Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

The basic helix-loop-helix protein Twist, a transcriptional repressor, is essential for embryogenesis in both invertebrates and vertebrates. Haploinsufficiency of the human TWIST1 gene, which causes the craniosynostosis disorder Saethre-Chotzen syndrome (SCS), is related to failure to repress transcription of CDKN1A (which encodes p21/WAF1/CIP1), promoting osteoblast differentiation. We have examined the functional significance of natural TWIST1 variants present in craniosynostosis patients and in their healthy relatives. Both deletion and duplication variants of the glycine-rich tract Gly5AlaGly5 inhibited E2A (E12/E47)-dependent transcription of CDKN1A to a similar degree as wild-type protein, indicating that the length of this glycine tract is not critical for efficient transcriptional repression. We also evaluated a newly identified heterozygous TWIST1 variant (c.115C>G, encoding p.Arg39Gly), located within a putative nuclear localization signal (NLS), that was present in a child with mild SCS and her clinically unaffected father and grandmother. Unlike wild-type protein, this mutant required cotransfected E12 to localize to the nucleus, indicating that the NLS, including amino acid 39, is essential for nuclear localization; inhibition of E2A-dependent transcription of CDKN1A occurred normally. This analysis further dissects the structure-function relationships of TWIST and corroborates with phenotypic observations of disease expressivity.

Original publication




Journal article


Hum Mutat

Publication Date





550 - 556


Amino Acid Motifs, Animals, COS Cells, Cercopithecus aethiops, Child, Preschool, Cyclin-Dependent Kinase Inhibitor p21, DNA Mutational Analysis, Female, Humans, Molecular Sequence Data, Mutation, Nuclear Localization Signals, Nuclear Proteins, Promoter Regions, Genetic, Transcriptional Activation, Twist-Related Protein 1, p300-CBP Transcription Factors