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:info:doi/10.1371/journal.pgen.1002278

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タイトル	Heterozygous Mutations of FREM1 Are Associated with an Increased Risk of Isolated Metopic Craniosynostosis in Humans and Mice
著者	Vissers, Lisenka E. L. M. Vissers, Lisenka E. L. M.
	Cox, Timothy C. Cox, Timothy C.
	Maga, A. Murat Maga, A. Murat
	Short, Kieran M. Short, Kieran M.
	Wiradjaja, Fenny Wiradjaja, Fenny
	Janssen, Irene M. Janssen, Irene M.
	Jehee, Fernanda Jehee, Fernanda
	Bertola, Debora Bertola, Debora
	Liu, Jia Liu, Jia
	Yagnik, Garima Yagnik, Garima
	Sekiguchi, Kiyotoshi Sekiguchi, Kiyotoshi
	Kiyozumi, Daiji Kiyozumi, Daiji
	Bokhoven, Hans van Bokhoven, Hans van
	Marcelis, Carlo Marcelis, Carlo
	Cunningham, Michael L. Cunningham, Michael L.
	Anderson, Peter J. Anderson, Peter J.
	Boyadjiev, Simeon A. Boyadjiev, Simeon A.
	Passos-Bueno, Maria Rita Passos-Bueno, Maria Rita
	Veltman, Joris A. Veltman, Joris A.
	Smyth, Ian Smyth, Ian
	Buckley, Michael F. Buckley, Michael F.
	Roscioli, Tony Roscioli, Tony
内容	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
抄録	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.
公開者	PLOS
掲載誌名	PLOS Genetics
巻	7
号	9
開始ページ	e1002278
刊行年月	2011-11
ISSN	15537390
ISSN	15537404
DOI	info:doi/10.1371/journal.pgen.1002278
URL	http://hdl.handle.net/11094/71801
権利情報	© 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.
言語	英語
カテゴリ	学術雑誌論文 Journal Article

著者版フラグ	publisher
NII資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
dcmi資源タイプ	text
DCTERMS.bibliographicCitation	PLOS Genetics.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	英語
DCTERMS.issued" scheme="DCTERMS.W3CDTF	2011-11
DC.identifier	info:doi/10.1371/journal.pgen.1002278
DC.identifier" scheme="DCTERMS.URI	http://hdl.handle.net/11094/71801
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.
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	英語
citation_date	2011-11
citation_journal_title	PLOS Genetics
citation_volume	7
citation_issue	9
citation_firstpage	e1002278
citation_issn	15537390
citation_issn	15537404
citation_doi	info:doi/10.1371/journal.pgen.1002278
citation_public_url	http://hdl.handle.net/11094/71801

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