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Mutations in the basic domain and the loop–helix II junction of TWIST abolish DNA binding in Saethre–Chotzen syndrome
Author(s) -
El Ghouzzi Vincent,
Legeai-Mallet Laurence,
Benoist-Lasselin Catherine,
Lajeunie Elisabeth,
Renier Dominique,
Munnich Arnold,
Bonaventure Jacky
Publication year - 2001
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(01)02238-4
Subject(s) - missense mutation , basic helix loop helix , biology , twist , genetics , mutation , twist transcription factor , nonsense mutation , gene , dna binding protein , transcription factor , nuclear protein , geometry , mathematics
Saethre–Chotzen syndrome is an autosomal dominant skull disorder resulting from premature fusion of coronal sutures (craniosynostosis). It is caused by mutations in the TWIST gene encoding a basic Helix–Loop–Helix transcription factor. Here we report on the identification of a novel mutation affecting a highly conserved residue of the basic domain. Unlike nonsense and missense mutations lying within helices, this mutation does not affect protein stability or heterodimerisation of TWIST with its partner E12. However, it does abolish TWIST binding capacity to a target E‐box as efficiently as two missense mutations in the loop–helix II junction. By contrast, elongation of the loop through a 7 amino acid insertion appears not to hamper binding to the DNA target. We conclude that loss of TWIST protein function in Saethre–Chotzen patients can occur at three different levels, namely protein stability, dimerisation, and DNA binding and that the loop–helix II junction is essential for effective protein–DNA interaction.