Limits...
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.

Show MeSH

Related in: MedlinePlus

Immunolocalization of CL-K1 protein with polyclonal antibody a. in mouse embryo whole sections (scale bar: main panel 1 mm, inset panels 500 μm); CL-K1 (DAB) is expressed in the developing murine nasal septum (I), cartilage primordium of the basisphenoid bone (II, arrow), Meckel's cartilage (II, mc), myocardium (III), bronchioles and vertebrae (IV) at E13.5. b. CL-K1 is highly expressed in the palatal mesenchyme (arrow) and epithelium (arrow head) at E13.5. Later, at E15.5 CL-K1 is downregulated in the fused palatal shelf (asterisk) while expression is maintained in the palatal shelf epithelium (arrow head) (scale bar: 500 μm). c. ATDC5 cells showing immuno-colocalisation of endogenous CL-K1 and Golgi marker 58K (scale bar: 10 μm). d. colec11 in situ hybridisation at 10s, 24 hpf, and 48 hpf stages. At 10s, expression is localised to the cranial paraxial mesendoderm (arrow heads and transverse section, inset). The eyes are demarcated by asterisks and the relative position of the section marked by a dotted line. Scale bar: 100 μm. At 24hpf, transcripts are detected in the glomeruli (arrow heads) and cranial ventral midline (arrow). Inset shows a dorsal flatmount at 24 hpf highlighting expression in the glomeruli and pronephric ducts (PNDs, black arrow). At 48 hpf, colec11 remains in the glomeruli (arrow head), weakly in the PNDs (black arrow), and strongly in the liver (white arrow). Scale bar: 200 μm.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3045628&req=5

Figure 2: Immunolocalization of CL-K1 protein with polyclonal antibody a. in mouse embryo whole sections (scale bar: main panel 1 mm, inset panels 500 μm); CL-K1 (DAB) is expressed in the developing murine nasal septum (I), cartilage primordium of the basisphenoid bone (II, arrow), Meckel's cartilage (II, mc), myocardium (III), bronchioles and vertebrae (IV) at E13.5. b. CL-K1 is highly expressed in the palatal mesenchyme (arrow) and epithelium (arrow head) at E13.5. Later, at E15.5 CL-K1 is downregulated in the fused palatal shelf (asterisk) while expression is maintained in the palatal shelf epithelium (arrow head) (scale bar: 500 μm). c. ATDC5 cells showing immuno-colocalisation of endogenous CL-K1 and Golgi marker 58K (scale bar: 10 μm). d. colec11 in situ hybridisation at 10s, 24 hpf, and 48 hpf stages. At 10s, expression is localised to the cranial paraxial mesendoderm (arrow heads and transverse section, inset). The eyes are demarcated by asterisks and the relative position of the section marked by a dotted line. Scale bar: 100 μm. At 24hpf, transcripts are detected in the glomeruli (arrow heads) and cranial ventral midline (arrow). Inset shows a dorsal flatmount at 24 hpf highlighting expression in the glomeruli and pronephric ducts (PNDs, black arrow). At 48 hpf, colec11 remains in the glomeruli (arrow head), weakly in the PNDs (black arrow), and strongly in the liver (white arrow). Scale bar: 200 μm.

Mentions: CL-K1 is a member of the protein family of C-type lectins, which contain a collagen-like domain and a carbohydrate recognition domain, thought to play a role in host-defense8 (PubMed 17179669). CL-K1 is highly conserved with homologs in chimpanzee, dog, cow, mouse, chicken, and zebrafish (Suppl Fig 5). Combined data from Serial Analysis of Gene Expression (SAGE) and eNorthern analyses suggest that human tissue expression is highest in brain, liver, kidney, spleen, lung, skin, breast, ovary, testis and placenta. We demonstrated broadly distributed expression in mouse tissues including craniofacial cartilage (nasal septum, meckel's cartilage and posterior palate), heart, bronchi, kidney, vertebral bodies at E13.5 (Fig 2a). Expression was also observed in palatal structures at E13.5 and E15.5 (Fig 2b).


