Alternative titles; symbols
HGNC Approved Gene Symbol: CFD
SNOMEDCT: 234607008;
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:859,664-863,641 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | Complement factor D deficiency | 613912 | Autosomal recessive | 3 |
The CFD gene encodes complement factor D, a serine protease that acts in the alternative complement pathway to complete the formation of the C3 convertase enzyme by cleaving factor B (CFB; 138470) bound to C3b (120700), yielding C3bBb. Factor D is the initial obligatory and rate-limiting catalytic component in the alternative complement pathway (summary by White et al., 1992 and Biesma et al., 2001).
White et al. (1992) isolated clones corresponding to the human CFD gene from a human glioma cDNA library. The deduced mature protein contains 228 amino acids and was determined to be the same as the adipsin protein identified in mice (Rosen et al., 1989). Northern blot analysis detected a 1.1-kb mRNA transcript in adipocytes, monocytes, and macrophages. The recombinant protein showed enzymatic activity of complement factor D, cleaving factor B only when B was complexed with activated component C3b. The findings suggested that adipose tissue may have a role in immune system biology.
Gross (2014) mapped the CFD gene to chromosome 19p13.3 based on an alignment of the CFD sequence (GenBank BC057807) with the genomic sequence (GRCh37).
White et al. (1992) found that adipose cells are the main source of factor D. There is a gradient in the concentration of factor D in the fat cells of the body; more is present in the upper than in the lower half of the body (Mathieson and Peters, 1997). In a review of the complement system, Walport (2001) noted that the C3 nephritic autoantibody can be associated with acquired partial lipodystrophy (613913). The C3 nephritic autoantibody stabilizes the C3bBb C3 convertase that forms in the immediate vicinity of adipocytes. The abnormally stabilized enzyme may then cleave enough C3 to allow assembly of the membrane-attack complex, which lyses adipocytes. The pattern of fat loss, which involves the upper half of the body, may reflect the content of factor D.
Crystal Structure
Forneris et al. (2010) presented crystal structures of the proconvertase C3bB at 4-angstrom resolution and its complex with factor D at 3.5-angstrom resolution. Their data showed how factor B (138470) binding to C3b forms an open 'activation' state of C3bB. Factor D specifically binds the open conformation of factor B through a site distant from the catalytic center and is activated by the substrate, which displaces factor D's self-inhibitory loop. This concerted proteolytic mechanism, which if cofactor-dependent and substrate-induced, restricts complement amplification to C3b-tagged target cells.
Factor D is unusual among serum proteins in having a single-banded pattern in isoelectric focusing. Hobart and Lachmann (1976) found a variant in 3 persons of West African parentage (2 Nigerians and a West Indian) among 120 tested. No variants were found among 115 British and 26 Asian Indians. The presence of the variant band was associated with weakening of the normal band. Both bands were of equal strength (Martin et al., 1976).
Complement Factor D Deficiency
In a Dutch family with factor D deficiency (CFDD; 613912), Biesma et al. (2001) identified a homozygous mutation in the CFD gene (134350.0001). The proband was a 23-year-old woman who presented with septic shock due to Neisseria meningitidis in blood and cerebrospinal fluid. A deceased family member had a history of recurrent bacterial meningitis. Laboratory studies showed absence of factor D activity in the proband. However, 3 other family members who did not have a history of recurrent infections also showed absence of factor D activity.
Sprong et al. (2006) described the clinical course of meningococcal disease in 2 children of a Turkish family with a novel factor D gene mutation (134350.0002) leading to undetectable factor D plasma concentrations.
Adipsin is a serine protease that is secreted by adipocytes into the bloodstream. It is deficient in several animal models of obesity. Rosen et al. (1989) purified recombinant mouse adipsin and studied its biochemical and enzymatic properties. Activated adipsin had little or no proteolytic activity toward most substrates but had the same activity as human complement factor D.
To assess the contribution of the alternative pathway in complement activation and host defense and its possible role in the regulation of systemic energy balance in vivo, Xu et al. (2001) generated factor D-deficient mice by gene targeting. Mutant mice had no apparent abnormality in development and their body weights were similar to those of factor D-sufficient littermates. Complement activation could not be initiated in the serum of deficient mice by alternative pathway activators, namely, rabbit erythrocytes and zymosan. Injection of cobra venom factor caused a profound and reproducible reduction in serum C3 levels, whereas, as expected, there was no C3 reduction in factor B-deficient mice treated similarly. Studies of C3 and factor B activation in vitro by cobra venom factor demonstrated that in factor D-deficient serum the alpha chain of C3 was cleaved gradually over a period of 60 minutes without detectable cleavage of factor B. Kinetics of opsonization of Streptococcus pneumoniae by C3 fragments was much slower in factor D-deficient serum, suggesting a significant contribution of the alternative pathway to antibacterial host defense early after infection.
