DISEASE: Alternative complement pathway component defects
Entry
H00104 Disease
Name
Alternative complement pathway component defects
Subgroup
Factor B deficiency Factor D deficiency Factor H deficiency Properdin deficiency
Supergrp
Disorders of innate immunity [DS:H02525] Primary immunodeficiency disease [DS:H01725]
Description
The alternative pathway (AP) is antibody independent and relies on native C3 undergoing minimal spontaneous hydrolysis. Hydrolyzed C3 binds factor B. Factor B, when bound to hydrolyzed C3, is cleaved by factor D into Ba and Bb. Hydrolyzed C3Bb is responsible for a constant low level of C3 cleavage into C3b. If C3b binds to an appropriate surface, factor B will bind with C3b to form C3bBb, a highly efficient C3-cleaving enzyme. This overall series of successive proteolytic steps is enhanced by the serum protein properdin, which stabilizes protein:protein interactions during the process. Factor H is essential in controlling the function of the alternative pathway by inhibiting the formation of and degrading C3bBb. Deficiencies of alternative pathway-specific components are rare, and usually lead to an increased frequency of Neisseria infections.
Category
Primary immunodeficiency
Brite
Human diseases in ICD-11 classification [BR:br08403]
04 Diseases of the immune system
Primary immunodeficiencies
4A00 Primary immunodeficiencies due to disorders of innate immunity
H00104 Alternative complement pathway component defects
Pathway-based classification of diseases [BR:br08402]
Immune system
nt06513 Complement cascade
H00104 Alternative complement pathway component defects
Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee.
C3 glomerulopathy (C3G) describes a pathologic pattern of injury diagnosed by renal biopsy characterized by the dominant deposition of the third component of complement (C3) in the renal glomerulus. Autoantibodies to the C3 and C5 convertases of complement are the most commonly detected drivers of complement dysregulation, although genetic mutations in complement genes can also be found.
Category
Immune system disease; Urinary system disease
Brite
Human diseases in ICD-11 classification [BR:br08403]
21 Symptoms, signs or clinical findings, not elsewhere classified
Symptoms, signs or clinical findings of the genitourinary system
Clinical findings in specimens from the urinary system
MF8Y Other specified clinical findings in specimens from the urinary system
H02579 C3 glomerulopathy
Pathway-based classification of diseases [BR:br08402]
Immune system
nt06513 Complement cascade
H02579 C3 glomerulopathy
Gale DP, de Jorge EG, Cook HT, Martinez-Barricarte R, Hadjisavvas A, McLean AG, Pusey CD, Pierides A, Kyriacou K, Athanasiou Y, Voskarides K, Deltas C, Palmer A, Fremeaux-Bacchi V, de Cordoba SR, Maxwell PH, Pickering MC
Title
Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis.
Basal laminar drusen (BLD, also termed cuticular drusen or early adult onset grouped drusen) is an early-onset-drusen phenotype that shows a pattern of uniform small (25 to 75 micrometer), slightly raised, yellow subretinal nodules randomly scattered in the macula. In later stages, these drusen often become more numerous, with clustered groups of drusen scattered throughout the retina. It has been reported that a variant in CFH gene is strongly associated with this disease.
Category
Nervous system disease
Brite
Human diseases in ICD-11 classification [BR:br08403]
09 Diseases of the visual system
Disorders of the eyeball posterior segment
Disorders of the retina
9B70 Inherited retinal dystrophies
H02108 Basal laminar drusen
Pathway-based classification of diseases [BR:br08402]
Immune system
nt06513 Complement cascade
H02108 Basal laminar drusen
Macular degeneration is the physical breakdown of the central portion of the retina called the macula. Age-related macular degeneration (AMD/ARMD) is the leading cause of blindness. AMD is a complex disease caused by the combination of genetic predisposition and environmental factors. Using genome linkage scan and association studies, multiple potentially causative genes have been identified. In AMD, there are two phenotypes, atrophic/ dry and neovascular/ wet. The former is characterized by the geographic atrophy due to death of retinal pigment epithelium, and the latter is usually characterized by the abnormal growth of new blood vessels under the macula, which causes severe loss of vision. While wet AMD can be treated by the inhibition of vascular endothelial growth factor or photodynamic therapy, so far there are no available treatments for dry AMD.
Category
Nervous system disease
Brite
Human diseases in ICD-11 classification [BR:br08403]
09 Diseases of the visual system
Disorders of the eyeball posterior segment
Disorders of the retina
9B75 Macular disorders
H00821 Age-related macular degeneration
Pathway-based classification of diseases [BR:br08402]
Cellular process
nt06535 Efferocytosis
H00821 Age-related macular degeneration
nt06527 Necroptosis
H00821 Age-related macular degeneration
Immune system
nt06513 Complement cascade
H00821 Age-related macular degeneration
nt06517 TLR signaling
H00821 Age-related macular degeneration
Schultz DW, Klein ML, Humpert AJ, Luzier CW, Persun V, Schain M, Mahan A, Runckel C, Cassera M, Vittal V, Doyle TM, Martin TM, Weleber RG, Francis PJ, Acott TS
Title
Analysis of the ARMD1 locus: evidence that a mutation in HEMICENTIN-1 is associated with age-related macular degeneration in a large family.
Rivera A, Fisher SA, Fritsche LG, Keilhauer CN, Lichtner P, Meitinger T, Weber BH
Title
Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk.
Zareparsi S, Buraczynska M, Branham KE, Shah S, Eng D, Li M, Pawar H, Yashar BM, Moroi SE, Lichter PR, Petty HR, Richards JE, Abecasis GR, Elner VM, Swaroop A
Title
Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration.
Seddon JM, Yu Y, Miller EC, Reynolds R, Tan PL, Gowrisankar S, Goldstein JI, Triebwasser M, Anderson HE, Zerbib J, Kavanagh D, Souied E, Katsanis N, Daly MJ, Atkinson JP, Raychaudhuri S
Title
Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration.
The haemolytic uraemic syndrome (HUS) is characterized by the triad of thrombocytopenia, microangiopathic haemolytic anaemia and acute renal failure. HUS may be classified as either diarrhoeal-associated (D+HUS) or non-diarrhoeal/atypical (aHUS). Approximately half of the patients with aHUS have mutations in genes that regulate the complement system. Several other conditions and factors, such as infection, drugs, pregnancy, and malignancy, have been reported to cause aHUS.
Category
Hematologic disease
Brite
Human diseases in ICD-11 classification [BR:br08403]
03 Diseases of the blood or blood-forming organs
Anaemias or other erythrocyte disorders
Haemolytic anaemias
Congenital haemolytic anaemia
3A10 Hereditary haemolytic anaemia
H01434 Atypical hemolytic uremic syndrome
Pathway-based classification of diseases [BR:br08402]
Immune system
nt06513 Complement cascade
H01434 Atypical hemolytic uremic syndrome
Goicoechea de Jorge E, Harris CL, Esparza-Gordillo J, Carreras L, Arranz EA, Garrido CA, Lopez-Trascasa M, Sanchez-Corral P, Morgan BP, Rodriguez de Cordoba S
Title
Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome.
