Alternative titles; symbols
SNOMEDCT: 234622003; ORPHA: 200421, 2134, 329918, 54370, 544472, 93571;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q31.3 | Complement factor H deficiency | 609814 | Autosomal dominant; Autosomal recessive | 3 | CFH | 134370 |
A number sign (#) is used with this entry because of evidence that complement factor H deficiency is caused by homozygous or compound heterozygous mutation in the gene encoding complement factor H (CFH; 134370) on chromosome 1q31. Heterozygous mutation carriers may show milder manifestations.
Mutation in the CFH gene can also cause increased susceptibility to atypical hemolytic-uremic syndrome (AHUS1; 235400).
Complement factor H deficiency (CFHD) has a variable phenotype. Some patients present with recurrent infections, including increased susceptibility to meningococcal infections, whereas others develop renal disease manifest primarily as C3 glomerulopathy. Affected individuals usually present in the first decades of life with nonspecific findings such as hematuria and may progress to chronic renal failure. As complement factor H is the key regulator of the alternative pathway of the complement system, CFH deficiency results in inappropriate activation of the alternative complement pathway. Laboratory features usually include decreased serum levels of factor H, due to the genetic defect, as well as secondarily decreased levels of complement component C3 (120700) and other alternative pathway components, consistent with consumption of these factors. The renal phenotype is now considered to be a form of C3 glomerulopathy (C3G), which is a pathologic entity in which C3 is deposited within the kidney glomerulus in the mesangial or intramembranous space; this occurs in the absence of immune complexes or immunoglobulins. Terms used to describe this disease include membranoproliferative glomerulonephritis type II (MPGN II), mesangial glomerulonephritis, dense deposit disease (DDD), and C3 glomerulonephritis (summary by Ault, 2000, reviews by Riedl et al., 2017 and Wong and Kavanagh, 2018).
Nomenclature and Classification
Several reviews (Ito et al., 2017, Riedl et al., 2017, Wong and Kavanagh, 2018) have noted that the definition and classification of C3G continues to evolve. Historically, C3G has been referred to as type II membranoproliferative glomerulonephritis (MPGN) or dense deposit disease (DDD) with mesangial or intramembranous deposition of electron dense material. In contrast, MPGN types I and III, which are usually associated with immune complex deposition, tend to show subendothelial and subepithelial electron dense deposits. However, there is significant variability, and the differentiation and distinction between these terms is often unclear. Welch (2002) also discussed the role of complement in renal disease.
A subgroup of patients with MGPN II who do not have mutations in the CFH gene are positive for serum C3 nephritic factor (C3NeF), which is an autoantibody directed against C3bBb, the convertase of the alternative pathway of the complement cascade. Presence of C3NeF prolongs the half-life of C3 convertase, which also results in inappropriate activation of the complement cascade (summary by Abrera-Abeleda et al., 2006).
Genetic Heterogeneity of C3G
C3G2 (610984) is caused by mutation in the CFI gene (217030) on chromosome 4q25, and C3G3 (614809) is caused by mutation in the CFHR5 gene (608593) on chromosome 1q31.
Wyatt et al. (1982) reported 2 families with partial factor H deficiency and glomerulonephritis. In 1 family, of Polish origin, a teenaged male had vasculitis, thrombocytopenia, proteinuria, and depressed levels of serum factor H and complement component C3. The mother, maternal uncle, and a cousin had depressed H levels. The second family was of English-Irish extraction living in Kentucky; 3 persons in 3 generations had H levels about half normal. The index case had depressed serum factors H and B levels and IgA nephropathy (161950) which progressed to renal failure. A sister also had IgA nephropathy and depressed serum H and C3 levels.
Levy et al. (1986) reported a consanguineous Algerian family in which 2 brothers had early-onset glomerulonephritis with C3 deposits and low levels (less than 10% of normal) of complement factor H. The factor H deficiency was defined by undetectable complement hemolytic activity by the classic (CH50) and alternate (AP50) pathways, and low levels of C3 and factor B (138470). The unaffected first-cousin parents and 2 healthy sibs, presumed heterozygotes, had half-normal H values. Renal disease was discovered at 14 and 4 months of age in the elder and younger brother, respectively. The elder had recurrent episodes of macroscopic hematuria occurring during the course of infections but did not seem to have an excessive number of infections; the younger had repeated upper and lower respiratory tract infections and nearly persistent macroscopic hematuria. Electron microscopy of renal biopsies from both patients were typical for intramembranous dense deposit disease, but immunofluorescence microscopy showed an atypical pattern with abundant granular C3 deposits within the mesangium and along the capillary walls.
