De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis
Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/E...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Timberlake, Andrew T [verfasserIn] |
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| Format: |
Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2017 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: Proceedings of the National Academy of Sciences of the United States of America - Washington, DC : NAS, 1877, 114(2017), 35, Seite E7341 |
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| Übergeordnetes Werk: |
volume:114 ; year:2017 ; number:35 ; pages:E7341 |
| Links: |
|---|
| DOI / URN: |
10.1073/pnas.1709255114 |
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| Katalog-ID: |
OLC1998535304 |
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| 245 | 1 | 3 | |a De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis |
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| 520 | |a Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 x 10-11). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity. | ||
| 650 | 4 | |a Wnt protein | |
| 650 | 4 | |a Congenital diseases | |
| 650 | 4 | |a Bone growth | |
| 650 | 4 | |a Animal models | |
| 650 | 4 | |a Offspring | |
| 650 | 4 | |a Pathogenesis | |
| 650 | 4 | |a Neurodegeneration | |
| 650 | 4 | |a Extracellular signal-regulated kinase | |
| 650 | 4 | |a Genetics | |
| 650 | 4 | |a Bone morphogenetic proteins | |
| 650 | 4 | |a Genes | |
| 650 | 4 | |a Skull | |
| 650 | 4 | |a Regulators | |
| 650 | 4 | |a Congenital defects | |
| 650 | 4 | |a Craniosynostosis | |
| 650 | 4 | |a Haploinsufficiency | |
| 650 | 4 | |a Rodents | |
| 650 | 4 | |a Osteogenesis | |
| 650 | 4 | |a Ras protein | |
| 650 | 4 | |a Damage | |
| 650 | 4 | |a Pathways | |
| 650 | 4 | |a Mutations | |
| 650 | 4 | |a Sutures | |
| 650 | 4 | |a Studies | |
| 650 | 4 | |a Bone | |
| 650 | 4 | |a Risk | |
| 650 | 4 | |a Bone morphogenetic protein 2 | |
| 650 | 4 | |a Mutation | |
| 650 | 4 | |a Signal transduction | |
| 700 | 1 | |a Furey, Charuta G |4 oth | |
| 700 | 1 | |a Choi, Jungmin |4 oth | |
| 700 | 1 | |a Nelson-Williams, Carol |4 oth | |
| 700 | 1 | |a Loring, Erin |4 oth | |
| 700 | 1 | |a Galm, Amy |4 oth | |
| 700 | 1 | |a Kahle, Kristopher T |4 oth | |
| 700 | 1 | |a Steinbacher, Derek M |4 oth | |
| 700 | 1 | |a Larysz, Dawid |4 oth | |
| 700 | 1 | |a Persing, John A |4 oth | |
| 700 | 1 | |a Lifton, Richard P |4 oth | |
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10.1073/pnas.1709255114 doi PQ20171228 (DE-627)OLC1998535304 (DE-599)GBVOLC1998535304 (PRQ)g1166-7208320074bb28aa6a0c36fd727afeeb5bd6ebdf52cd0e0975a3b6821aa83d9b0 (KEY)0583363920170000114003507341novomutationsininhibitorsofwntbmpandraserksignalin DE-627 ger DE-627 rakwb eng 500 DE-101 570 AVZ LING fid BIODIV fid Timberlake, Andrew T verfasserin aut De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis 2017 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 x 10-11). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity. Wnt protein Congenital diseases Bone growth Animal models Offspring Pathogenesis Neurodegeneration Extracellular signal-regulated kinase Genetics Bone morphogenetic proteins Genes Skull Regulators Congenital defects Craniosynostosis Haploinsufficiency Rodents Osteogenesis Ras protein Damage Pathways Mutations Sutures Studies Bone Risk Bone morphogenetic protein 2 Mutation Signal transduction Furey, Charuta G oth Choi, Jungmin oth Nelson-Williams, Carol oth Loring, Erin oth Galm, Amy oth Kahle, Kristopher T oth Steinbacher, Derek M oth Larysz, Dawid oth Persing, John A oth Lifton, Richard P oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 114(2017), 35, Seite E7341 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:114 year:2017 number:35 pages:E7341 http://dx.doi.org/10.1073/pnas.1709255114 Volltext https://search.proquest.com/docview/1946433995 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 114 2017 35 E7341 |
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10.1073/pnas.1709255114 doi PQ20171228 (DE-627)OLC1998535304 (DE-599)GBVOLC1998535304 (PRQ)g1166-7208320074bb28aa6a0c36fd727afeeb5bd6ebdf52cd0e0975a3b6821aa83d9b0 (KEY)0583363920170000114003507341novomutationsininhibitorsofwntbmpandraserksignalin DE-627 ger DE-627 rakwb eng 500 DE-101 570 AVZ LING fid BIODIV fid Timberlake, Andrew T verfasserin aut De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis 2017 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 x 10-11). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity. Wnt protein Congenital diseases Bone growth Animal models Offspring Pathogenesis Neurodegeneration Extracellular signal-regulated kinase Genetics Bone morphogenetic proteins Genes Skull Regulators Congenital defects Craniosynostosis Haploinsufficiency Rodents Osteogenesis Ras protein Damage Pathways Mutations Sutures Studies Bone Risk Bone morphogenetic protein 2 Mutation Signal transduction Furey, Charuta G oth Choi, Jungmin oth Nelson-Williams, Carol oth Loring, Erin oth Galm, Amy oth Kahle, Kristopher T oth Steinbacher, Derek M oth Larysz, Dawid oth Persing, John A oth Lifton, Richard P oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 114(2017), 35, Seite E7341 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:114 year:2017 number:35 pages:E7341 http://dx.doi.org/10.1073/pnas.1709255114 Volltext https://search.proquest.com/docview/1946433995 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 114 2017 35 E7341 |
