title: Isolated sagittal and coronal craniosynostosis associated with TWIST box mutations.
abstract: Craniosynostosis, the premature fusion of one or more cranial sutures, affects 1 in 2,500 live births. Isolated single-suture fusion is most prevalent, with sagittal synostosis occurring in 1/5,000 live births. The etiology of isolated (nonsyndromic) single-suture craniosynostosis is largely unknown. In syndromic craniosynostosis, there is a highly nonrandom pattern of causative autosomal dominant mutations involving TWIST1 and fibroblast growth factor receptors (FGFRs). Prior to our study, there were no published TWIST1 mutations in the anti-osteogenic C-terminus, recently coined the TWIST Box, which binds and inhibits RUNX2 transactivation. RUNX2 is the principal master switch for osteogenesis. We performed mutational analysis on 164 infants with isolated, single-suture craniosynostosis for mutations in TWIST1, the IgIIIa exon of FGFR1, the IgIIIa and IgIIIc exons of FGFR2, and the Pro250Arg site of FGFR3. We identified two patients with novel TWIST Box mutations: one with isolated sagittal synostosis and one with isolated coronal synostosis. Kress et al. [2006] reported a TWIST Box "nondisease-causing polymorphism" in a patient with isolated sagittal synostosis. However, compelling evidence suggests that their and our sequence alterations are pathogenic: (1) a mouse with a mutation of the same residue as our sagittal synostosis patient developed sagittal synostosis, (2) mutation of the same residue precluded TWIST1 interaction with RUNX2, (3) each mutation involved nonconservative amino acid substitutions in highly conserved residues across species, and (4) control chromosomes lacked TWIST Box sequence alterations. We suggest that genetic testing of patients with isolated sagittal or coronal synostosis should include TWIST1 mutational analysis.
authors.affiliation: Division of Craniofacial Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195-6320, USA. mseto@u.washington.edu
authors.forename: Marianne L
authors.initials: ML
authors.lastname: Seto
authors.forename: Anne V
authors.initials: AV
authors.lastname: Hing
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Chang
authors.forename: Ming
authors.initials: M
authors.lastname: Hu
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Kapp-Simon
authors.forename: Pravin K
authors.initials: PK
authors.lastname: Patel
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Burton
authors.forename: Alex A
authors.initials: AA
authors.lastname: Kane
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Smyth
authors.forename: Richard
authors.initials: R
authors.lastname: Hopper
authors.forename: Richard G
authors.initials: RG
authors.lastname: Ellenbogen
authors.forename: Kevin
authors.initials: K
authors.lastname: Stevenson
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Speltz
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cunningham
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D003398:Craniosynostoses / Q000235:genetics*; D006801:Humans; D007223:Infant; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D051879:Twist-Related Protein 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D009687:Nuclear Proteins; C493709:RUNX2 protein, human; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1