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HGNC Approved Gene Symbol: CFHR4
Cytogenetic location: 1q31.3 Genomic coordinates (GRCh38) : 1:196,888,052-196,918,633 (from NCBI)
Human complement factor H (CFH; 134370) and 5 factor H-related proteins, CFHR1 (134371), CFHR2 (600889), CFHR3 (605336), CFHR4, and CFHR5 (608593), are exclusively composed of highly-related short consensus repeats (SCRs), each of which contains 4 cysteine residues and additional conserved amino acids. By biochemical purification of an apoprotein from triglyceride-rich lipoproteins, followed by partial amino acid sequence analysis and screening of a liver cDNA library with a CFHR3 probe, Skerka et al. (1997) isolated a cDNA encoding CFHR4. The deduced 331-amino acid protein contains a potential 19-amino acid signal peptide, 4 potential N-linked glycosylation sites, and 5 SCRs. The CFHR4 SCRs share sequence identities of 63 to 70% with those of CFH, except for SCR 5, which is only 39% identical to SCR 20 of CFH. The CFHR4 C-terminal SCRs are over 93% identical to those of CFHR3. Northern blot analysis of liver RNA revealed expression of 1.4-, 2.2-, and 2.5-kb transcripts, with the shorter transcript predicted to be CFHR4 specific. Western blot analysis showed that CFHR4 in serum is an 86-kD dimeric protein and a 63-kD monomeric protein after extensive reducing treatment, whereas the recombinant proteins are 84 kD and 42 kD, suggesting that the difference is due to carbohydrate attachment.
Jozsi et al. (2005) found that 2 distinct mRNA transcripts are derived from the FHR4 gene by alternative splicing. The short form, which they called FHR-4B, is a truncated variant and encodes a secreted protein of 5 complement control protein (CCP) domains, and was the form previously designated FHR4. The long transcript, FHR-4A, encodes a protein composed of 9 complement control protein (CCP) domains. FHR-4A has a tandem arrangement of 4 CCP domains forming a 'natural dimer' of the FHR-4B isoform. The FHR-4A protein was identified in human plasma as an 86-kD protein. The difference between the predicted and observed molecular masses was explained by glycosylation. Jozsi et al. (2005) compared the deduced protein sequence of FHR-4A with peptides from an 86-kD apolipoprotein, described by Skerka et al. (1997), and suggested that the long form, FHR-4A, represents this apolipoprotein.
By genomic analysis, Jozsi et al. (2005) determined that the FHR4 gene is composed of 10 exons.
Hellwage et al. (1999) determined that CFHR4, unlike CFHR3, does not bind to heparin. However, Biacore (surface plasmon resonance) and opsonization analyses showed that both proteins bind to C3b and C3d but not to C3c. Both CFHR3 and CFHR4 enhance the cofactor activity of factor H in C3b inactivation.
By radiation hybrid analysis, Diaz-Guillen et al. (1999) and McRae et al. (2002) determined that the 5 factor H-related genes are all closely linked to the CFH gene on chromosome 1q31-q32.1.
Diaz-Guillen, M. A., Rodriguez de Cordoba, S., Heine-Suner, D. A radiation hybrid map of complement factor H and factor H-related genes. Immunogenetics 49: 549-552, 1999. [PubMed: 10380701] [Full Text: https://doi.org/10.1007/s002510050534]
Hellwage, J., Jokiranta, T. S., Koistinen, V., Vaarala, O., Meri, S., Zipfel, P. F. Functional properties of complement factor H-related proteins FHR-3 and FHR-4: binding to the C3d region of C3b and differential regulation by heparin. FEBS Lett. 462: 345-352, 1999. [PubMed: 10622723] [Full Text: https://doi.org/10.1016/s0014-5793(99)01554-9]
Jozsi, M., Richter, H., Loschmann, I., Skerka, C., Buck, F., Beisiegel, U., Erdei, A., Zipfel, P. F. FHR-4A: a new factor H-related protein is encoded by the human FHR-4 gene. Europ. J. Hum. Genet. 13: 321-329, 2005. [PubMed: 15562282] [Full Text: https://doi.org/10.1038/sj.ejhg.5201324]
McRae, J. L., Murphy, B. E., Eyre, H. J., Sutherland, G. R., Crawford, J., Cowan, P. J. Location and structure of the human FHR-5 gene. Genetica 114: 157-161, 2002. [PubMed: 12041828] [Full Text: https://doi.org/10.1023/a:1015114512924]
Skerka, C., Hellwage, J., Weber, W., Tilkorn, A., Buck, F., Marti, T., Kampen, E., Beisiegel, U., Zipfel, P. F. The human factor H-related protein 4 (FHR4): a novel short consensus repeat-containing protein is associated with human triglyceride-rich lipoproteins. J. Biol. Chem. 272: 5627-5634, 1997. [PubMed: 9038172] [Full Text: https://doi.org/10.1074/jbc.272.9.5627]