Immunodeficiency Associated with<i>FCN3</i>Mutation and Ficolin-3 Deficiency

C1 inhibitor (C1-INH) is known to form complexes with the lectin complement pathway serine proteases MASP-1 and MASP-2. Deficiency of C1-INH is associated with hereditary angioedema (HAE), an autosomal inherited disease characterized by swelling attacks caused by elevated levels of bradykinin. MASP-1 was shown to cleave high m.w. kininogen into bradykinin; therefore, we hypothesized that MASP-1 levels and the quantity of MASP-1/C1-INH complexes might be associated with different paraclinical and clinical outcomes of HAE. We measured MASP-1 serum concentrations and endogenous MASP-1/C1-INH complex levels in 128 HAE patients and 100 controls. Relatively high levels of pre-existing MASP-1/C1-INH complexes were observed in normal serum, and we found that both the serum levels of MASP-1 and the complex formation between MASP-1 and C1-INH were significantly reduced in HAE patients compared with matched controls (p < 0.0001). The level of MASP-1 and MASP-1/C1-INH complexes in HE patients correlated with the level of C1-INH (p = 0.0009 and p = 0.0047, respectively), the level of C4 (p = 0.0084 and p < 0.0001, respectively), and the number of attacks in the year of blood sampling (p = 0.0075 and p = 0.0058, respectively). In conclusion, we show that MASP-1/C1-INH complexes circulate in normal human blood. The levels of MASP-1 and MASP-1/C1-INH complexes are reduced in HAE patients compared with controls. Both MASP-1 and MASP-1/C1-INH complexes are related to the degree of complement C4 consumption, as well as the severity of disease. These results suggest that MASP-1 may exert a previously unrecognized role in the pathophysiology of HAE.

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“…Three individuals deficient in the complement components MASP-2, ficolin-3, and MBL were described previously (17)(18)(19).…”

Section: Complement-deficient Individualsmentioning

confidence: 99%

The Levels of the Lectin Pathway Serine Protease MASP-1 and Its Complex Formation with C1 Inhibitor Are Linked to the Severity of Hereditary Angioedema

Hansen

Csuka

Munthe-Fog

et al. 2015

The Journal of Immunology

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“…Unlike L-and M-ficolins, a frame-shift mutation in the FCN3 gene was found to be associated with H-ficolin protein deficiency. A patient who was homozygous for this mutation had recurrent infections (Munthe-Fog et al, 2009). Along with MASP1 (MASP-1/3 and MAp44 proteins) and MASP2 (MASP-2 and MAp19 proteins), a number of SNPs have been described for FCNs (Garred et al, 2010;Degn et al, 2011).…”

Section: Components Of the Lectin Pathwaymentioning

confidence: 99%

Complement genetics, deficiencies, and disease associations

Mayilyan

2012

Protein Cell

144

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The complement system is a key component of innate immunity. More than 45 genes encoding the proteins of complement components or their isotypes and subunits, receptors, and regulators have been discovered. These genes are distributed throughout different chromosomes, with 19 genes comprising three significant complement gene clusters in the human genome. Genetic deficiency of any early component of the classical pathway (C1q, C1r/s, C2, C4, and C3) is associated with autoimmune diseases due to the failure of clearance of immune complexes (IC) and apoptotic materials, and the impairment of normal humoral response. Deficiencies of mannan-binding lectin (MBL) and the early components of the alternative (factor D, properdin) and terminal pathways (from C3 onward components: C5, C6, C7, C8, C9) increase susceptibility to infections and their recurrence. While the association of MBL deficiency with a number of autoimmune and infectious disorders has been well established, the effects of the deficiency of other lectin pathway components (ficolins, MASPs) have been less extensively investigated due to our incomplete knowledge of the genetic background of such deficiencies and the functional activity of those components. For complement regulators and receptors, the consequences of their genetic deficiency vary depending on their specific involvement in the regulatory or signalling steps within the complement cascade and beyond. This article reviews current knowledge and concepts about the genetic load of complement component deficiencies and their association with diseases. An integrative presentation of genetic data with the latest updates provides a background to further investigations of the disease association investigations of the complement system from the perspective of systems biology and systems genetics.

