Heterozygous TWIST mutations were identified in 8 of 10 patients with Saethre-Chotzen syndrome and in 2 of 43 craniosynostosis patients with no clear diagnosis.
Mutations in the coding region of the TWIST gene (encoding a basic helix-loop-helix transcription factor) have been identified in some cases of Saethre-Chotzen syndrome.
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.
Comprehensive studies in patients with the clinical diagnosis of Saethre-Chotzen syndrome have demonstrated a TWIST gene abnormality in about 80%, up to 37% of which may be large deletions [Johnson et al., 1998].
However, the absence of MSX2 mutations in some of the FPP patients analysed and the presence of FPP associated with chromosome 11p deletions in DEFECT 11 (OMIM 601224) patients or associated with Saethre-Chotzen syndrome suggests genetic heterogeneity for this disorder.
We have identified Twist target genes using human mutant calvaria osteoblastic cells from a child with Saethre-Chotzen syndrome with a Twist mutation that introduces a stop codon upstream of the bHLH domain.
Saethre-Chotzen syndrome (SCS) is a human autosomal dominant disorder characterized by premature fusion of cranial sutures caused by mutations of the Twist gene encoding a basic helix-loop-helix (bHLH) transcription factor.
These studies provide novel evidence that Twist haploinsufficiency in SCS promotes osteoblast apoptosis by a TNFalpha-caspase-2-caspase-8-caspases-3, -6, -7 cascade, and uncover a molecular mechanism in which Twist plays an anti-apoptotic role in human calvarial osteoblasts.
Mice heterozygous for a null mutation of the Twist gene replicate certain features of Saethre-Chotzen syndrome, but have not been reported to exhibit craniosynostosis.
Increased risk for developmental delay in Saethre-Chotzen syndrome is associated with TWIST deletions: an improved strategy for TWIST mutation screening.
Increased risk for developmental delay in Saethre-Chotzen syndrome is associated with TWIST deletions: an improved strategy for TWIST mutation screening.