MUTATIONS OF THE TWIST GENE IN THE SAETHRE-CHOTZEN SYNDROME

Saethre-Chotzen syndrome (acrocephalo-syndactyly type III, ACS III) is an autosomal dominant craniosynostosis with brachydactyly, soft tissu e syndactyly and facial dysmorphism including ptosis, facial asymmetry and prominent ear crura. ACS III has been mapped to chromosome 7p21-2 2. Of interest, TWIST, the human counterpart of the murine Twist gene, has been localized on chromosome 7p21 as well, The Twist gene product is a transcription factor containing a basic helix-loop-helix (b-HLH) domain, required in head mesenchyme for cranial neural tube morphogen esis in mice, The co-localisation of ACS III and TWIST prompted us to screen ACS III patients for TWIST gene mutations especially as mice he terozygous for Twist null mutations displayed skull defects and duplic ation of hind leg digits. Here, we report 21-bp insertions and nonsens e mutations of the TWIST gene (S127X, E130X) in seven ACS III probands and describe impairment of head mesenchyme induction by TWIST as a no vel pathophysiological mechanism in human craniosynostoses.