Heterozygous Mutations of FREM1 Are Associated with an Increased Risk of Isolated Metopic Craniosynostosis in Humans and Mice

Vissers, Lisenka E. L. M.; Cox, Timothy C.; Maga, A. Murat; Short, Kieran M.; Wiradjaja, Fenny; Janssen, Irene M.; Jehee, Fernanda; Bertola, Debora; Liu, Jia; Yagnik, Garima; Sekiguchi, Kiyotoshi; Kiyozumi, Daiji; Bokhoven, Hans van; Marcelis, Carlo; Cunningham, Michael L.; Anderson, Peter J.; Boyadjiev, Simeon A.; Passos-Bueno, Maria Rita; Veltman, Joris A.; Smyth, Ian; Buckley, Michael F.; Roscioli, Tony

doi:https://doi.org/10.1371/journal.pgen.1002278

Heterozygous Mutations of FREM1 Are Associated with an Increased Risk of Isolated Metopic Craniosynostosis in Humans and Mice

Vissers, Lisenka E. L. M.; Cox, Timothy C.; Maga, A. Murat et al.

PLOS Genetics, 2011, 7(9), e1002278

Number of Access:1,439（2025-08-18 14:24 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/71801

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Title	Heterozygous Mutations of FREM1 Are Associated with an Increased Risk of Isolated Metopic Craniosynostosis in Humans and Mice
Creator	CreatorName Vissers, Lisenka E. L. M.
	CreatorName Cox, Timothy C.
	CreatorName Maga, A. Murat
	CreatorName Short, Kieran M.
	CreatorName Wiradjaja, Fenny
	CreatorName Janssen, Irene M.
	CreatorName Jehee, Fernanda
	CreatorName Bertola, Debora
	CreatorName Liu, Jia
	CreatorName Yagnik, Garima
	NRID 1000050187845 1000050187845 researchmap permalink read0054833 read0054833 Scopus Author ID 7201662709 7201662709 ORCID 0000-0002-6433-1410 0000-0002-6433-1410 CreatorName Sekiguchi, Kiyotoshi
	NRID 1000070452430 1000070452430 ORCID 0000-0003-3289-227X 0000-0003-3289-227X researchmap permalink dkiyozumi dkiyozumi Scopus Author ID 6506341053 6506341053 CreatorName Kiyozumi, Daiji
	CreatorName Bokhoven, Hans van
	CreatorName Marcelis, Carlo
	CreatorName Cunningham, Michael L.
	CreatorName Anderson, Peter J.
	CreatorName Boyadjiev, Simeon A.
	CreatorName Passos-Bueno, Maria Rita
	CreatorName Veltman, Joris A.
	CreatorName Smyth, Ian
	CreatorName Buckley, Michael F.
	CreatorName Roscioli, Tony
Description	Vissers LELM, Cox TC, Maga AM, Short KM, Wiradjaja F, Janssen IM, et al. (2011) Heterozygous Mutations of FREM1 Are Associated with an Increased Risk of Isolated Metopic Craniosynostosis in Humans and Mice. PLoS Genet 7(9): e1002278. https://doi.org/10.1371/journal.pgen.1002278
Abstract	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.
Publisher	PLOS
Source Title	PLOS Genetics
Volume (Issue)	7(9)
Page	e1002278
Date of Issued	2011-11
Language	English
Handle URL	https://hdl.handle.net/11094/71801
PISSN	15537390
eISSN	15537404
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1371/journal.pgen.1002278
Access Rights	open access
CopyRight	© 2011 Vissers et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	PLOS Genetics. 2011, 7(9), p. e1002278
DC.title	Heterozygous Mutations of FREM1 Are Associated with an Increased Risk of Isolated Metopic Craniosynostosis in Humans and Mice
DC.creator	Vissers, Lisenka E. L. M.
	Cox, Timothy C.
	Maga, A. Murat
	Short, Kieran M.
	Wiradjaja, Fenny
	Janssen, Irene M.
	Jehee, Fernanda
	Bertola, Debora
	Liu, Jia
	Yagnik, Garima
	Sekiguchi, Kiyotoshi
	Kiyozumi, Daiji
	Bokhoven, Hans van
	Marcelis, Carlo
	Cunningham, Michael L.
	Anderson, Peter J.
	Boyadjiev, Simeon A.
	Passos-Bueno, Maria Rita
	Veltman, Joris A.
	Smyth, Ian
	Buckley, Michael F.
	Roscioli, Tony
DC.publisher	PLOS
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2011-11
DC.identifier	https://doi.org/10.1371/journal.pgen.1002278
DC.description	Vissers LELM, Cox TC, Maga AM, Short KM, Wiradjaja F, Janssen IM, et al. (2011) Heterozygous Mutations of FREM1 Are Associated with an Increased Risk of Isolated Metopic Craniosynostosis in Humans and Mice. PLoS Genet 7(9): e1002278. https://doi.org/10.1371/journal.pgen.1002278
DCTERMS.abstract	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.
DC.rights	© 2011 Vissers et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DC.format	71801
citation_title	Heterozygous Mutations of FREM1 Are Associated with an Increased Risk of Isolated Metopic Craniosynostosis in Humans and Mice
citation_author	Vissers, Lisenka E. L. M.
	Cox, Timothy C.
	Maga, A. Murat
	Short, Kieran M.
	Wiradjaja, Fenny
	Janssen, Irene M.
	Jehee, Fernanda
	Bertola, Debora
	Liu, Jia
	Yagnik, Garima
	Sekiguchi, Kiyotoshi
	Kiyozumi, Daiji
	Bokhoven, Hans van
	Marcelis, Carlo
	Cunningham, Michael L.
	Anderson, Peter J.
	Boyadjiev, Simeon A.
	Passos-Bueno, Maria Rita
	Veltman, Joris A.
	Smyth, Ian
	Buckley, Michael F.
	Roscioli, Tony
citation_publisher	PLOS
citation_language	English
citation_date	2011-11
citation_journal_title	PLOS Genetics
citation_volume	7
citation_issue	9
citation_firstpage	e1002278
citation_doi	https://doi.org/10.1371/journal.pgen.1002278
citation_public_url	https://hdl.handle.net/11094/71801

Heterozygous Mutations of FREM1 Are Associated with an Increased Risk of Isolated Metopic Craniosynostosis in Humans and Mice

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