Munye Mustafa M, Diaz-Font Anna, Ocaka Louise, Henriksen Maiken L, Lees Melissa, Brady Angela, Jenkins Dagan, Morton Jenny, Hansen Soren W, Bacchelli Chiara, Beales Philip L, Hernandez-Hernandez Victor
Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
PLoS Genet. 2017 Mar 16;13(3):e1006679. doi: 10.1371/journal.pgen.1006679. eCollection 2017 Mar.
3MC syndrome is an autosomal recessive heterogeneous disorder with features linked to developmental abnormalities. The main features include facial dysmorphism, craniosynostosis and cleft lip/palate; skeletal structures derived from cranial neural crest cells (cNCC). We previously reported that lectin complement pathway genes COLEC11 and MASP1/3 are mutated in 3MC syndrome patients. Here we define a new gene, COLEC10, also mutated in 3MC families and present novel mutations in COLEC11 and MASP1/3 genes in a further five families. The protein products of COLEC11 and COLEC10, CL-K1 and CL-L1 respectively, form heteromeric complexes. We show COLEC10 is expressed in the base membrane of the palate during murine embryo development. We demonstrate how mutations in COLEC10 (c.25C>T; p.Arg9Ter, c.226delA; p.Gly77Glufs*66 and c.528C>G p.Cys176Trp) impair the expression and/or secretion of CL-L1 highlighting their pathogenicity. Together, these findings provide further evidence linking the lectin complement pathway and complement factors COLEC11 and COLEC10 to morphogenesis of craniofacial structures and 3MC etiology.
3MC综合征是一种常染色体隐性异质性疾病，其特征与发育异常有关。主要特征包括面部畸形、颅缝早闭和唇腭裂；这些特征源于颅神经嵴细胞（cNCC）的骨骼结构。我们之前报道过，凝集素补体途径基因COLEC11和MASP1/3在3MC综合征患者中发生了突变。在此，我们确定了一个新基因COLEC10，它在3MC家族中也发生了突变，并在另外五个家族中发现了COLEC11和MASP1/3基因的新突变。COLEC11和COLEC10的蛋白质产物分别是CL-K1和CL-L1，它们形成异源复合物。我们发现COLEC10在小鼠胚胎发育过程中腭的基底膜中表达。我们证明了COLEC10中的突变（c.25C>T；p.Arg9Ter、c.226delA；p.Gly77Glufs*66和c.528C>G p.Cys176Trp）如何损害CL-L1的表达和/或分泌，突出了它们的致病性。这些发现共同提供了进一步的证据，将凝集素补体途径以及补体因子COLEC11和COLEC10与颅面结构的形态发生和3MC病因联系起来。
