COLEC10 is mutated in 3MC patients and regulates early craniofacial development.
COLEC10 is mutated in 3MC patients and regulates early craniofacial development.
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DOI：
10.1371/journal.pgen.1006679
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发表时间：
2017-03
期刊：
影响因子：
4.5
通讯作者：
Hernandez-Hernandez V
中科院分区：
文献类型：
--
作者：
Munye MM;Diaz-Font A;Ocaka L;Henriksen ML;Lees M;Brady A;Jenkins D;Morton J;Hansen SW;Bacchelli C;Beales PL;Hernandez-Hernandez V
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、颅缝紧闭和唇腭裂；颅神经嵴细胞（cNCC）衍生的骨骼结构。我们之前报道了凝集素补体途径基因COLEC11和MASP1/3在3MC综合征患者中发生突变。在这里，我们定义了一个新的基因COLEC10，也在3MC家族中发生突变，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的蛋白产物CL-K1和CL-L1形成异质复合物。我们发现COLEC10在小鼠胚胎发育过程中在腭基膜中表达。我们证明COLEC10突变（c.25C>T; p.Arg9Ter, c.226delA; p.Gly77Glufs*66和c.528C>G . cys176trp）如何损害CL-L1的表达和/或分泌，从而突出其致病性。总之，这些发现进一步证明了凝集素补体途径和补体因子COLEC11和COLEC10与颅面结构的形态发生和3MC病因之间的联系。3MC综合征是四种具有重叠特征的罕见隐性遗传疾病的统一术语，即；Mingarelli, Malpuech， Michels和Carnevale综合症。它的特征是面部畸形，包括高弓眉毛，唇腭裂，远端畸形，发育迟缓和听力丧失。我们之前报道了凝集素补体途径基因COLEC11和MASP1/3在3MC综合征患者中发生突变。在这里，我们描述了一个来自相同途径的新基因，COLEC10，在3MC患者中发生突变。我们的研究结果表明，COLEC10在颅面组织发育过程中表达。我们展示了COLEC10表达的蛋白质CL-L1如何在体外作为细胞化学引诱剂，控制细胞的运动和迁移。我们在患者中发现过表达携带COLEC10无义突变的构建体，CL-L1无法表达和分泌。此外，当我们表达错义的COLEC10构建体时，CL-L1被表达但不能分泌。总之，我们发现了一个新的基因COLEC10在3MC综合征中发生突变，我们提出了与CL-L1功能失败及其颅面发育后果有关的3MC的致病机制。
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. The 3MC syndrome is a unifying term amalgamating four rare recessive genetic disorders with overlapping features namely; Mingarelli, Malpuech, Michels and Carnevale syndromes. It is characterised by facial malformations including, high-arched eyebrows, cleft lip/palate, hypertelorism, developmental delay and hearing loss. We previously reported that lectin complement pathway genes COLEC11 and MASP1/3 were mutated in 3MC syndrome patients. Here we describe a new gene from the same pathway, COLEC10, mutated in 3MC patients. Our results show that COLEC10 is expressed in craniofacial tissues during development. We demonstrate how CL-L1, the protein expressed by COLEC10, can act as a cellular chemoattractant in vitro, controlling cell movement and migration. We overexpressed constructs carrying COLEC10 non-sense mutations found in our patients, CL-L1 failed to be expressed and secreted. Moreover, when we expressed a missense COLEC10 construct, CL-L1 was expressed but failed to be secreted. In sum, we discovered a new gene, COLEC10, mutated in 3MC syndrome and we propose a pathogenic mechanism for 3MC relating to the failure of CL-L1 function and its craniofacial developmental consequences.