Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis.
Craniosynostosis, the premature fusion of the cranial sutures, is a heterogeneous disorder with a prevalence of ∼1 in 2,200 (refs. 1,2). A specific genetic etiology can be identified in ∼21% of cases, including mutations of TWIST1, which encodes a class II basic helix-loop-helix (bHLH) transcription...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2013
|
| _version_ | 1797101611876614144 |
|---|---|
| author | Sharma, V Fenwick, A Brockop, MS McGowan, S Goos, J Hoogeboom, A Brady, A Jeelani, N Lynch, SA Mulliken, J Murray, D Phipps, J Sweeney, E Tomkins, SE Wilson, L Bennett, S Cornall, R Broxholme, J Kanapin, A Johnson, D Wall, SA van der Spek, P Mathijssen, I Maxson, R Twigg, SR |
| author_facet | Sharma, V Fenwick, A Brockop, MS McGowan, S Goos, J Hoogeboom, A Brady, A Jeelani, N Lynch, SA Mulliken, J Murray, D Phipps, J Sweeney, E Tomkins, SE Wilson, L Bennett, S Cornall, R Broxholme, J Kanapin, A Johnson, D Wall, SA van der Spek, P Mathijssen, I Maxson, R Twigg, SR |
| author_sort | Sharma, V |
| collection | OXFORD |
| description | Craniosynostosis, the premature fusion of the cranial sutures, is a heterogeneous disorder with a prevalence of ∼1 in 2,200 (refs. 1,2). A specific genetic etiology can be identified in ∼21% of cases, including mutations of TWIST1, which encodes a class II basic helix-loop-helix (bHLH) transcription factor, and causes Saethre-Chotzen syndrome, typically associated with coronal synostosis. Using exome sequencing, we identified 38 heterozygous TCF12 mutations in 347 samples from unrelated individuals with craniosynostosis. The mutations predominantly occurred in individuals with coronal synostosis and accounted for 32% and 10% of subjects with bilateral and unilateral pathology, respectively. TCF12 encodes one of three class I E proteins that heterodimerize with class II bHLH proteins such as TWIST1. We show that TCF12 and TWIST1 act synergistically in a transactivation assay and that mice doubly heterozygous for loss-of-function mutations in Tcf12 and Twist1 have severe coronal synostosis. Hence, the dosage of TCF12-TWIST1 heterodimers is critical for normal coronal suture development. |
| first_indexed | 2024-03-07T05:54:20Z |
| format | Journal article |
| id | oxford-uuid:e9fcf6f4-cba5-4c77-a281-b1cdc0fff517 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:54:20Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:e9fcf6f4-cba5-4c77-a281-b1cdc0fff5172022-03-27T10:58:26ZMutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e9fcf6f4-cba5-4c77-a281-b1cdc0fff517EnglishSymplectic Elements at Oxford2013Sharma, VFenwick, ABrockop, MSMcGowan, SGoos, JHoogeboom, ABrady, AJeelani, NLynch, SAMulliken, JMurray, DPhipps, JSweeney, ETomkins, SEWilson, LBennett, SCornall, RBroxholme, JKanapin, AJohnson, DWall, SAvan der Spek, PMathijssen, IMaxson, RTwigg, SRCraniosynostosis, the premature fusion of the cranial sutures, is a heterogeneous disorder with a prevalence of ∼1 in 2,200 (refs. 1,2). A specific genetic etiology can be identified in ∼21% of cases, including mutations of TWIST1, which encodes a class II basic helix-loop-helix (bHLH) transcription factor, and causes Saethre-Chotzen syndrome, typically associated with coronal synostosis. Using exome sequencing, we identified 38 heterozygous TCF12 mutations in 347 samples from unrelated individuals with craniosynostosis. The mutations predominantly occurred in individuals with coronal synostosis and accounted for 32% and 10% of subjects with bilateral and unilateral pathology, respectively. TCF12 encodes one of three class I E proteins that heterodimerize with class II bHLH proteins such as TWIST1. We show that TCF12 and TWIST1 act synergistically in a transactivation assay and that mice doubly heterozygous for loss-of-function mutations in Tcf12 and Twist1 have severe coronal synostosis. Hence, the dosage of TCF12-TWIST1 heterodimers is critical for normal coronal suture development. |
| spellingShingle | Sharma, V Fenwick, A Brockop, MS McGowan, S Goos, J Hoogeboom, A Brady, A Jeelani, N Lynch, SA Mulliken, J Murray, D Phipps, J Sweeney, E Tomkins, SE Wilson, L Bennett, S Cornall, R Broxholme, J Kanapin, A Johnson, D Wall, SA van der Spek, P Mathijssen, I Maxson, R Twigg, SR Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis. |
| title | Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis. |
| title_full | Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis. |
| title_fullStr | Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis. |
| title_full_unstemmed | Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis. |
| title_short | Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis. |
| title_sort | mutations in tcf12 encoding a basic helix loop helix partner of twist1 are a frequent cause of coronal craniosynostosis |
| work_keys_str_mv | AT sharmav mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT fenwicka mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT brockopms mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT mcgowans mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT goosj mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT hoogebooma mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT bradya mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT jeelanin mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT lynchsa mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT mullikenj mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT murrayd mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT phippsj mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT sweeneye mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT tomkinsse mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT wilsonl mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT bennetts mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT cornallr mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT broxholmej mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT kanapina mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT johnsond mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT wallsa mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT vanderspekp mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT mathijsseni mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT maxsonr mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis AT twiggsr mutationsintcf12encodingabasichelixloophelixpartneroftwist1areafrequentcauseofcoronalcraniosynostosis |