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10.1073/pnas.1709255114 doi PQ20171228 (DE-627)OLC1998535304 (DE-599)GBVOLC1998535304 (PRQ)g1166-7208320074bb28aa6a0c36fd727afeeb5bd6ebdf52cd0e0975a3b6821aa83d9b0 (KEY)0583363920170000114003507341novomutationsininhibitorsofwntbmpandraserksignalin DE-627 ger DE-627 rakwb eng 500 DE-101 570 AVZ LING fid BIODIV fid Timberlake, Andrew T verfasserin aut De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis 2017 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 x 10-11). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity. Wnt protein Congenital diseases Bone growth Animal models Offspring Pathogenesis Neurodegeneration Extracellular signal-regulated kinase Genetics Bone morphogenetic proteins Genes Skull Regulators Congenital defects Craniosynostosis Haploinsufficiency Rodents Osteogenesis Ras protein Damage Pathways Mutations Sutures Studies Bone Risk Bone morphogenetic protein 2 Mutation Signal transduction Furey, Charuta G oth Choi, Jungmin oth Nelson-Williams, Carol oth Loring, Erin oth Galm, Amy oth Kahle, Kristopher T oth Steinbacher, Derek M oth Larysz, Dawid oth Persing, John A oth Lifton, Richard P oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 114(2017), 35, Seite E7341 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:114 year:2017 number:35 pages:E7341 http://dx.doi.org/10.1073/pnas.1709255114 Volltext https://search.proquest.com/docview/1946433995 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 114 2017 35 E7341 |
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10.1073/pnas.1709255114 doi PQ20171228 (DE-627)OLC1998535304 (DE-599)GBVOLC1998535304 (PRQ)g1166-7208320074bb28aa6a0c36fd727afeeb5bd6ebdf52cd0e0975a3b6821aa83d9b0 (KEY)0583363920170000114003507341novomutationsininhibitorsofwntbmpandraserksignalin DE-627 ger DE-627 rakwb eng 500 DE-101 570 AVZ LING fid BIODIV fid Timberlake, Andrew T verfasserin aut De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis 2017 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 x 10-11). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity. Wnt protein Congenital diseases Bone growth Animal models Offspring Pathogenesis Neurodegeneration Extracellular signal-regulated kinase Genetics Bone morphogenetic proteins Genes Skull Regulators Congenital defects Craniosynostosis Haploinsufficiency Rodents Osteogenesis Ras protein Damage Pathways Mutations Sutures Studies Bone Risk Bone morphogenetic protein 2 Mutation Signal transduction Furey, Charuta G oth Choi, Jungmin oth Nelson-Williams, Carol oth Loring, Erin oth Galm, Amy oth Kahle, Kristopher T oth Steinbacher, Derek M oth Larysz, Dawid oth Persing, John A oth Lifton, Richard P oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 114(2017), 35, Seite E7341 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:114 year:2017 number:35 pages:E7341 http://dx.doi.org/10.1073/pnas.1709255114 Volltext https://search.proquest.com/docview/1946433995 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 114 2017 35 E7341 |
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10.1073/pnas.1709255114 doi PQ20171228 (DE-627)OLC1998535304 (DE-599)GBVOLC1998535304 (PRQ)g1166-7208320074bb28aa6a0c36fd727afeeb5bd6ebdf52cd0e0975a3b6821aa83d9b0 (KEY)0583363920170000114003507341novomutationsininhibitorsofwntbmpandraserksignalin DE-627 ger DE-627 rakwb eng 500 DE-101 570 AVZ LING fid BIODIV fid Timberlake, Andrew T verfasserin aut De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis 2017 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 x 10-11). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity. Wnt protein Congenital diseases Bone growth Animal models Offspring Pathogenesis Neurodegeneration Extracellular signal-regulated kinase Genetics Bone morphogenetic proteins Genes Skull Regulators Congenital defects Craniosynostosis Haploinsufficiency Rodents Osteogenesis Ras protein Damage Pathways Mutations Sutures Studies Bone Risk Bone morphogenetic protein 2 Mutation Signal transduction Furey, Charuta G oth Choi, Jungmin oth Nelson-Williams, Carol oth Loring, Erin oth Galm, Amy oth Kahle, Kristopher T oth Steinbacher, Derek M oth Larysz, Dawid oth Persing, John A oth Lifton, Richard P oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 114(2017), 35, Seite E7341 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:114 year:2017 number:35 pages:E7341 http://dx.doi.org/10.1073/pnas.1709255114 Volltext https://search.proquest.com/docview/1946433995 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 114 2017 35 E7341 |
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Timberlake, Andrew T @@aut@@ Furey, Charuta G @@oth@@ Choi, Jungmin @@oth@@ Nelson-Williams, Carol @@oth@@ Loring, Erin @@oth@@ Galm, Amy @@oth@@ Kahle, Kristopher T @@oth@@ Steinbacher, Derek M @@oth@@ Larysz, Dawid @@oth@@ Persing, John A @@oth@@ Lifton, Richard P @@oth@@ |
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novo mutations in inhibitors of wnt, bmp, and ras/erk signaling pathways in non-syndromic midline craniosynostosis |
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De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis |
| abstract |
Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 x 10-11). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity. |
| abstractGer |
Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 x 10-11). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity. |
| abstract_unstemmed |
Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 x 10-11). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity. |
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Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 x 10-11). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Wnt protein</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Congenital diseases</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Bone growth</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Animal models</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Offspring</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Pathogenesis</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Neurodegeneration</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Extracellular signal-regulated 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