title: COLEC10 is mutated in 3MC patients and regulates early craniofacial development.
abstract: 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.
authors.affiliation: Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
authors.forename: Mustafa M
authors.initials: MM
authors.lastname: Munye
authors.affiliation: Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Diaz-Font
authors.affiliation: Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
authors.forename: Louise
authors.initials: L
authors.lastname: Ocaka
authors.affiliation: Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Maiken L
authors.initials: ML
authors.lastname: Henriksen
authors.affiliation: Department of Clinical Genetics, Great Ormond Street Hospital, London, United Kingdom.
authors.forename: Melissa
authors.identifier: 0000-0003-0287-4134
authors.initials: M
authors.lastname: Lees
authors.affiliation: North West Thames Regional Genetics Service, Kennedy-Galton Centre, Northwick Park Hospital, London, United Kingdom.
authors.forename: Angela
authors.initials: A
authors.lastname: Brady
authors.affiliation: Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
authors.forename: Dagan
authors.initials: D
authors.lastname: Jenkins
authors.affiliation: Department of Clinical Genetics, Birmingham Women's Hospital, Birmingham, United Kingdom.
authors.forename: Jenny
authors.initials: J
authors.lastname: Morton
authors.affiliation: Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Soren W
authors.initials: SW
authors.lastname: Hansen
authors.affiliation: Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bacchelli
authors.affiliation: Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Beales
authors.affiliation: Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
authors.forename: Victor
authors.identifier: 0000-0002-4424-1848
authors.initials: V
authors.lastname: Hernandez-Hernandez
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D002972:Cleft Palate / Q000235:genetics* / Q000378:metabolism; D037222:Collectins / Q000235:genetics* / Q000378:metabolism; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000378:metabolism; D003398:Craniosynostoses / Q000235:genetics* / Q000378:metabolism; D059472:Exome / Q000235:genetics; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D017422:Sequence Analysis, DNA / Q000379:methods; D013577:Syndrome
chemical_list: C445459:COLEC10 protein, human; C518521:Colec11 protein, human; D037222:Collectins