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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

DOI

10.1002/humu.20176

Type

Journal article

Journal

Hum Mutat

Publication Date

06/2005

Volume

25

Pages

550 - 556

Keywords

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