Lopez-Larrea et al. (1987) studied a family in which 3 female sibs had undetectable levels of factor H and C3 nephritic factor, low levels of factor B, C3, and C5 (see 120500), and normal levels of C4-binding protein (120830), factor I (217030), and classic pathway factors. C4 (see 120810) levels were low in 1 patient. Two of the sibs had Neisseria meningitidis sepsis; all 3 developed membranoproliferative glomerulonephritis.
Brai et al. (1988) and Misiano et al. (1993) described a consanguineous Italian family in which 3 sibs had deficiency of factor H and its spliced isoform FHL1. The proband had systemic lupus erythematosus (152700) with chronic renal failure, reduced C3 serum levels, and low concentrations of C5-C9. She had suffered from skin lesions (chronic discoid plaques on sun-exposed areas), with ulcerations and central nervous system involvement with psychosis. Her 2 affected brothers showed a similar serum complement profile. They had suffered from 3 and 1 episodes, respectively, of meningococcal meningitis, without autoimmune disease. Factor H was undetectable in all affected sibs, and both parents presented serum concentrations of factor H that were about 50% of normal. Western blot analysis showed the absence of both factor H and FHL1 in the affected sibs. The father and 2 of the H-deficient sibs, including the proband, also had a partial C2 deficiency (217000).
Nielsen et al. (1989) described a 15-year-old girl with a complete deficiency of factor H. Both parents had half normal levels. The girl had 2 episodes of meningococcal disease. The degree of H reduction was sufficient to cause increased, spontaneous activation of the alternative complement pathway.
Fijen et al. (1996) described a Dutch family in which both heterozygous and homozygous factor H deficiency was observed. The proband of the family suffered from subacute cutaneous lupus erythematosus and had had meningococcal meningitis. Western blot analysis showed complete factor H deficiency. Among 21 relatives of the proband encompassing 3 generations, 10 had low factor H levels, including 2 children of the proband, indicating heterozygosity. Serum studies showed decreased levels of components of the alternative complement pathway.
Vogt et al. (1995) reported a 6-year-old Native American (Sioux) boy who presented at age 13 months with hypocomplementemic hypertensive renal disease. Renal biopsy showed changes consistent with membranoproliferative glomerulonephritis, deposition of type III collagen (120180), and segmental complement C3 deposition in capillary loops. Decreased levels of serum C3 and factor B but normal levels of serum C4 and factor I were found; factor H was undetectable by radial immunodiffusion analysis. Slightly depressed levels of factor H were present in both parents; his sibs had normal levels. Ault et al. (1997) reported that the child originally described by Vogt et al. (1995) underwent renal transplantation at age 7; serum C3 concentrations remained low thereafter, as did factor H levels. Western blot analysis of the patient's plasma before and after renal transplantation showed slightly increased concentration of the 45-kD factor H and no detectable 150-kD factor H when compared with 7 normal plasma samples. Ault et al. (1997) demonstrated that the patient's fibroblasts retained 155-kD factor H protein, which was not degraded even after 12 hours, and showed that factor H was retained in the endoplasmic reticulum.
Licht et al. (2006) reported 2 girls, born of consanguineous Turkish parents, with early onset of membranoproliferative glomerulonephritis type II. Renal biopsies showed thickening of the glomerular basement membrane caused by dense deposits in the lamina densa. Immunohistochemistry showed deposition of C3. Laboratory analysis showed activation of both the alternative and classical complement pathway, and both patients and their asymptomatic mother also had autoantibodies to C3 nephritic factor (C3Nef). Genetic analysis identified a homozygous mutation in the CFH gene (134370.0014) in the patients; both parents were heterozygous for the mutation.
Servais et al. (2007) described a unique form of glomerulonephritis characterized by isolated mesangial C3 deposits without dense intramembranous deposits or mesangial proliferation, which the authors termed 'glomerulonephritis C3.' Heterozygous mutations in complement regulatory genes were identified in 4 of 6 unrelated patients with glomerulonephritis C3, including 2 patients each with mutations in the CFH (see, e.g., 134370.0017) and CFI genes (see, e.g., 217030.0007), respectively. In addition, 1 of 13 unrelated patients with glomerulonephritis with MPGN also had a heterozygous CFH mutation. The findings indicated that dysregulation of the complement alternative pathway is associated with a wide spectrum of diseases ranging from HUS to MPGN with C3 deposits.
Licht et al. (2006) noted that a defect in complement factor H results in continuous activation of the alternative complement pathway and continuous generation of the convertase C3BbB. This results in hypocomplementemia and activation of complement on tissue surfaces that lack endogenous regulators, such as the glomerular basement membrane. Continuous C3 deposition results in the formation of dense deposits, thickening of the basement membrane, impaired renal filtration, and progressive loss of renal function.
In a Native American boy reported by Vogt et al. (1995) who had factor H deficiency and membranoproliferative glomerulonephritis, Ault et al. (1997) identified compound heterozygosity for 2 mutations (134370.0002 and 134370.0003) in the CFH gene.
