title: Mutations within or upstream of the basic helix-loop-helix domain of the TWIST gene are specific to Saethre-Chotzen syndrome.
abstract: Saethre-Chotzen syndrome (ACS III) is an autosomal dominant craniosynostosis syndrome recently ascribed to mutations in the TWIST gene, a basic helix-loop-helix (b-HLH) transcription factor regulating head mesenchyme cell development during cranial neural tube formation in mouse. Studying a series of 22 unrelated ACS III patients, we have found TWIST mutations in 16/22 cases. Interestingly, these mutations consistently involved the b-HLH domain of the protein. Indeed, mutant genotypes included frameshift deletions/insertions, nonsense and missense mutations, either truncating or disrupting the b-HLH motif of the protein. This observation gives additional support to the view that most ACS III cases result from loss-of-function mutations at the TWIST locus. The P250R recurrent FGFR 3 mutation was found in 2/22 cases presenting mild clinical manifestations of the disease but 4/22 cases failed to harbour TWIST or FGFR 3 mutations. Clinical re-examination of patients carrying TWIST mutations failed to reveal correlations between the mutant genotype and severity of the phenotype. Finally, since no TWIST mutations were detected in 40 cases of isolated coronal craniosynostosis, the present study suggests that TWIST mutations are specific to Saethre-Chotzen syndrome.
authors: Unité de Recherches sur les Handicaps Génétiques de l'Enfant, Institut Necker, Paris, France.
authors: V
authors: V
authors: El Ghouzzi
authors: E
authors: E
authors: Lajeunie
authors: M
authors: M
authors: Le Merrer
authors: V
authors: V
authors: Cormier-Daire
authors: D
authors: D
authors: Renier
authors: A
authors: A
authors: Munnich
authors: J
authors: J
authors: Bonaventure
mesh_terms: D000168:Acrocephalosyndactylia / Q000235:genetics*; D001483:Base Sequence; D017931:DNA Primers; D005838:Genotype; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics; D014157:Transcription Factors; D051879:Twist-Related Protein 1
chemical_list: D017931:DNA Primers; D009687:Nuclear Proteins; D017468:Receptors, Fibroblast Growth Factor; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; C496365:FGFR3 protein, human; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3