Characterization of a polymorphism in the coding sequence of FCN3 resulting in a Ficolin-3 (Hakata antigen) deficiency state

Munthe-Fog, Lea; Hummelshøj, Tina; Jie, Ying; Hansen, Bo Moelholm; Koch, Claus; Madsen, Hans O.; Skjødt, Karsten; Garred, Peter

doi:10.1016/j.molimm.2007.12.012

Cited by 118 publications

(133 citation statements)

References 17 publications

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“…However, literature reviews have identified that the FCN3 variant (1637delC; rs28357092) has been reported previously. 19 The FCN3 gene produces a ficolin protein that has a role in the innate immune system. Homozygosity of this variation has been reported in a single individual with immunodeficiency and recurrent infections.…”

Section: Sequence Resultsmentioning

confidence: 99%

A novel locus for episodic ataxia:UBR4 the likely candidate

et al. 2013

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Episodic ataxias (EAs) are rare neurological channelopathies that are characterized by spells of imbalance and a lack of co-ordination. There are seven clinically recognized EAs and multiple isolated cases. Five disease-causing genes have been identified to date. We describe a novel form of autosomal dominant EA in a large three-generation Irish family. This form of EA presents in early childhood with periods of unsteadiness generalized weakness and slurred speech during an attack, which may be triggered by physical tiredness or stress. Linkage analysis undertaken in 13 related individuals identified a single disease locus (1p36.13-p34.3) with a LOD score of 3.29. Exome sequencing was performed. Following data analysis, which included presence/absence within the linkage peak, two candidate variants were identified. These are located in the HSPG2 and UBR4 genes. UBR4 is an ubiquitin ligase protein that is known to interact with calmodulin, a Ca 2 þ protein, in the cytoplasm. It also co-localizes with ITPR1 a calcium release channel that is a major determinant of mammal co-ordination. Although UBR4 is not an ion channel gene, the potential for disrupted Ca 2 þ control within neuronal cells highlights its potential for a role in this form of EA.

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Section: Sequence Resultsmentioning

confidence: 99%

A novel locus for episodic ataxia:UBR4 the likely candidate

et al. 2013

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“…After the final washing steps and magnetic separation the beads were boiled in SDS loading buffer and subjected to SDS-PAGE and immunoblotting probed with biotinylated antibodies to MAP-1, MBL, or ficolin-3. The same precipitation procedure as described above was performed with mAbs to MBL (Hyb 131-11; Bioporto), ficolin-2 (FCN219) (16), and ficolin-3 (FCN334) (17). To compensate for differences in serum concentrations of MBL and ficolin-2 and -3, we precipitated from 1 ml, 300 l, and 100 l of serum, respectively.…”

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

confidence: 99%

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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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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“…The ficolins are multimeric macromolecules, structurally and functionally related to collectins. Ficolin-1, ficolin-2, and ficolin-3 are found in serum (15)(16)(17), with ficolin-1 being the least abundant (15). Ficolins primarily recognize acetylated compounds via the fibrinogen-like domain, such as N-acetyl-D-glucosamine (GlcNAc) and acetylated BSA (AcBSA) (18,19).…”

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confidence: 99%

Cholesterol Crystals Activate the Lectin Complement Pathway via Ficolin-2 and Mannose-Binding Lectin: Implications for the Progression of Atherosclerosis

Pilely

Rosbjerg

Genster

et al. 2016

The Journal of Immunology

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Cholesterol crystals (CC) play an essential role in the formation of atherosclerotic plaques. CC activate the classical and the alternative complement pathways, but the role of the lectin pathway is unknown. We hypothesized that the pattern recognition molecules (PRMs) from the lectin pathway bind CC and function as an upstream innate inflammatory signal in the pathophysiology of atherosclerosis. We investigated the binding of the PRMs mannose-binding lectin (MBL), ficolin-1, ficolin-2, and ficolin-3, the associated serine proteases, and complement activation products to CC in vitro using recombinant proteins, specific inhibitors, as well as deficient and normal sera. Additionally, we examined the deposition of ficolin-2 and MBL in human carotid plaques by immunohistochemistry and fluorescence microscopy. The results showed that the lectin pathway was activated on CC by binding of ficolin-2 and MBL in vitro, resulting in activation and deposition of complement activation products. MBL bound to CC in a calcium-dependent manner whereas ficolin-2 binding was calcium-independent. No binding was observed for ficolin-1 or ficolin-3. MBL and ficolin-2 were present in human carotid plaques, and binding of MBL to CC was confirmed in vivo by immunohistochemistry, showing localization of MBL around CC clefts. Moreover, we demonstrated that IgM, but not IgG, bound to CC in vitro and that C1q binding was facilitated by IgM. In conclusion, our study demonstrates that PRMs from the lectin pathway recognize CC and provides evidence for an important role for this pathway in the inflammatory response induced by CC in the pathophysiology of atherosclerosis.

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Characterization of a polymorphism in the coding sequence of FCN3 resulting in a Ficolin-3 (Hakata antigen) deficiency state

Cited by 118 publications

References 17 publications

A novel locus for episodic ataxia:UBR4 the likely candidate

A novel locus for episodic ataxia:UBR4 the likely candidate

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

Cholesterol Crystals Activate the Lectin Complement Pathway via Ficolin-2 and Mannose-Binding Lectin: Implications for the Progression of Atherosclerosis

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