In 3 affected sibs of a consanguineous Italian family with complement factor H deficiency reported by Brai et al. (1988) and Misiano et al. (1993), Sanchez-Corral et al. (2000) identified a homozygous nonsense mutation in the CFH gene (134370.0006).
In 1 of the brothers reported by Levy et al. (1986), Dragon-Durey et al. (2004) identified a homozygous mutation in the CFH gene (134370.0010). Dragon-Durey et al. (2004) identified homozygous mutations in the CFH gene in 3 additional patients with MPGN, including 2 Turkish brothers (134370.0013).
Hogasen et al. (1995) reported hereditary membranoproliferative glomerulonephritis type II caused by factor H deficiency in the Norwegian Yorkshire pig. Affected animals had excessive complement activation and massive deposits of complement in the renal glomeruli; they died of renal failure within 11 weeks of birth. Hegasy et al. (2002) identified mutations in the factor H gene as the basis for porcine factor H deficiency and membranoproliferative glomerulonephritis. Studies showed that the mutant factor H was not properly secreted from cells.
Pickering et al. (2002) showed that mice deficient in factor H (Cfh -/- mice) develop membranoproliferative glomerulonephritis spontaneously and are hypersensitive to developing renal injury caused by immune complexes. Introducing a second mutation in the gene encoding complement factor B (CFB; 138470), which prevents C3 turnover in vivo, prevented development of the phenotype of Cfh -/- mice. The authors concluded that uncontrolled C3 activation in vivo is essential for the development of membranoproliferative glomerulonephritis associated with deficiency of factor H.
Abrera-Abeleda, M. A., Nishimura, C., Smith, J. L. H., Sethi, S., McRae, J. L., Murphy, B. F., Silvestri, G., Skerka, C., Jozsi, M., Zipfel, P. F., Hageman, G. S., Smith, R. J. H. Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease). J. Med. Genet. 43: 582-589, 2006. [PubMed: 16299065] [Full Text: https://doi.org/10.1136/jmg.2005.038315]
Appel, G. B., Cook, H. T., Hageman, G., Jennette, J. C., Kashgarian, M., Kirschfink, M., Lambris, J. D., Lanning, L., Lutz, H. U., Meri, S., Rose, N. R., Salant, D. J., and 9 others. Membranoproliferative glomerulonephritis type II (dense deposit disease): an update. J. Am. Soc. Nephrol. 16: 1392-1404, 2005. [PubMed: 15800116] [Full Text: https://doi.org/10.1681/ASN.2005010078]
Ault, B. H., Schmidt, B. Z., Fowler, N. L., Kashtan, C. E., Ahmed, A. E., Vogt, B. A., Colten, H. R. Human factor H deficiency: mutations in framework cysteine residues and block in H protein secretion and intracellular catabolism. J. Biol. Chem. 272: 25168-25175, 1997. [PubMed: 9312129] [Full Text: https://doi.org/10.1074/jbc.272.40.25168]
Ault, B. H. Factor H and the pathogenesis of renal diseases. Pediat. Nephrol. 14: 1045-1053, 2000. [PubMed: 10975323] [Full Text: https://doi.org/10.1007/s004670050069]
Brai, M., Misiano, G., Maringhini, S., Cutaja, I., Hauptmann, G. Combined homozygous factor H and heterozygous C2 deficiency in an Italian family. J. Clin. Immun. 8: 50-56, 1988. [PubMed: 2966809] [Full Text: https://doi.org/10.1007/BF00915156]
Dragon-Durey, M.-A., Fremeaux-Bacchi, V., Loirat, C., Blouin, J., Niaudet, P., Deschenes, G., Coppo, P., Fridman, W. H., Weiss, L. Heterozygous and homozygous factor H deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases. J. Am. Soc. Nephrol. 15: 787-795, 2004. [PubMed: 14978182] [Full Text: https://doi.org/10.1097/01.asn.0000115702.28859.a7]
Fijen, C. A. P., Kuijper, E. J., Te Bulte, M. T., Van De Heuvel, M. M., Holdrinet, A. C. J. M., Sim, R. B., Daha, M. R., Dankert, J. Heterozygous and homozygous factor H deficiency states in a Dutch family. Clin. Exp. Immun. 105: 511-516, 1996. [PubMed: 8809142] [Full Text: https://doi.org/10.1046/j.1365-2249.1996.d01-777.x]