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)

Immunolocalization of CL-K1 protein with polyclonal antibody a. in mouse embryo whole sections (scale bar: main panel 1 mm, inset panels 500 μm); CL-K1 (DAB) is expressed in the developing murine nasal septum (I), cartilage primordium of the basisphenoid bone (II, arrow), Meckel's cartilage (II, mc), myocardium (III), bronchioles and vertebrae (IV) at E13.5. b. CL-K1 is highly expressed in the palatal mesenchyme (arrow) and epithelium (arrow head) at E13.5. Later, at E15.5 CL-K1 is downregulated in the fused palatal shelf (asterisk) while expression is maintained in the palatal shelf epithelium (arrow head) (scale bar: 500 μm). c. ATDC5 cells showing immuno-colocalisation of endogenous CL-K1 and Golgi marker 58K (scale bar: 10 μm). d. colec11 in situ hybridisation at 10s, 24 hpf, and 48 hpf stages. At 10s, expression is localised to the cranial paraxial mesendoderm (arrow heads and transverse section, inset). The eyes are demarcated by asterisks and the relative position of the section marked by a dotted line. Scale bar: 100 μm. At 24hpf, transcripts are detected in the glomeruli (arrow heads) and cranial ventral midline (arrow). Inset shows a dorsal flatmount at 24 hpf highlighting expression in the glomeruli and pronephric ducts (PNDs, black arrow). At 48 hpf, colec11 remains in the glomeruli (arrow head), weakly in the PNDs (black arrow), and strongly in the liver (white arrow). Scale bar: 200 μm.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Immunolocalization of CL-K1 protein with polyclonal antibody a. in mouse embryo whole sections (scale bar: main panel 1 mm, inset panels 500 μm); CL-K1 (DAB) is expressed in the developing murine nasal septum (I), cartilage primordium of the basisphenoid bone (II, arrow), Meckel's cartilage (II, mc), myocardium (III), bronchioles and vertebrae (IV) at E13.5. b. CL-K1 is highly expressed in the palatal mesenchyme (arrow) and epithelium (arrow head) at E13.5. Later, at E15.5 CL-K1 is downregulated in the fused palatal shelf (asterisk) while expression is maintained in the palatal shelf epithelium (arrow head) (scale bar: 500 μm). c. ATDC5 cells showing immuno-colocalisation of endogenous CL-K1 and Golgi marker 58K (scale bar: 10 μm). d. colec11 in situ hybridisation at 10s, 24 hpf, and 48 hpf stages. At 10s, expression is localised to the cranial paraxial mesendoderm (arrow heads and transverse section, inset). The eyes are demarcated by asterisks and the relative position of the section marked by a dotted line. Scale bar: 100 μm. At 24hpf, transcripts are detected in the glomeruli (arrow heads) and cranial ventral midline (arrow). Inset shows a dorsal flatmount at 24 hpf highlighting expression in the glomeruli and pronephric ducts (PNDs, black arrow). At 48 hpf, colec11 remains in the glomeruli (arrow head), weakly in the PNDs (black arrow), and strongly in the liver (white arrow). Scale bar: 200 μm.
Mentions: CL-K1 is a member of the protein family of C-type lectins, which contain a collagen-like domain and a carbohydrate recognition domain, thought to play a role in host-defense8 (PubMed 17179669). CL-K1 is highly conserved with homologs in chimpanzee, dog, cow, mouse, chicken, and zebrafish (Suppl Fig 5). Combined data from Serial Analysis of Gene Expression (SAGE) and eNorthern analyses suggest that human tissue expression is highest in brain, liver, kidney, spleen, lung, skin, breast, ovary, testis and placenta. We demonstrated broadly distributed expression in mouse tissues including craniofacial cartilage (nasal septum, meckel's cartilage and posterior palate), heart, bronchi, kidney, vertebral bodies at E13.5 (Fig 2a). Expression was also observed in palatal structures at E13.5 and E15.5 (Fig 2b).

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