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

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Abstract

3MC syndrome has been proposed as a unifying term encompassing the overlapping Carnevale, Mingarelli, Malpuech and Michels syndromes. These rare autosomal recessive disorders exhibit a spectrum of developmental features, including characteristic facial dysmorphism, cleft lip and/or palate, craniosynostosis, learning disability and genital, limb and vesicorenal anomalies. Here we studied 11 families with 3MC syndrome and identified two mutated genes, COLEC11 and MASP1, both of which encode proteins in the lectin complement pathway (collectin kidney 1 (CL-K1) and MASP-1 and MASP-3, respectively). CL-K1 is highly expressed in embryonic murine craniofacial cartilage, heart, bronchi, kidney and vertebral bodies. Zebrafish morphants for either gene develop pigmentary defects and severe craniofacial abnormalities. Finally, we show that CL-K1 serves as a guidance cue for neural crest cell migration. Together, these findings demonstrate a role for complement pathway factors in fundamental developmental processes and in the etiology of 3MC syndrome.

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Figure 1: Summary of mutations identified in 3MC syndrome.
Figure 2: Immunolocalization of CL-K1 protein with polyclonal antibody.
Figure 3: Defects in zebrafish colec11 morphants.
Figure 4: Morphological defects in zebrafish masp1 morphants.
Figure 5: Effects of colec11 and masp1 knockdown on neural crest cell migration in zebrafish.
Figure 6: Cell migration assays.

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  • 09 March 2016

    In the version of this article initially published, the authors neglected to acknowledge funding from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London to author Philip L. Beales. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

This work was supported in part by grants from NEWLIFE (P.L.B., A.D.-F. and C.R.), the Wellcome Trust (P.L.B.), Dubai Harvard Foundation for Medical Research (F.S.A.), the University Hospital of Bordeaux (C.R.), the UK Medical Research Council (A.W.) and EU-FP7 (201804-EUCILIA) (V.H.-H., D.J. and D.P.S.O.). This research was supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London (P.L.B.). P.L.B. is a Wellcome Trust Senior Research Fellow.

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C.R., A.D.-F. and D.P.S.O. planned and carried out experiments, analyzed data and co-wrote the manuscript. E.C., V.H.-H. and A.W. carried out experiments and analyzed data. H.S., J.K. and D.J. carried out experiments. A.A.K., G.F.L., B.D., F.C. and M.L. clinically ascertained patients and samples. M.B.-G. clinically ascertained patients and samples and planned the study. R.H. clinically ascertained patients and samples, planned the study, analyzed data and edited the manuscript. P.S. provided samples and analyzed data. A.J.B. and H.P. planned and carried out experiments and analyzed data. F.S.A. planned the study, ascertained samples, carried out experiments, analyzed data and edited the manuscript. P.L.B. planned and supervised the study, analyzed data, and co-wrote and edited the manuscript.

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Correspondence to Philip L Beales.

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Supplementary Figures 1–11 and Supplementary Tables 1 and 2 (PDF 3813 kb)

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Rooryck, C., Diaz-Font, A., Osborn, D. et al. Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome. Nat Genet 43, 197–203 (2011). https://doi.org/10.1038/ng.757

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