Structure of the murine complement factor H gene.

Vik, D P; Keeney, Jill B.; Muñoz‐Cánoves, Pura; Chaplin, David; Tack, Brian F.

doi:10.1016/s0021-9258(18)37450-7

Cited by 51 publications

(14 citation statements)

References 36 publications

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“…The C4BPa gene spans over 40 kb of DNA and comprises 12 exons . The organization of the C4BPa gene matches a general pattern found in other RCA genes like MCP, CR2, CR1, CRl-like, DAF, and H, for the location of most of the splicejunctions (36)(37)(38)(39)(40) . The similarities observed between C4BPa and other RCA genes can be summarized as follows: (a) C4BPa presents identical genomic arrangement for the boundary between the signal peptide and the mature polypeptide to that found in the CR1, CR2, and DAF genes (36,39,41) .…”

Section: Discussionsupporting

confidence: 68%

Structure of the gene coding for the alpha polypeptide chain of the human complement component C4b-binding protein.

Córdoba

Sánchez-Corral

Rey-Campos

1991

The Journal of Experimental Medicine

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SummaryThe human gene coding for the 70-kD polypeptide of the complement regulatory component C4b-binding protein (C4BPa) spans over 40 kb of DNA and is composed of twelve exons. Upon transcription in liver, or in Hep-G2 cells, this gene produces a single transcript of 2,262 nucleotides, excepting the poly A tail, that presents an unusually long 5' untranslated region (5' UTR) of 223 nucleotides . The C4BPa gene is organized as follows : the first exon codes for the first 198 nucleotides of the 5' UTR. It is separated by a large intron from the second axon including the remaining of the 5' UTR and the coding region for the signal peptide. Each of the eight 60-amino acid repeats (short consensus repeats [SCRs]) that compose the C4BPa polypeptide chain is encoded by a single exon, except for the second SCR, which is split in two exons. At the 3' end of the C4BPa gene, the twelfth exon codes for the COOH-terminal 57 amino acids of the mature protein, which have no similarities to the SCRs, and the 245 nucleotides of the 3' UTR . Examination of the nucleotide sequence of the first exon revealed an interesting characteristic, strongly suggesting that this exon may specify a functional domain of the C4BPa transcript . It includes two in-phase ATG codons, in a different frame respect to that coding the C4BPa polypeptide, followed by an in-frame termination codon, also within the first exon .Comparison between mouse and human C4BPa transcripts indicates conservation of this structure within the 5' UTR. C4BP is expressed in the liver and is an acute phase protein . A computer search of the genomic sequences upstream the transcription start site demonstrates the presence of potential cis-acting regulatory elements similar to those found in the promoters of other liverexpressed and/or acute phase genes.

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Section: Discussionsupporting

confidence: 68%

Structure of the gene coding for the alpha polypeptide chain of the human complement component C4b-binding protein.

Córdoba

Sánchez-Corral

Rey-Campos

1991

The Journal of Experimental Medicine

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“…Recent evidence from the analyses of the C3b/C4b binding capacities of CRl deletion mutants lacking one or more LHRs indicated that the specificity for these ligands is determined by the first two SCRs in each LHR (22). These observations are consistent with the second SCR in murine factor H being encoded by two exons and the localization of the C3b binding site of human factor H to the NH2 terminus of this molecule (37,38).…”

Section: Discussionmentioning

confidence: 56%

“…In the CRI gene, the signal peptide, and the transmembrane and cytoplasmic regions are encoded by separate exons, while most of the SCRs are found in exons of -200 by as has been reported in human C4BP, C2, factor B and IL-2R (Tac-I) and in murine factor H (34)(35)(36)(37). That the second SCR in each LHR is encoded by two exons is an indication of specialized functional capacities of this repeat unit.…”

Section: Discussionmentioning

confidence: 83%

Structure of the human CR1 gene. Molecular basis of the structural and quantitative polymorphisms and identification of a new CR1-like allele.

