CFD Gene

Last updated on: 27.04.2022

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The CFD gene (CFD refers to "complement factor D") is a protein-coding gene located on chromosome 19p13.3. Alternative splicing of this gene results in multiple transcript variants. At least one of these variants encodes a preprotein that is proteolytically processed to form the mature protease.

General information
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The CFD gene encodes a member of the S1 or chymotrypsin family of serine peptidases. This protease catalyzes the cleavage of factor B when complexed with factor C3b. In a 2nd step, the C3bbb complex is activated, which then becomes the C3 convertase of the alternative pathway (Barratt J et al. 2021). Its function is homologous to that of C1s in the classical pathway. The CFD serine protease also functions as an adipokine, a cell signaling protein secreted by adipocytes that is known from animal experiments to regulate insulin secretion.

Mutations in the CFD gene can lead to a deficiency of complement factor D. Deficiency of complement factor D leads to recurrent severe bacterial meningitis in human patients.

Fundamentally, complement factor D influences adipogenesis via associated metabolic pathways and the innate immune system via the alternative pathway of complement activation.

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The complement system is crucial for the defense against pathogens and the elimination of dying cells or immune complexes. Therefore, clinical indications of possible total complement deficiency include recurrent mild or severe bacterial infections and autoimmune diseases. In a larger sequencing analysis of 212 patients with total or subtotal complement deficiency (El Sissy C et al. 2019), 107 different hemizygous, homozygous, or compound heterozygous pathogenic variants were detected in 14 complement genes. The following genes were affected: C1Qβ (n = 1), C1r (n = 3), C1s (n = 2), C2 (n = 12), C3 (n = 5), C5 (n = 12), C6 (n = 9), C7 (n = 17), C8 β (n = 7), C9 (n = 3), CFH (n = 7), CFI (n = 18), CFP (n = 10), CFD (n = 2). This study confirms the strong association of meningococcal infections by terminal pathway deficiency and highlights the risk of pneumococcal and autoimmune diseases in the classical and alternative pathways.

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  1. Barratt J et al (2021) Complement Factor D as a Strategic Target for Regulating the Alternative Complement Pathway. Front Immunol 12:712572.
  2. Biesma DH et al (2001) A family with complement factor D deficiency. J Clin Invest 108: 233-240.
  3. El Sissy C et al (2019) Clinical and Genetic Spectrum of a Large Cohort With Total and Sub-total Complement Deficiencies. Front Immunol 10:1936.
  4. Hiemstra PS et al (1989) Complete and partial deficiencies of complement factor D in a Dutch family. J Clin Invest 84: 1957-1961.
  5. Kluin-Nelemans HC et al (1984) Functional deficiency of complement factor D in monozygous twin. Clin Exp Immun 58: 724-730.
  6. Sprong T et al (2006) 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.

Last updated on: 27.04.2022