TWIST1 and the Saethre–Chotzen Syndrome

Abstract

Abstract Saethre–Chotzen syndrome (OMIM 101400) is one of the most common craniosynostosis syndromes with autosomal dominant inheritance. The most frequently observed features are the premature fusion of coronal sutures resulting in brachycephaly, low frontal hairline, facial asymmetry, ptosis of the eyelids, prominent helical crus, syndactyly, and broad great toes. This syndrome is caused by mutations in the TWIST1 gene that map to chromosome 7p21 and codes for a basic helix–loop–helix (bHLH) transcription factor (OMIM 601622). At least 97 different mutations, including missense and nonsense changes, small insertions and deletions leading to frameshifts, and duplications, have been identified in patients. These mutations lead to loss of the ability of the HLH domain to dimerize or the basic region to bind to its target(s). Loss of the entire gene and potential regulatory elements as far away as a few megabases from the coding region of TWIST1 can also cause the Saethre–Chotzen syndrome phenotype. Chromosomal rearrangements or deletions involving the 7p21-p22 region are more often found than intragenic mutations in patients with mental retardation. Twist1 heterozygous null mice with craniofacial and limb abnormalities that resemble Saethre–Chotzen syndrome further support loss of function as the mechanism by which mutant TWIST1 leads to the phenotype. Previously, patients with Saethre–Chotzen-like features and duplication of the great toe or radial ray hypoplasia were diagnosed as having separate clinical entities, Robinow–Sorauf or Baller–Gerold syndrome, respectively. These patients also have TWIST1 mutations and are now thought to represent phenotypic variability in the Saethre– Chotzen syndrome. Normally, TWIST1 has an inhibitory role in osteoblast and myocyte differentiation which is mediated through targets such as histone acetyltransferase, cell cycle regulators, and cytokines. Thus, loss of this inhibitory effect in Saethre–Chotzen syndrome leads to increased osteoblast proliferation, decreased differentiation, and apoptosis resulting in synostosis at cranial sutures and abnormalities of limb development. Potential modifiers of the effect of TWIST1 mutations include interacting proteins and components of several developmental pathways including the bHLH proteins TWIST2, SNAI1, SNAI2, ID1, and HAND2; transcription factors RUNX2, MSX2, and ALX4; and fibroblast growth factor receptors (FGFRs). Selection of dimer partners and posttranslational modification are additional mechanisms by which the severity of craniosynostosis and limb anomalies are modulated in Saethre–Chotzen syndrome.