In 5 affected members of a consanguineous Dutch family with complement factor D deficiency (613912), Biesma et al. (2001) identified a homozygous C-to-A transversion in the CFD gene, resulting in a ser42-to-ter (S42X) substitution. The proband was a 23-year-old woman who presented with septic shock due to Neisseria meningitidis in blood and CSF. A deceased family member had a history of recurrent bacterial meningitis. Laboratory studies showed absence of factor D activity in the proband. However, 3 other family members who did not have a history of recurrent infections also showed absence of factor D activity.
In a sister and brother, born of consanguineous parents, with invasive meningococcal disease due to complement factor D deficiency (613912) Sprong et al. (2006) identified homozygosity for a mutant allele containing 2 missense mutations in cis in the CFD gene: a 638T-G transversion, resulting in a val213-to-gly (V213G) substitution, and a 640T-C transition, resulting in a cys214-to-arg (C214R) substitution. These mutations both occurred in conserved residues, and the C214R change destroyed an internal disulfide bond between 2 conserved cysteines. The unaffected parents and an unaffected sib were heterozygous for the complex allele. The 19-month-old girl developed N. meningitis and died in refractory shock about 47 hours after hospital admission. Four years later, the 13-month-old brother was admitted to the same hospital because of sudden onset of fever and a petechial rash. At the age of 4 months, he had been hospitalized for a respiratory syncytial virus infection complicated by bacterial superinfection. Blood cultures grew N. meningitidis. Immunologic studies indicated that factor D was undetectable. Because of this deficiency, the boy was put on antibiotic prophylaxis and was vaccinated for N. meningitidis.
Biesma, D. H., Hannema, A. J., van Velzen-Blad, H., Mulder, L., van Zwieten, R., Kluijt, I., Roos, D. A family with complement factor D deficiency. J. Clin. Invest. 108: 233-240, 2001. [PubMed: 11457876] [Full Text: https://doi.org/10.1172/JCI12023]
Forneris, F., Ricklin, D., Wu, J., Tzekou, A., Wallace, R. S., Lambris, J. D., Gros, P. Structures of C3b in complex with factors B and D give insight into complement convertase formation. Science 330: 1816-1820, 2010. [PubMed: 21205667] [Full Text: https://doi.org/10.1126/science.1195821]
Gross, M. B. Personal Communication. Baltimore, Md. 6/27/2014.
Hobart, M. J., Lachmann, P. J. Allotypes of complement components in man. Transplant. Rev. 32: 26-42, 1976. [PubMed: 824769] [Full Text: https://doi.org/10.1111/j.1600-065x.1976.tb00227.x]
Martin, A., Lachmann, P. J., Halbwachs, L., Hobart, M. J. Haemolytic diffusion plate assays for factors B and D of the alternative pathway of complement activation. Immunochemistry 13: 317-324, 1976. [PubMed: 820630] [Full Text: https://doi.org/10.1016/0019-2791(76)90341-4]
Mathieson, P. W., Peters, D. K. Lipodystrophy in MCGN type II: the clue to links between the adipocyte and the complement system. Nephrol. Dial. Transplant 12: 1804-1806, 1997. [PubMed: 9306323] [Full Text: https://doi.org/10.1093/ndt/12.9.1804]
Rosen, B. S., Cook, K. S., Yaglom, J., Groves, D. L., Volanakis, J. E., Damm, D., White, T., Spiegelman, B. M. Adipsin and complement factor D activity: an immune-related defect in obesity. Science 244: 1483-1487, 1989. [PubMed: 2734615] [Full Text: https://doi.org/10.1126/science.2734615]
Sprong, T., Roos, D., Weemaes, C., Neeleman, C., Geesing, C. L. M., Mollnes, T. E., van Deuren, M. Deficient alternative complement pathway activation due to factor D deficiency by 2 novel mutations in the complement factor D gene in a family with meningococcal infections. Blood 107: 4865-4870, 2006. [PubMed: 16527897] [Full Text: https://doi.org/10.1182/blood-2005-07-2820]
Volanakis, J. E., Schrohenloher, R. E., Stroud, R. M. Human factor D of the alternative complement pathway: purification and characterization. J. Immun. 119: 337-342, 1977. [PubMed: 874324]
Walport, M. J. Complement (first of two parts). New Eng. J. Med. 344: 1058-1066, 2001. [PubMed: 11287977] [Full Text: https://doi.org/10.1056/NEJM200104053441406]
White, R. T., Damm, D., Hancock, N., Rosen, B. S., Lowell, B. B., Usher, P., Flier, J. S., Spiegelman, B. M. Human adipsin is identical to complement factor D and is expressed at high levels in adipose tissue. J. Biol. Chem. 267: 9210-9213, 1992. [PubMed: 1374388]
Xu, Y., Ma, M., Ippolito, G. C., Schroeder, H. W., Jr., Carroll, M. C., Volanakis, J. E. Complement activation in factor D-deficient mice. Proc. Nat. Acad. Sci. 98: 14577-14582, 2001. [PubMed: 11724962] [Full Text: https://doi.org/10.1073/pnas.261428398]