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“…Complement Activation AssayThe influence of MAP-1 on the MBL and ficolin-3-mediated complement factor C4 deposition was assessed essentially as described previously (19,20). Briefly, mannan (MBL ligand) (Sigma-Aldrich M7504) or acetylated bovine serum albumin (AcBSA) (ficolin-3 ligand) was immobilized to Maxisorp ELISA plates (Nunc) at 10 g/ml.…”

Section: Alignment Of the Masp1 Gene And Its Splice Variants-thementioning

confidence: 99%

“…Briefly, mannan (MBL ligand) (Sigma-Aldrich M7504) or acetylated bovine serum albumin (AcBSA) (ficolin-3 ligand) was immobilized to Maxisorp ELISA plates (Nunc) at 10 g/ml. After washing, rMBL or rficolin-3 (0.4 g/ml) was added and incubated for 1.5 h. The rMAP-1 or rMASP-2 was applied for 1 h in 2-fold serial dilutions in the first dimension followed by incubation for 45 min at 37°C with serial dilutions of serum deficient of MBL (21) or ficolin-3 (20) in the second dimension. The C4 deposition was measured using a polyclonal antibody to C4c (Q0369, Dako).…”

Section: Alignment Of the Masp1 Gene And Its Splice Variants-thementioning

confidence: 99%

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A Novel Mannose-binding Lectin/Ficolin-associated Protein Is Highly Expressed in Heart and Skeletal Muscle Tissues and Inhibits Complement Activation

Skjoedt

Hummelshøj

Palarasah

et al. 2010

Journal of Biological Chemistry

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137

146

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The human lectin complement pathway involves circulating complexes consisting of mannose-binding lectin (MBL) or three ficolins (ficolin-1, -2, and -3) in association with three MBL/ ficolin-associated serine proteases (MASP) (MASP-1, -2, and -3) and a nonenzymatic sMAP. MASP-1 and MASP-3 (MASP1 isoforms 1 and 2, respectively) are splice variants of the MASP1 gene, whereas MASP-2 and sMAP are splice variants of the MASP2 gene. We have identified a novel serum protein of 45 kDa that is associated with MBL and the ficolins. This protein is named MBL/ficolin-associated protein 1 (MAP-1 corresponding to MASP1 isoform 3). The transcript generating MAP-1 (MASP1_v3) contains exons 1-8 and a novel exon encoding an in-frame stop codon. The corresponding protein lacks the serine protease domains but contains most of the common heavy chain of MASP-1 and MASP-3. Additionally MAP-1 contains 17 unique C-terminal amino acids. By use of quantitative PCR and MAP-1-specific immunohistochemistry, we found that MAP-1 is highly expressed in myocardial and skeletal muscle tissues as well as in liver hepatocytes with a different expression profile than that observed for MASP-1 and MASP-3. MAP-1 co-precipitated from human serum with MBL, ficolin-2, and ficolin-3, and recombinant MAP-1 was able to inhibit complement C4 deposition via both the ficolin-3 and MBL pathway. In conclusion we have identified a novel 45-kDa serum protein derived from the MASP1 gene, which is highly expressed in striated muscle tissues. It is found in complex with MBL and ficolins and may function as a potent inhibitor of the complement system in vivo.Activation of the complement system is accomplished via three different initiation pathways: the alternative pathway, the classical pathway, and the lectin pathway (1). In humans, four recognition molecules of the lectin pathway have been described: mannose-binding lectin (MBL), 3 ficolin-1 (also called M-ficolin), ficolin-2 (also called L-ficolin), and ficolin-3 (also called H-ficolin or Hakata antigen) (2). MBL and the ficolins bind structures on different classes of microorganisms and are involved in sequestration and removal of dying host cells (2, 3). Three MBL/ficolin-associated serine proteases have been described so far (MASP-1, MASP-2, and MASP-3), as well as a protein lacking a serine protease domain named sMAP or MAp19 (4). Present consensus places MASP-2 as the main initiator of the lectin complement pathway by cleaving C4 and C2 to form the C4b2a complex leading to further downstream complement activation (5). Although the functions of the other MASPs are poorly understood, MASP-1 appears to play a role as an amplifier of complement activation (6, 7). Additionally, MASP-1 is able to cleave fibrinogen to fibrin, whereas MASP-2 is able to generate active thrombin by cleavage of prothrombin (8,9). No conclusive biological function has yet been attributed to MASP-3 and sMAP. MASP-1 and MASP-2 were originally named after their association with MBL (5, 10). Subsequently, MASP-3 and sMAP (also named Map19) we...

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Immunodeficiency Associated withFCN3Mutation and Ficolin-3 Deficiency

Cited by 156 publications

References 22 publications

The Levels of the Lectin Pathway Serine Protease MASP-1 and Its Complex Formation with C1 Inhibitor Are Linked to the Severity of Hereditary Angioedema

The Levels of the Lectin Pathway Serine Protease MASP-1 and Its Complex Formation with C1 Inhibitor Are Linked to the Severity of Hereditary Angioedema

Complement genetics, deficiencies, and disease associations

A Novel Mannose-binding Lectin/Ficolin-associated Protein Is Highly Expressed in Heart and Skeletal Muscle Tissues and Inhibits Complement Activation

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