MUTATIONS IN TWIST, A BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTOR, INSAETHRE-CHOTZEN SYNDROME

Saethre-Chotzen syndrome is one of the most common autosomal dominant disorders of craniosynostosis in humans and is characterized by cranio facial and limb anomalies. The locus for Saethre-Chotzen syndrome maps to chromosome 7p21-p22, We have evaluated TWIST; a basic helix-loop-h elix transcription factor, as a candidate gene for this condition beca use its expression pattern and mutant phenotypes in Drosophila and mou se are consistent with the Saethre-Chotzen phenotype. We mapped TWIST to human chromosome 7p21-p22 and mutational analysis reveals nonsense, missense, insertion and deletion mutations in patients. These mutatio ns occur within the basic DNA binding, helix I and loop domains, or re sult in premature termination of the protein, Studies in Drosophila in dicate that twist may affect the transcription of fibroblast growth fa ctor receptors (FGFRs), another gene family implicated in human cranio synostosis. The emerging cascade of molecular components involved in c raniofacial and limb development now includes TWIST, which may functio n as an upstream regulator of FGFRs.