Hegasy, G. A., Manuelian, T., Hogasen, K., Jansen, J. H., Zipfel, P. F. The molecular basis for hereditary porcine membranoproliferative glomerulonephritis type II: point mutations in the factor H coding sequence block protein secretion. Am. J. Path. 161: 2027-2034, 2002. [PubMed: 12466119] [Full Text: https://doi.org/10.1016/S0002-9440(10)64481-1]
Hogasen, K., Jansen, J. H., Mollnes, T. E., Hovdenes, J., Harboe, M. Hereditary porcine membranoproliferative glomerulonephritis type II is caused by factor H deficiency. J. Clin. Invest. 95: 1054-1061, 1995. [PubMed: 7883953] [Full Text: https://doi.org/10.1172/JCI117751]
Ito, N., Ohashi, R., Nagata, M. C3 glomerulopathy and current dilemmas. Clin. Exp. Nephrol. 2017 Aug;21(4): 541-551, 2017. Note: Erratum: Clin. Exp. Nephrol. 21: 1142 only, 2017. [PubMed: 27878657] [Full Text: https://doi.org/10.1007/s10157-016-1358-5]
Levy, M., Halbwachs-Mecarelli, L., Gubler, M.-C., Kohout, G., Bensenouci, A., Niaudet. P., Hauptmann, G., Lesavre, P. H deficiency in two brothers with atypical dense intramembranous deposit disease. Kidney Int. 30: 949-956, 1986. [PubMed: 2950269] [Full Text: https://doi.org/10.1038/ki.1986.278]
Licht, C., Heinen, S., Jozsi, M., Loschmann, I., Saunders, R. E., Perkins, S. J., Waldherr, R., Skerka, C., Kirschfink, M., Hoppe, B., Zipfel, P. F. Deletion of lys224 in regulatory domain 4 of factor H reveals a novel pathomechanism for dense deposit disease (MPGN II). Kidney Int. 70: 42-50, 2006. [PubMed: 16612335] [Full Text: https://doi.org/10.1038/sj.ki.5000269]
Lopez-Larrea, C., Dieguez, M. A., Enguix, A., Dominguez, O., Marin, B., Gomez, E. A familial deficiency of complement factor H. Biochem. Soc. Trans. 15: 648-649, 1987.
Misiano, G., Soames, C. J., Fontaine, M., Accardo, P., Sim, R. B., Brai, M. Expression of H-related gene products in a factor H deficient family. (Abstract) Molec. Immun. 30 (suppl. 1): 33 only, 1993.
Nielsen, H. E., Christensen, K. C., Koch, C., Thomsen, B. S., Heegaard, N. H. H., Tranum-Jensen, J. Hereditary, complete deficiency of complement factor H associated with recurrent meningococcal disease. Scand. J. Immun. 30: 711-718, 1989. [PubMed: 2532396] [Full Text: https://doi.org/10.1111/j.1365-3083.1989.tb02480.x]
Pickering, M. C., Cook, H. T., Warren, J., Bygrave, A. E., Moss, J., Walport, M. J., Botto, M. Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H. Nature Genet. 31: 424-428, 2002. [PubMed: 12091909] [Full Text: https://doi.org/10.1038/ng912]
Riedl, M., Thorner, P., Licht, C. C3 glomerulopathy. Pediat. Nephrol. 32: 43-57, 2017. [PubMed: 27056062] [Full Text: https://doi.org/10.1007/s00467-015-3310-4]
Sanchez-Corral, P., Bellavia, D., Amico, L., Brai, M., Rodriguez de Cordoba, S. Molecular basis for factor H and FHL-1 deficiency in an Italian family. Immunogenetics 51: 366-369, 2000. [PubMed: 10803850] [Full Text: https://doi.org/10.1007/s002510050631]
Servais, A., Fremeaux-Bacchi, V., Lequintrec, M., Salomon, R., Blouin, J., Knebelmann, B., Grunfeld, J.-P., Lesavre, P., Noel, L.-H., Fakhouri, F. Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uremic syndrome. J. Med. Genet. 44: 193-199, 2007. [PubMed: 17018561] [Full Text: https://doi.org/10.1136/jmg.2006.045328]
Vogt, B. A., Wyatt, R. J., Burke, B. A., Simonton, S. C., Kashtan, C. E. Inherited factor H deficiency and collagen type III glomerulopathy. Pediat. Nephrol. 9: 11-15, 1995. [PubMed: 7742208] [Full Text: https://doi.org/10.1007/BF00858956]
Welch, T. R. Complement in glomerulonephritis. Nature Genet. 31: 333-334, 2002. [PubMed: 12091912] [Full Text: https://doi.org/10.1038/ng933]
Wong, E. K. S., Kavanagh, D. Diseases of complement dysregulation--an overview. Semin. Immunopath. 40: 49-64, 2018. [PubMed: 29327071] [Full Text: https://doi.org/10.1007/s00281-017-0663-8]
Wyatt, R. J., Julian, B. A., Weinstein, A., Rothfield, N. F., McLean, R. H. Partial H (beta-1H) deficiency and glomerulonephritis in two families. J. Clin. Immun. 2: 110-117, 1982. [PubMed: 6461667] [Full Text: https://doi.org/10.1007/BF00916894]