Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice

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 & 2 others Michael F. Buckley, Tony Roscioli

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere1002278
JournalPLoS Genetics
Volume7
Issue number9
DOIs
StatePublished - Sep 2011
Externally publishedYes

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sutures
mutation
Sutures
mutants
Mutation
mice
Craniosynostoses
gene
allele
alleles
chromosome elimination
gene dosage
micro-computed tomography
penetrance
Alleles
Frontal Bone
Dura Mater
Chromosome Deletion
Gene Dosage
Penetrance

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Vissers, L. E. L. M., Cox, T. C., Maga, A. M., Short, K. M., Wiradjaja, F., Janssen, I. M., ... Roscioli, T. (2011). Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice. PLoS Genetics, 7(9), [e1002278]. 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; Short, Kieran M.; Wiradjaja, Fenny; Janssen, Irene M.; Jehee, Fernanda; Bertola, Debora; Liu, Jia; Yagnik, Garima; Sekiguchi, Kiyotoshi; Kiyozumi, Daiji; van Bokhoven, Hans; 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.

In: PLoS Genetics, Vol. 7, No. 9, e1002278, 09.2011.

Research output: Contribution to journalArticle

Vissers, LELM, Cox, TC, Maga, AM, Short, KM, Wiradjaja, F, Janssen, IM, Jehee, F, Bertola, D, Liu, J, Yagnik, G, Sekiguchi, K, Kiyozumi, D, van Bokhoven, H, Marcelis, C, Cunningham, ML, Anderson, PJ, Boyadjiev, SA, Passos-Bueno, MR, Veltman, JA, Smyth, I, Buckley, MF & Roscioli, T 2011, 'Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice', PLoS Genetics, vol. 7, no. 9, e1002278. https://doi.org/10.1371/journal.pgen.1002278
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 ; van Bokhoven, Hans ; 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. / Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice. In: PLoS Genetics. 2011 ; Vol. 7, No. 9.
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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.",
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AU - Vissers, Lisenka E L M

AU - Cox, Timothy C.

AU - Maga, A. Murat

AU - Short, Kieran M.

AU - Wiradjaja, Fenny

AU - Janssen, Irene M.

AU - Jehee, Fernanda

AU - Bertola, Debora

AU - Liu, Jia

AU - Yagnik, Garima

AU - Sekiguchi, Kiyotoshi

AU - Kiyozumi, Daiji

AU - van Bokhoven, Hans

AU - Marcelis, Carlo

AU - Cunningham, Michael L.

AU - Anderson, Peter J.

AU - Boyadjiev, Simeon A.

AU - Passos-Bueno, Maria Rita

AU - Veltman, Joris A.

AU - Smyth, Ian

AU - Buckley, Michael F.

AU - Roscioli, Tony

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