Wong

Cahill

Rosen

et al. 1989

The Journal of Experimental Medicine

109

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The human receptor for the complement cleavage fragments C3b and C4b (complement receptor type 1, CRl) is found on the surfaces of erythrocytes, most peripheral blood leukocytes, glomerular podocytes, and follicular dendritic cells, and in plasma (1-3). Besides the removal of C3b-or C4b-coated microorganisms or immune complexes (4), CRl also serves as an inhibitor of the C3 and the C5 convertases by dissociating C2b and Bb fragments and by acting as a cofactor for the factor I-mediated cleavage of C3b and C4b (5, 6) . This regulatory capacity is shared by the structurally related members of a supergene family, termed the regulator of complement activation (RCA)t region, located on chromosome 1 (7-13) .Human CRl is a single chain glycoprotein with four allotypic variants that differ in Mr on SDS-PAGE by increments of 40-50 kD (14-17). The two most common variants are termed F and S (or A and B allotypes) and exhibit Mr of 250 and 290 kD, respectively. These variations reflect differing lengths of the polypeptides and not posttranslational modifications, since distinct unglycosylated precursors have been described (18) and incremental differences of 1.3 to 1.5 kb were also observed in the CRl transcripts from various allotypes (19,20). The cDNA that encodes the entire F allotype of 2,039 amino acids (aa) has been sequenced and the extracellular portion of the molecule is found to comprise 30 short consensus repeats (SCR). A feature that distinguishes CR1 from the other proteins of this gene family is the organization of the NH2-terminal 28 SCRs into four tandem long homologous repeats (LHR) of about 450 aa, each containing seven SCRs . Extensive sequence homologies of 60 to 99% have been observed among the LHRs, suggesting that they have arisen by gene duplication (21,22).

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“…In the normal individual, FH is expressed at relatively high levels in the blood, with concentrations ranging from 116-562 mg/ml depending on genetic and environmental factors (24,25). The murine equivalent of FH (mFH) has been shown to be both structurally and functionally like human FH (hFH) (26,27). Furthermore, in both mouse and man FH-related proteins (FHRs) (28)(29)(30)(31) have been identified, it is likely these proteins play important roles in immune evasion and fine tuning the level of complement activation at surfaces (29,(32)(33)(34).…”

Section: Introductionmentioning

confidence: 99%

Homodimeric Minimal Factor H: In Vivo Tracking and Extended Dosing Studies in Factor H Deficient Mice

Kamala¹,

Malik²,

Hallam³

et al. 2021

Front. Immunol.

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C3 glomerulopathy (C3G) is associated with dysregulation of the alternative pathway (AP) of complement and treatment options remain inadequate. Factor H (FH) is a potent regulator of the AP. An in-depth analysis of FH-related protein dimerised minimal (mini)-FH constructs has recently been published. This analysis showed that addition of a dimerisation module to mini-FH not only increased serum half-life but also improved complement regulatory function, thus providing a potential treatment option for C3G. Herein, we describe the production of a murine version of homodimeric mini-FH [mHDM-FH (mFH1–5^18–20^R1–2)], developed to reduce the risk of anti-drug antibody formation during long-term experiments in murine models of C3G and other complement-driven pathologies. Our analysis of mHDM-FH indicates that it binds with higher affinity and avidity to WT mC3b when compared to mouse (m)FH (mHDM-FH KD=505 nM; mFH KD=1370 nM) analogous to what we observed with the respective human proteins. The improved binding avidity resulted in enhanced complement regulatory function in haemolytic assays. Extended interval dosing studies in CFH-/- mice (5mg/kg every 72hrs) were partially effective and bio-distribution analysis in CFH-/- mice, through in vivo imaging technologies, demonstrates that mHDM-FH is preferentially deposited and remains fixed in the kidneys (and liver) for up to 4 days. Extended dosing using an AAV- human HDM-FH (hHDM-FH) construct achieved complete normalisation of C3 levels in CFH-/- mice for 3 months and was associated with a significant reduction in glomerular C3 staining. Our data demonstrate the ability of gene therapy delivery of mini-FH constructs to enhance complement regulation in vivo and support the application of this approach as a novel treatment strategy in diseases such as C3G.

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Structure of the murine complement factor H gene.

Cited by 51 publications

References 36 publications

Structure of the gene coding for the alpha polypeptide chain of the human complement component C4b-binding protein.

Structure of the gene coding for the alpha polypeptide chain of the human complement component C4b-binding protein.

Structure of the human CR1 gene. Molecular basis of the structural and quantitative polymorphisms and identification of a new CR1-like allele.

Homodimeric Minimal Factor H: In Vivo Tracking and Extended Dosing Studies in Factor H Deficient Mice

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