Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome

Rooryck, Caroline; Dı́az-Font, Anna; Osborn, Daniel P. S.; Chabchoub, Elyes; Hernández, Víctor; Shamseldin, Hanan E.; Kenny, Joanna; Waters, Aoife; Jenkins, Dagan; Kaissi, Ali Al; Leal, Gabriela Ferraz; Dallapiccola, Bruno; Carnevale, Franco A.; Bitner‐Glindzicz, Maria; Lees, Melissa; Hennekam, Raoul C. M.; Stanier, Philip; Burns, Alan J.; Peeters, Hilde; Alkuraya, Fowzan S.; Beales, Philip L.

doi:10.1038/ng.757

Cited by 239 publications

(274 citation statements)

References 25 publications

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“…Although MASP-2 is thought to play a key role in activation of the lectin pathway, these data suggested that MASP-1 and/or MASP-3 may be more important than MASP-2 in the phagocytosis and clearance of bacteria. Recently, mutations in the MASP-3 gene have been reported to be a cause of the Carnevale, Mingarelli, Malpuech and Michels syndromes (the so-called 3MC syndrome), a disorder that includes craniofacial defects (27). MASP-3 may also play an important role in embryonic development.…”

Section: Discussionmentioning

confidence: 99%

The Role of Mannose-Binding Lectin-Associated Serine Protease-3 in Activation of the Alternative Complement Pathway

Iwaki

Kanno

Takahashi

et al. 2011

The Journal of Immunology

129

112

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Mannose-binding lectin (MBL)-associated serine proteases (MASPs) are responsible for activation of the lectin complement pathway. Three types of MASPs (MASP-1, MASP-2, and MASP-3) are complexed with MBL and ficolins in serum. Although MASP-1 and MASP-2 are known to contribute to complement activation, the function of MASP-3 remains unclear. In this study, we investigated the mechanism of MASP-3 activation and its substrate using the recombinant mouse MASP-3 (rMASP-3) and several different types of MASP-deficient mice. A proenzyme rMASP-3 was obtained that was not autoactivated during preparation. The recombinant enzyme was activated by incubation with Staphylococcus aureus in the presence of MBL-A, but not MBL-C. In vivo studies revealed the phagocytic activities of MASP-1/3–deficient mice and all MASPs (MASP-1/2/3)–deficient mice against S. aureus and bacterial clearance in these mice were lower than those in wild-type and MASP-2–deficient mice. Sera from all MASPs-deficient mice showed significantly lower C3 deposition activity on the bacteria compared with that of wild-type serum, and addition of rMASP-3 to the deficient serum restored C3 deposition. The low C3 deposition in sera from all MASPs-deficient mice was probably caused by the low level factor B activation that was ameliorated by the addition of rMASP-3. Furthermore, rMASP-3 directly activated factors B and D in vitro. These results suggested that MASP-3 complexed with MBL is converted to an active form by incubation with bacterial targets, and that activated MASP-3 triggered the initial activation step of the alternative complement pathway.

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Section: Discussionmentioning

confidence: 99%

The Role of Mannose-Binding Lectin-Associated Serine Protease-3 in Activation of the Alternative Complement Pathway

Iwaki

Kanno

Takahashi

et al. 2011

The Journal of Immunology

129

112

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“…Recombinant MASP-3 has some activity on insulin-like growth factor-binding protein-5 and some synthetic substrates (27). A critical role of MASP-3 in insulin-like growth factor-binding protein-5 availability during craniofacial, muscle, and neural crest development was suggested based on specific mutations (28)(29)(30). In mice, MASP-1 and MASP-3 play a role in the alternative pathway of complement activation and thus might act as a backup system when the lectin pathway is deficient (31).…”

