Alt. symbols: CFHL5 | FHR5 | FHR-5

Approved name: complement factor H related 5
Alt. names: complement factor H-related 5 | factor H related protein 5

Location: 1q31.3: 196975010 - 197009678 (+)
Gene type: protein_coding, 7 transcripts.

Scores: LoFtool: 0.613000 | pLI: 0.00000000 | LOEUF: 1.829

HGNC: 24668

NCBI: 81494, RefSeq: NG_016365.1

Ensembl: ENSG00000134389.11

LRG_227 | Status: public

OMIM: 608593

Expression | ProteinAtlas

The factor H/CFHR family comprises a group of highly related proteins that includes the five Complement Factor H Related proteins (CFHR1-5), factor H and the spliced variant factor H-like protein 1 (FHL-1). CFHR proteins circulate in human plasma and act around, in competition with, or in concert with the main alternative pathway regulator factor H. Like factor H, CFHR5 has the ability to bind C3b and C3d; but it can also bind iC3b, heparin, and CRP, the last of which recruits it to sites of tissue damage to inactivate C3b (PMID: 8663389). They can support factor H activities, such as by enhancing its cofactor activity; provide additional layers of regulation, such as by inhibiting the terminal pathway; or compete with factor H for binding to C3b. Thus, the balance between CFHR and factor H protein levels is important to maintain. The five CFHR genes are located downstream of the factor H gene on a distinct segment of human chromosome 1q32 (PMID: 23830046). This segment is characterized by large genomic repeat regions with a high degree of sequence identity, thus predisposing to non-homologous allelic recombination (NAHR) events. This can lead to diverse structural rearrangements, often involving loss of single or several CFHR genes, but also forming new hybrid proteins that can also involve parts of factor H. Each CFHR gene encodes a plasma protein composed of short consensus repeat domains. The longest CFHR, CFHR5, is composed of nine SCR domains, of which at least seven show high sequence identity to the SCRs of factor H. CFHR5 can dimerize via its N-terminal SCR domains and circulates in the plasma as homodimers or as heterodimers with CFHR1 (PMID: 23487775).

The chromosome 1 segment that includes the CFHR genes and factor H gene contains multiple low-copy repeats, resulting in a high degree of sequence identity between factor H and CFHRs genes as well as between the intergenic regions, resulting in frequent deletions, duplications or rearrangements. Heterozygous intragenic CFHR5 variants, as well as more complex structural variants involving CFHR5 along with the other CFHR genes, have been associated with various forms of nephropathy [OMIM:614809], including atypical hemolytic uremic syndrome (aHUS), IgA nephropathy, and membranoproliferative glomerulonephritis, but functional studies remain outstanding for most (PMID: 23830046, 31980588). HUS is a rare, renal thrombotic microangiopathy characterized by the triad of hemolytic anemia with fragmented erythrocytes, thrombocytopenia and acute renal failure. Approximately 60% of patients develop end stage renal disease (PMID: 19846853). While “typical” HUS is associated with bacterial infection, “atypical” HUS is associated with genetic determinants. CFHR5 mutations (E75X, L105R, S195T, E234K, V277N, V379L, W436C) have been reported in familial and/or sporadic aHUS cases, but the functional consequences have largely not been studied though L105R has been noted to lead to higher CFHR5 protein levels than in controls (PMID: 20513133, 22622361, 30905589). C3 glomerulopathies are characterized by the isolated deposition of C3 within or along the glomerular basement membrane combined with alternative complement pathway overactivation. These include membranoproliferative glomerulonephritis type II or dense deposit disease (MPGN II/DDD), glomerulonephritis with isolated C3 deposits (C3GN) and CFHR5 glomerulopathy (PMID: 20606628). A heterozygous single nucleotide insertion in exon 4 of CFHR5 was reported in a patient with post-streptococcal glomerulonephritis who later developed membranoproliferative changes, and electron-dense deposits consistent with C3 glomerulopathy (PMID: 22503529). Although the change was predicted to engender a premature stop codon and the proband had low CFHR5 levels, a parent with the same mutation had normal CFHR5 levels. CFHR5 polymorphisms have also been associated with MPGN II/DDD (PMID: 16299065). Two SNPs in the promoter region of CFHR5 (rs942766 and rs9427662) are thought to affect transcription by respectively removing a C/EBPbeta binding site or adding a GATA1 binding site, while a third (rs12097550) affects an exon 2 residue in the domain important for heparin and CRP binding. An internal duplication in the CFHR5 gene that results in reduced binding to membrane-associated C3b causes autosomal dominant CFHR5 nephropathy in patients of Cypriot origin, and is thought to be a founder effect (PMID: 20800271). The laboratory complement profile of patients is normal, without decreased C3 levels, suggesting that complement activation occurs locally in the kidney and that CFHR5 is important for inhibiting C3 activation at the glomerular basement membrane rather than systemically. Recent functional studies showed that this duplication of the dimerization domain (SCR1 and SCR2 in CFHR5) favors the formation of abnormal CHFR5, CFHR1 and/or CFHR2-containing oligomers that more efficiently compete with factor H for binding to cell-bound C3b, leading to impaired cell surface protection from complement attack (PMID: 23487775). [Load More]