Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice.
The premature fusion of the paired frontal bones results in metopic craniosynostosis (MC) and gives rise to the clinical phenotype of trigonocephaly. Deletions of chromosome 9p22.3 are well described as a cause of MC with variably penetrant midface hypoplasia. In order to identify the gene responsib...
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doaj-af1e6f0904f7438a819309fe394401712020-11-24T21:45:37ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042011-09-0179e100227810.1371/journal.pgen.1002278Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice.Lisenka E L M VissersTimothy C CoxA Murat MagaKieran M ShortFenny WiradjajaIrene M JanssenFernanda JeheeDebora BertolaJia LiuGarima YagnikKiyotoshi SekiguchiDaiji KiyozumiHans van BokhovenCarlo MarcelisMichael L CunninghamPeter J AndersonSimeon A BoyadjievMaria Rita Passos-BuenoJoris A VeltmanIan SmythMichael F BuckleyTony RoscioliThe premature fusion of the paired frontal bones results in metopic craniosynostosis (MC) and gives rise to the clinical phenotype of trigonocephaly. Deletions of chromosome 9p22.3 are well described as a cause of MC with variably penetrant midface hypoplasia. In order to identify the gene responsible for the trigonocephaly component of the 9p22.3 syndrome, a cohort of 109 patients were assessed by high-resolution arrays and MLPA for copy number variations (CNVs) involving 9p22. Five CNVs involving FREM1, all of which were de novo variants, were identified by array-based analyses. The remaining 104 patients with MC were then subjected to targeted FREM1 gene re-sequencing, which identified 3 further mutant alleles, one of which was de novo. Consistent with a pathogenic role, mouse Frem1 mRNA and protein expression was demonstrated in the metopic suture as well as in the pericranium and dura mater. Micro-computed tomography based analyses of the mouse posterior frontal (PF) suture, the human metopic suture equivalent, revealed advanced fusion in all mice homozygous for either of two different Frem1 mutant alleles, while heterozygotes exhibited variably penetrant PF suture anomalies. Gene dosage-related penetrance of midfacial hypoplasia was also evident in the Frem1 mutants. These data suggest that CNVs and mutations involving FREM1 can be identified in a significant percentage of people with MC with or without midface hypoplasia. Furthermore, we present Frem1 mutant mice as the first bona fide mouse model of human metopic craniosynostosis and a new model for midfacial hypoplasia.http://europepmc.org/articles/PMC3169541?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lisenka E L M Vissers Timothy C Cox A Murat Maga Kieran M Short Fenny Wiradjaja Irene M Janssen Fernanda Jehee Debora Bertola Jia Liu Garima Yagnik Kiyotoshi Sekiguchi Daiji Kiyozumi Hans van Bokhoven Carlo Marcelis Michael L Cunningham Peter J Anderson Simeon A Boyadjiev Maria Rita Passos-Bueno Joris A Veltman Ian Smyth Michael F Buckley Tony Roscioli |
spellingShingle |
Lisenka E L M Vissers Timothy C Cox A Murat Maga Kieran M Short Fenny Wiradjaja Irene M Janssen Fernanda Jehee Debora Bertola Jia Liu Garima Yagnik Kiyotoshi Sekiguchi Daiji Kiyozumi Hans van Bokhoven Carlo Marcelis Michael L Cunningham Peter J Anderson Simeon A Boyadjiev Maria Rita Passos-Bueno Joris A Veltman Ian Smyth Michael F Buckley Tony Roscioli Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice. PLoS Genetics |
author_facet |
Lisenka E L M Vissers Timothy C Cox A Murat Maga Kieran M Short Fenny Wiradjaja Irene M Janssen Fernanda Jehee Debora Bertola Jia Liu Garima Yagnik Kiyotoshi Sekiguchi Daiji Kiyozumi Hans van Bokhoven Carlo Marcelis Michael L Cunningham Peter J Anderson Simeon A Boyadjiev Maria Rita Passos-Bueno Joris A Veltman Ian Smyth Michael F Buckley Tony Roscioli |
author_sort |
Lisenka E L M Vissers |
title |
Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice. |
title_short |
Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice. |
title_full |
Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice. |
title_fullStr |
Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice. |
title_full_unstemmed |
Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice. |
title_sort |
heterozygous mutations of frem1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2011-09-01 |
description |
The premature fusion of the paired frontal bones results in metopic craniosynostosis (MC) and gives rise to the clinical phenotype of trigonocephaly. Deletions of chromosome 9p22.3 are well described as a cause of MC with variably penetrant midface hypoplasia. In order to identify the gene responsible for the trigonocephaly component of the 9p22.3 syndrome, a cohort of 109 patients were assessed by high-resolution arrays and MLPA for copy number variations (CNVs) involving 9p22. Five CNVs involving FREM1, all of which were de novo variants, were identified by array-based analyses. The remaining 104 patients with MC were then subjected to targeted FREM1 gene re-sequencing, which identified 3 further mutant alleles, one of which was de novo. Consistent with a pathogenic role, mouse Frem1 mRNA and protein expression was demonstrated in the metopic suture as well as in the pericranium and dura mater. Micro-computed tomography based analyses of the mouse posterior frontal (PF) suture, the human metopic suture equivalent, revealed advanced fusion in all mice homozygous for either of two different Frem1 mutant alleles, while heterozygotes exhibited variably penetrant PF suture anomalies. Gene dosage-related penetrance of midfacial hypoplasia was also evident in the Frem1 mutants. These data suggest that CNVs and mutations involving FREM1 can be identified in a significant percentage of people with MC with or without midface hypoplasia. Furthermore, we present Frem1 mutant mice as the first bona fide mouse model of human metopic craniosynostosis and a new model for midfacial hypoplasia. |
url |
http://europepmc.org/articles/PMC3169541?pdf=render |
work_keys_str_mv |
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