Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis.
Nat Genet
; 45(3): 304-7, 2013 Mar.
Article
de En
| MEDLINE
| ID: mdl-23354436
ABSTRACT
Craniosynostosis, the premature fusion of the cranial sutures, is a heterogeneous disorder with a prevalence of â¼1 in 2,200 (refs. 1,2). A specific genetic etiology can be identified in â¼21% 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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Protéines nucléaires
/
Craniosynostoses
/
Facteurs de transcription à motif basique hélice-boucle-hélice
/
Protéine-1 apparentée à Twist
Type d'étude:
Prognostic_studies
/
Risk_factors_studies
Limites:
Animals
/
Humans
Langue:
En
Journal:
Nat Genet
Sujet du journal:
GENETICA MEDICA
Année:
2013
Type de document:
Article
Pays d'affiliation:
Royaume-Uni