A survey ofTWIST for mutations in craniosynostosis reveals a variable length polyglycine tract in asymptomatic individuals

Abstract

The human TWIST gene encodes a 202 amino acid transcription factor characterized by a highly conserved basic‐helix‐loop‐helix motif in the C‐terminal half, and a less conserved N‐terminal half that has binding activity toward the histone acetyltransferase p300. Between these domains is a repeat region of unknown function that encodes the glycine‐rich sequence (Gly)₅Ala(Gly)₅. Heterozygous mutations of TWIST were previously described in Saethre‐Chotzen craniosynostosis syndrome [El Ghouzzi et al., 1997; Howard et al., 1997]. During a search for TWIST mutations in patients with craniosynostosis, we identified, in addition to 11 novel and one previously described bona fide mutations, several individuals with rearrangements of the glycine‐rich region, involving either deletion of 18 nucleotides or insertion of three, 15, or 21 nucleotides. None of these rearrangements was consistently associated with clinical disease and we conclude that they are at most weakly pathogenic. The glycine stretch may serve as a flexible linker between the functional domains of the TWIST protein, and as such may be subject to reduced evolutionary constraint. Hum Mutat 18:535–541, 2001.