2	AR	116920		LAD I

AR: autosomal recessive; CP: classical pathway; AD: autosomal dominant; GOF: gain of function; LOF: loss of function; XLR: X-linked recessive; SLE: systemic lupus erythematosus; aHUS: atypical hemolytic uremic syndrome; LP: lectin pathway; AMD: age-related macular degeneration; MBL: mannose-binding lectin; MASP: mannan-binding lectin-associated protease; 3MC1: name pooled from identical but four separately named disorders; AP: alternative pathway; MAC: membrane attack complex; PBC: peripheral blood cells; HELLP: hemolysis, elevated liver enzymes, and low platelets; C3G: C3 glomerulopathy; CVID: common variable immunodeficiency; CHAPLE disease: CD55 deficiency with hyper-activation of complement, angiopathic thrombosis, and severe protein-losing enteropathy; CR2: complement receptor 2; CR3: complement receptor type 3; CR4: complement receptor type 4; LAD: leukocyte adhesion deficiency 1.

* C3 is the central component of all three activation pathways.

¶ MASP-3 is alternatively spliced from the MASP-1 gene.

Adapted from: Tangye SG, Al-Herz W, Bousfiha A, et al. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 2022. Copyright © 2022 The Authors. Available at: https://link.springer.com/article/10.1007/s10875-022-01289-3 (Accessed on November 10, 2022). Reproduced under the terms of the Creative Commons Attribution License 4.0.

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Disease-associated inherited deficiencies of complement