Section: Lectin Pathway In Critically Ill Childrenmentioning

confidence: 99%

Lectin pathway of complement activation and relation with clinical complications in critically ill children

et al. 2013

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Background:Critically ill children are susceptible to nosocomial infections, which contribute to adverse outcomes. Deficiencies in the innate immunity lectin pathway of complement activation are implicated in a child's vulnerability to infections in conditions such as cancer, but the role during critical illness remains unclear. We hypothesized that low on-admission levels of the pathway proteins are, in part, genetically determined and associated with susceptibility to infectious complications and adverse outcomes. Methods: We studied protein levels of mannose-binding lectin (MBL), H-ficolin and M-ficolin, three MBL-associatedserine proteases (MASPs) and MBL-associated protein (MAp44), and relation with functional genetic polymorphisms, in 130 healthy children and upon intensive care unit (ICU) admission in 700 critically ill children of a randomized study on glycemic control. results: Levels of MASP-1, MASP-2, MASP-3, and MAp-44 were lower and the levels of M-ficolin were higher in ICU patients on admission than those in matched healthy controls. Only a low on-admission MASP-3 level was independently associated with risk of new ICU infections and prolonged ICU stay, after correcting for other risk factors. On-admission MASP-3 varied with age, illness severity, and genetic variation. conclusion: Low on-admission MASP-3 levels in critically ill children were independently associated with subsequent acquisition of infection and prolonged ICU stay. The biological explanation needs further investigation.

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“…However, the exact role is still unclear, because we recently found that a patient deficient in both MASP-1 and MASP-3 retained a functional alternative pathway (9). MASP-3 has an important function during development because its absence causes the so-called 3MC syndrome (16,17). A suggested complement-regulatory role for MAp19 (18) could not be confirmed by us (19), whereas we found that MAp44 competitively inhibited binding of MASP-2 to MBL and, hence, attenuated lectin pathway activity (3).…”

mentioning

confidence: 99%

Co-Complexes of MASP-1 and MASP-2 Associated with the Soluble Pattern-Recognition Molecules Drive Lectin Pathway Activation in a Manner Inhibitable by MAp44

Degn

Jensen

Olszowski

et al. 2013

The Journal of Immunology

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The lectin pathway of complement is an integral component of innate immunity. It is activated upon binding of mannan-binding lectin (MBL) or ficolins (H-, L-, and M-ficolin) to suitable ligand patterns on microorganisms. MBL and ficolins are polydisperse homo-oligomeric molecules, found in complexes with MBL-associated serine proteases (MASP-1, -2, and -3) and MBL-associated proteins (MAp19 and MAp44). This scenario is far more complex than the well-defined activation complex of the classical pathway, C1qC1r2C1s2, and the composition of the activating complexes of the lectin pathway is ill defined. We and other investigators recently demonstrated that both MASP-1 and MASP-2 are crucial to lectin pathway activation. MASP-1 transactivates MASP-2 and, although MASP-1 also cleaves C2, MASP-2 cleaves both C4 and C2, allowing formation of the C3 convertase, C4bC2a. Juxtaposition of MASP-1 and MASP-2 during activation must be required for transactivation. We previously presented a possible scenario, which parallels that of the classical pathway, in which MASP-1 and MASP-2 are found together in the same MBL or ficolin complex. In this study, we demonstrate that, although MASPs do not directly form heterodimers, the addition of MBL or ficolins allows the formation of MASP-1–MASP-2 co-complexes. We find that such co-complexes have a functional role in activating complement and are present in serum at varying levels, impacting on the degree of complement activation. This raises the novel possibility that MAp44 may inhibit complement, not simply by brute force displacement of MASP-2 from MBL or ficolins, but by disruption of co-complexes, hence impairing transactivation. We present support for this contention.

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Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome

Cited by 239 publications

References 25 publications

The Role of Mannose-Binding Lectin-Associated Serine Protease-3 in Activation of the Alternative Complement Pathway

The Role of Mannose-Binding Lectin-Associated Serine Protease-3 in Activation of the Alternative Complement Pathway

Lectin pathway of complement activation and relation with clinical complications in critically ill children

Co-Complexes of MASP-1 and MASP-2 Associated with the Soluble Pattern-Recognition Molecules Drive Lectin Pathway Activation in a Manner Inhibitable by MAp44

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