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

Rooryck C, Diaz-Font A, Osborn DP, Chabchoub E, Hernandez-Hernandez V, Shamseldin H, Kenny J, Waters A, Jenkins D, Kaissi AA, Leal GF, Dallapiccola B, Carnevale F, Bitner-Glindzicz M, Lees M, Hennekam R, Stanier P, Burns AJ, Peeters H, Alkuraya FS, Beales PL - Nat. Genet. (2011)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Molecular Medicine Unit, University College London Institute of Child Health, London, UK.

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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a. General morphology of masp1 zebrafish morphants showing pigmentation defect (arrows; scale bar; main panel = 500 μm; inset = 200 μm) b. Alcian blue cartilage staining at 5 dpf showing cartilage defects in masp1 morphants (6 ng) (panel second from left). Alcian blue staining in morphants double-injected with suboptimal doses of colec11 (2 ng) and masp1 (3ng) MO (panel far right). We observed a cartilage defect only in double-injected morphants compared with single suboptimal injections of either colec11 or masp1 MO (panels third and fourth from left).
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Figure 4: a. General morphology of masp1 zebrafish morphants showing pigmentation defect (arrows; scale bar; main panel = 500 μm; inset = 200 μm) b. Alcian blue cartilage staining at 5 dpf showing cartilage defects in masp1 morphants (6 ng) (panel second from left). Alcian blue staining in morphants double-injected with suboptimal doses of colec11 (2 ng) and masp1 (3ng) MO (panel far right). We observed a cartilage defect only in double-injected morphants compared with single suboptimal injections of either colec11 or masp1 MO (panels third and fourth from left).

Mentions: Next, we examined in zebrafish the effects of loss of masp1 in vivo. Two antisense morpholinos were designed; one directed against the initiation site (masp1-ATG-MO) and another against the exon 3-intron 3 splice site (masp1-SPL-MO) (Suppl Fig 7). Injection of both ATG and splice MOs at the one-cell stage gave rise to pigment (Fig 4a) and craniofacial cartilage defects (Fig 4b) similar to those seen in colec11 morphants.


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

Rooryck C, Diaz-Font A, Osborn DP, Chabchoub E, Hernandez-Hernandez V, Shamseldin H, Kenny J, Waters A, Jenkins D, Kaissi AA, Leal GF, Dallapiccola B, Carnevale F, Bitner-Glindzicz M, Lees M, Hennekam R, Stanier P, Burns AJ, Peeters H, Alkuraya FS, Beales PL - Nat. Genet. (2011)

a. General morphology of masp1 zebrafish morphants showing pigmentation defect (arrows; scale bar; main panel = 500 μm; inset = 200 μm) b. Alcian blue cartilage staining at 5 dpf showing cartilage defects in masp1 morphants (6 ng) (panel second from left). Alcian blue staining in morphants double-injected with suboptimal doses of colec11 (2 ng) and masp1 (3ng) MO (panel far right). We observed a cartilage defect only in double-injected morphants compared with single suboptimal injections of either colec11 or masp1 MO (panels third and fourth from left).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3045628&req=5

Figure 4: a. General morphology of masp1 zebrafish morphants showing pigmentation defect (arrows; scale bar; main panel = 500 μm; inset = 200 μm) b. Alcian blue cartilage staining at 5 dpf showing cartilage defects in masp1 morphants (6 ng) (panel second from left). Alcian blue staining in morphants double-injected with suboptimal doses of colec11 (2 ng) and masp1 (3ng) MO (panel far right). We observed a cartilage defect only in double-injected morphants compared with single suboptimal injections of either colec11 or masp1 MO (panels third and fourth from left).
Mentions: Next, we examined in zebrafish the effects of loss of masp1 in vivo. Two antisense morpholinos were designed; one directed against the initiation site (masp1-ATG-MO) and another against the exon 3-intron 3 splice site (masp1-SPL-MO) (Suppl Fig 7). Injection of both ATG and splice MOs at the one-cell stage gave rise to pigment (Fig 4a) and craniofacial cartilage defects (Fig 4b) similar to those seen in colec11 morphants.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Molecular Medicine Unit, University College London Institute of Child Health, London, UK.

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.

Show MeSH
Related in: MedlinePlus