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

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, craniosyn...

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Published inNature genetics Vol. 43; no. 3; pp. 197 - 203
Main Authors Beales, Philip L, Rooryck, Caroline, Diaz-Font, Anna, Osborn, Daniel P S, Chabchoub, Elyes, Hernandez-Hernandez, Victor, Shamseldin, Hanan, Kenny, Joanna, Waters, Aoife, Jenkins, Dagan, Kaissi, Ali Al, Leal, Gabriela F, Dallapiccola, Bruno, Carnevale, Franco, Bitner-Glindzicz, Maria, Lees, Melissa, Hennekam, Raoul, Stanier, Philip, Burns, Alan J, Peeters, Hilde, Alkuraya, Fowzan S
Format Journal Article
LanguageEnglish
Published New York, NY Nature Publishing Group 01.03.2011
Subjects
Abnormalities, Multiple - genetics
Animals
Biological and medical sciences
Cell Movement
Cleft Lip - genetics
Cleft Palate - genetics
Collectins - genetics
Complement Pathway, Mannose-Binding Lectin - genetics
Complex syndromes
Craniofacial Abnormalities - genetics
Craniosynostoses - genetics
Danio rerio
Epistasis, Genetic
Experiments
Fundamental and applied biological sciences. Psychology
Gene expression
Gene mutations
Genetic aspects
Genetic disorders
Genetics of eukaryotes. Biological and molecular evolution
Health aspects
Lectins
Mannose-Binding Protein-Associated Serine Proteases - genetics
Medical genetics
Medical sciences
Mutation
Neural Crest - cytology
Proteins
Studies
Syndrome
Zebrafish
United Kingdom
Complement
Mutation
Gene
Syndrome
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Summary: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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AUTHOR CONTRIBUTIONS
CR planned, performed experiments, analysed data and co-wrote the manuscript; ADF planned, performed experiments, analysed data and co-wrote the manuscript; DO planned, performed experiments, analysed data and co-wrote the manuscript; EC performed experiments and analysed data; VHH performed experiments and analysed data; HS performed experiments; JK performed experiments; AW performed experiments and analysed data; DJ performed experiments; AAK clinically ascertained patients and samples; GFL clinically ascertained patients and samples; BD clinically ascertained patients and samples; FC clinically ascertained patients and samples; MB clinically ascertained patients and samples and planned study; ML clinically ascertained patients and samples; RH clinically ascertained patients and samples, planned study, analysed data and edited ms; PS provided samples and analysed data; AJB planned, performed experiments and analysed data; HP planned, performed experiments and analysed data. FSA planned study, ascertained samples, performed experiments, analysed data and edited ms. PLB planned, supervised, analysed data, co-wrote and edited ms.
These authors contributed equally
ISSN:1061-4036
1546-1718
DOI:10.1038/ng.757